50 results on '"Di Fiore, R"'
Search Results
2. 281. Gynocare cost action ca18117 “european network for gynaecological rare cancer research: From concept to cure”
- Author
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Calleja Agius, J., primary, Di Fiore, R., additional, Suleiman, S., additional, and Savona-Ventura, C., additional
- Published
- 2022
- Full Text
- View/download PDF
3. GONADOBLASTOMA: A BRIEF REPORT
- Author
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Di Fiore, R., primary, Agius, A., additional, Camenzuli, C., additional, Suleiman, S., additional, Calleja Agius, J., additional, and Savona Ventura, C., additional
- Published
- 2022
- Full Text
- View/download PDF
4. Different modulatory effect of the synthetic cannabinoid WIN55,212-2 on tumor cell migration
- Author
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Notaro, A., Fiasconaro, G., Sabella, S., Di Fiore, R., D'Anneo, A., Lauricella, M., Calvaruso, G., Giuliano, M., Notaro, A, Fiasconaro, G, Sabella, S, Di Fiore, R, D'Anneo, A, Lauricella, M, Calvaruso, G, and Giuliano, M.
- Subjects
Breast cancer ,EMT in cancer cells ,osteosarcoma ,cannabinoids ,miRNAs ,cannabinoid ,miRNA - Abstract
MicroRNAs are small non-coding regulatory molecules exerting pleiotropic action in different biological processes such as proliferation, differentiation, apoptosis, migration and metastasis. Deregulation of miRNA expression has been observed in various cancers, and accumulating data suggest that miRNAs can display an oncogenic, antioncogenic or an ambiguous behavior in relationship to tumor environment. In a previous research we showed that the synthetic cannabinoid WIN55,212-2 is able to reduce the migratory activity of osteosarcoma MG63 cells analyzed by means of wound healing assay. So we undertook a study to evaluate the biochemical mechanism through which WIN plays this action. To this purpose we evaluated the levels of miR-29b1, a member of miR-29 family which has been shown to impact critical steps in the migratory and metastatic cascade, such as EMT, apoptosis and angiogenesis. RT-PCR experiments showed that in MG63 cells 5 M WIN increased the level of miR-29b1 of about 700-fold. This effect was accompanied by the reduction in its putative targets MMP-2, PDGF-B and N-MYC, thus indicating that the miRNA is functionally active. Moreover, cells stably overexpressing miR-29b1 did not close the wound after 48 h, mimicking the effect of WIN in untransfected control cells. Notably, ERα(+) MCF-7 and triple negative MDA-MB-231 cells, two different breast cancer models, treated with the cannabinoid migrated into the scratched area significantly faster than the respective control cells. In these cells WIN also increased the level of miR-29b1 targets. Therefore, differently from osteosarcoma cells, these preliminary observations seem to indicate that WIN promotes migration ability in breast cancer cells. The reasons for this diverse behaviour could rely on miR-29b1, whose expression can change in different cell types or show temporal differences dictated by cell physiology and tumor microenvironment impact. Studies are in progress to shed light on the molecular mechanisms underlying this different response.
- Published
- 2015
5. Non-canonical roles of caspase-8 in MDA-MB-231 breast cancer cell line
- Author
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De Blasio, A., Di Fiore, R., Morreale, M., Montalbano, M., Carlisi, D., Vento, R., De Blasio, A, Di Fiore, R, Morreale, M, Montalbano, M, Carlisi, D, and Vento, R
- Subjects
caspase-8, breast cancer, metastatic capacity - Abstract
Caspase-8 (casp-8) is well known as an initiator caspase involved in cell death signalling, although its activity in many cancer cell types seems to work under non-apoptotic conditions. Moreover, in several types of cancer, casp-8 is only rarely mutated and often its expression is very elevated. Since cancer cell growth also depends on evasion of apoptosis, the upregulation of casp-8 in tumours may suggest one or more non-apoptotic roles (1). Here we report our recent studies carried out in MDA-MB-231 cells, derived from clinically aggressive forms of Triple-Negative Breast Cancer, where we have assessed the non-canonical roles of casp-8. Firstly, we evaluated casp-8 mRNA and protein levels in MDA-MB-231 cells, demonstrating that they were upregulated with respect to HMEC (normal Human Mammalian Epithelial Cells). Thereafter, to assess the role of casp-8, we silenced it by small interfering-RNA. Interestingly casp-8-knockdown, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypophosphorylated/active form of pRb levels. No effects were evidenced on cell viability. To assess the metastatic capacity of MDA-MB-231 cells, the gene expression profiles of the relative markers after casp-8 knockdown were also measured. Surprisingly the expression of a number of genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2 potently increased accompanied by migratory and metastatic capacities of cells, as shown by wound healing and matrigel assays. We suggest that among these genes, KLF4, a transcriptional factor with a dual role (activator and repressor), and responsible for p21 and p27 induction, could play critical roles (2). Casp-8 through KLF4 down-regulation, could manage the expression of critical proliferative and migratory/invasive genes. We suggest that these unusual roles played by casp-8 in MDA-MB-231 cells, should be better explored, in order to identify it as a molecular therapeutic target. References 1. Stupack DG. Caspase-8 as a Therapeutic Target in Cancer. Cancer Lett 332:133–140, 2013. 2. Tiwari N et al. Klf4 Is a Transcriptional Regulator of Genes Critical for EMT, Including Jnk1 (Mapk8). PLoS One 8, 2013.
- Published
- 2015
6. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead
- Author
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Goodson, W.H., III Lowe, L. Carpenter, D.O. Gilbertson, M. Ali, A.M. de Cerain Salsamendi, A.L. Lasfar, A. Carnero, A. Azqueta, A. Amedei, A. Charles, A.K. Collins, A.R. Ward, A. Salzberg, A.C. Colacci, A. Olsen, A.-K. Berg, A. Barclay, B.J. Zhou, B.P. Blanco-Aparicio, C. Baglole, C.J. Dong, C. Mondello, C. Hsu, C.-W. Naus, C.C. Yedjou, C. Curran, C.S. Laird, D.W. Koch, D.C. Carlin, D.J. Felsher, D.W. Roy, D. Brown, D.G. Ratovitski, E. Ryan, E.P. Corsini, E. Rojas, E. Moon, E.-Y. Laconi, E. Marongiu, F. Al-Mulla, F. Chiaradonna, F. Darroudi, F. Martin, F.L. Van Schooten, F.J. Goldberg, G.S. Wagemaker, G. Nangami, G. Calaf, G.M. Williams, G. Wolf, G.T. Koppen, G. Brunborg, G. Kim Lyerly, H. Krishnan, H. Hamid, H.A. Yasaei, H. Sone, H. Kondoh, H. Salem, H.K. Hsu, H.-Y. Park, H.H. Koturbash, I. Miousse, I.R. Ivana Scovassi, A. Klaunig, J.E. Vondráček, J. Raju, J. Roman, J. Wise, J.P., Sr. Whitfield, J.R. Woodrick, J. Christopher, J.A. Ochieng, J. Martinez-Leal, J.F. Weisz, J. Kravchenko, J. Sun, J. Prudhomme, K.R. Narayanan, K.B. Cohen-Solal, K.A. Moorwood, K. Gonzalez, L. Soucek, L. Jian, L. D'Abronzo, L.S. Lin, L.-T. Li, L. Gulliver, L. McCawley, L.J. Memeo, L. Vermeulen, L. Leyns, L. Zhang, L. Valverde, M. Khatami, M. Romano, M.F. Chapellier, M. Williams, M.A. Wade, M. Manjili, M.H. Lleonart, M. Xia, M. Gonzalez, M.J. Karamouzis, M.V. Kirsch-Volders, M. Vaccari, M. Kuemmerle, N.B. Singh, N. Cruickshanks, N. Kleinstreuer, N. Van Larebeke, N. Ahmed, N. Ogunkua, O. Krishnakumar, P.K. Vadgama, P. Marignani, P.A. Ghosh, P.M. Ostrosky-Wegman, P. Thompson, P. Dent, P. Heneberg, P. Darbre, P. Leung, P.S. Nangia-Makker, P. Cheng, Q.S. Brooks Robey, R. Al-Temaimi, R. Roy, R. Andrade-Vieira, R. Sinha, R.K. Mehta, R. Vento, R. Di Fiore, R. Ponce-Cusi, R. Dornetshuber-Fleiss, R. Nahta, R. Castellino, R.C. Palorini, R. Hamid, R.A. Langie, S.A.S. Eltom, S. Brooks, S.A. Ryeom, S. Wise, S.S. Bay, S.N. Harris, S.A. Papagerakis, S. Romano, S. Pavanello, S. Eriksson, S. Forte, S. Casey, S.C. Luanpitpong, S. Lee, T.-J. Otsuki, T. Chen, T. Massfelder, T. Sanderson, T. Guarnieri, T. Hultman, T. Dormoy, V. Odero-Marah, V. Sabbisetti, V. Maguer-Satta, V. Kimryn Rathmell, W. Engström, W. Decker, W.K. Bisson, W.H. Rojanasakul, Y. Luqmani, Y. Chen, Z. Hu, Z.
- Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. © The Author 2015.
- Published
- 2015
7. Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis
- Author
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Carlisi, D, primary, Buttitta, G, additional, Di Fiore, R, additional, Scerri, C, additional, Drago-Ferrante, R, additional, Vento, R, additional, and Tesoriere, G, additional
- Published
- 2016
- Full Text
- View/download PDF
8. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
- Author
-
Goodson, WH, Lowe, L, Carpenter, DO, Gilbertson, M, Ali, AM, de Cerain Salsamendi, AL, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, AK, Collins, AR, Ward, A, Salzberg, AC, Colacci, A, Olsen, A-K, Berg, A, Barclay, BJ, Zhou, BP, Blanco-Aparicio, C, Baglole, CJ, Dong, C, Mondello, C, Hsu, C-W, Naus, CC, Yedjou, C, Curran, CS, Laird, DW, Koch, DC, Carlin, DJ, Felsher, DW, Roy, D, Brown, DG, Ratovitski, E, Ryan, EP, Corsini, E, Rojas, E, Moon, E-Y, Laconi, E, Marongiu, F, Al-Mulla, F, Chiaradonna, F, Darroudi, F, Martin, FL, Van Schooten, FJ, Goldberg, GS, Wagemaker, G, Nangami, G, Calaf, GM, Williams, G, Wolf, GT, Koppen, G, Brunborg, G, Lyerly, HK, Krishnan, H, Ab Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, HK, Hsu, H-Y, Park, HH, Koturbash, I, Miousse, IR, Scovassi, AI, Klaunig, JE, Vondracek, J, Raju, J, Roman, J, Wise, JP, Whitfield, JR, Woodrick, J, Christopher, JA, Ochieng, J, Fernando Martinez-Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, KR, Narayanan, KB, Cohen-Solal, KA, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, LS, Lin, L-T, Li, L, Gulliver, L, McCawley, LJ, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, MF, Chapellier, M, Williams, MA, Wade, M, Manjili, MH, Lleonart, M, Xia, M, Gonzalez, MJ, Karamouzis, MV, Kirsch-Volders, M, Vaccari, M, Kuemmerle, NB, Singh, N, Cruickshanks, N, Kleinstreuer, N, van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, PK, Vadgama, P, Marignani, PA, Ghosh, PM, Ostrosky-Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, PS, Nangia-Makker, P, Cheng, QS, Robey, RB, Al-Temaimi, R, Roy, R, Andrade-Vieira, R, Sinha, RK, Mehta, R, Vento, R, Di Fiore, R, Ponce-Cusi, R, Dornetshuber-Fleiss, R, Nahta, R, Castellino, RC, Palorini, R, Abd Hamid, R, Langie, SAS, Eltom, S, Brooks, SA, Ryeom, S, Wise, SS, Bay, SN, Harris, SA, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, SC, Luanpitpong, S, Lee, T-J, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero-Marah, V, Sabbisetti, V, Maguer-Satta, V, Rathmell, WK, Engstrom, W, Decker, WK, Bisson, WH, Rojanasakul, Y, Luqmani, Y, Chen, Z, Hu, Z, Goodson, WH, Lowe, L, Carpenter, DO, Gilbertson, M, Ali, AM, de Cerain Salsamendi, AL, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, AK, Collins, AR, Ward, A, Salzberg, AC, Colacci, A, Olsen, A-K, Berg, A, Barclay, BJ, Zhou, BP, Blanco-Aparicio, C, Baglole, CJ, Dong, C, Mondello, C, Hsu, C-W, Naus, CC, Yedjou, C, Curran, CS, Laird, DW, Koch, DC, Carlin, DJ, Felsher, DW, Roy, D, Brown, DG, Ratovitski, E, Ryan, EP, Corsini, E, Rojas, E, Moon, E-Y, Laconi, E, Marongiu, F, Al-Mulla, F, Chiaradonna, F, Darroudi, F, Martin, FL, Van Schooten, FJ, Goldberg, GS, Wagemaker, G, Nangami, G, Calaf, GM, Williams, G, Wolf, GT, Koppen, G, Brunborg, G, Lyerly, HK, Krishnan, H, Ab Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, HK, Hsu, H-Y, Park, HH, Koturbash, I, Miousse, IR, Scovassi, AI, Klaunig, JE, Vondracek, J, Raju, J, Roman, J, Wise, JP, Whitfield, JR, Woodrick, J, Christopher, JA, Ochieng, J, Fernando Martinez-Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, KR, Narayanan, KB, Cohen-Solal, KA, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, LS, Lin, L-T, Li, L, Gulliver, L, McCawley, LJ, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, MF, Chapellier, M, Williams, MA, Wade, M, Manjili, MH, Lleonart, M, Xia, M, Gonzalez, MJ, Karamouzis, MV, Kirsch-Volders, M, Vaccari, M, Kuemmerle, NB, Singh, N, Cruickshanks, N, Kleinstreuer, N, van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, PK, Vadgama, P, Marignani, PA, Ghosh, PM, Ostrosky-Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, PS, Nangia-Makker, P, Cheng, QS, Robey, RB, Al-Temaimi, R, Roy, R, Andrade-Vieira, R, Sinha, RK, Mehta, R, Vento, R, Di Fiore, R, Ponce-Cusi, R, Dornetshuber-Fleiss, R, Nahta, R, Castellino, RC, Palorini, R, Abd Hamid, R, Langie, SAS, Eltom, S, Brooks, SA, Ryeom, S, Wise, SS, Bay, SN, Harris, SA, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, SC, Luanpitpong, S, Lee, T-J, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero-Marah, V, Sabbisetti, V, Maguer-Satta, V, Rathmell, WK, Engstrom, W, Decker, WK, Bisson, WH, Rojanasakul, Y, Luqmani, Y, Chen, Z, and Hu, Z
- Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
- Published
- 2015
9. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead
- Author
-
Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, Hu, Z, CHIARADONNA, FERDINANDO, PALORINI, ROBERTA, Hu, Z., Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, Hu, Z, CHIARADONNA, FERDINANDO, PALORINI, ROBERTA, and Hu, Z.
- Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
- Published
- 2015
10. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
- Author
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Dustin G. Brown, Tove Hultman, Judith Weisz, H. Kim Lyerly, Paola A. Marignani, Ann-Karin Olsen, Rabindra Roy, Kim Moorwood, Masoud H. Manjili, Monica Vaccari, Jesse Roman, Hasiah Ab Hamid, Kalan R. Prudhomme, Periyadan K. Krishnakumar, Chenfang Dong, Tiziana Guarnieri, Leandro S. D'Abronzo, Gloria M. Calaf, Amelia K Charles, Emanuela Corsini, Yunus A. Luqmani, Graeme Williams, Louis Vermeulen, Pankaj Vadgama, Sarah N Bay, Véronique Maguer-Satta, Sabine A. S. Langie, Christian C. Naus, Le Jian, Gladys N. Nangami, Lorenzo Memeo, Stephanie C. Casey, Thomas Sanderson, Takemi Otsuki, Nichola Cruickshanks, William H. Bisson, Sudjit Luanpitpong, Jonathan Whitfield, Ahmed Lasfar, Yon Rojanasakul, A. Ivana Scovassi, Shelley A. Harris, Ferdinando Chiaradonna, Richard Ponce-Cusi, Gregory T. Wolf, Valérian Dormoy, Roslida Abd Hamid, Hyun Ho Park, Matilde E. Lleonart, William K. Decker, Maria Romano, Leroy Lowe, Fabio Marongiu, Jan Vondráček, Chiara Mondello, Luc Leyns, Josiah Ochieng, Pratima Nangia-Makker, Edward A. Ratovitski, Zhiwei Hu, Jayadev Raju, Hemad Yasaei, Rafaela Andrade-Vieira, Jordan Woodrick, Hideko Sone, Harini Krishnan, W. Kimryn Rathmell, Andrew Collins, Luoping Zhang, Barry J. Barclay, Amaya Azqueta, Laura Soucek, Marc A. Williams, David O. Carpenter, Roberta Palorini, Rita Nahta, Juan Fernando Martinez-Leal, Firouz Darroudi, Rita Dornetshuber-Fleiss, James E. Klaunig, Elizabeth P. Ryan, Qiang Shawn Cheng, Arthur Berg, Andrew Ward, Gudrun Koppen, Tao Chen, Petr Heneberg, Michael Gilbertson, Amedeo Amedei, Sakina E. Eltom, Ezio Laconi, Joseph Christopher, Hiroshi Kondoh, Neetu Singh, Danielle J Carlin, Marion Chapellier, Michalis V. Karamouzis, Rekha Mehta, Tae-Jin Lee, Annamaria Colacci, Venkata S. Sabbisetti, Mark Wade, Micheline Kirsch-Volders, Patricia Ostrosky-Wegman, Isabelle R. Miousse, Patricia A. Thompson, Philippa D. Darbre, Frederik J. van Schooten, Sofia Pavanello, Igor Koturbash, Binhua P. Zhou, Ranjeet Kumar Sinha, Anna C. Salzberg, Mahara Valverde, Fahd Al-Mulla, Julia Kravchenko, Nicole Kleinstreuer, Carolyn J. Baglole, Menghang Xia, Samira A. Brooks, Amancio Carnero, Gunnar Brunborg, Sandra S. Wise, Daniel C. Koch, John Pierce Wise, Rabeah Al-Temaimi, Laetitia Gonzalez, Lisa J. McCawley, R. Brooks Robey, Gary S. Goldberg, Thierry Massfelder, Linda S M Gulliver, Olugbemiga Ogunkua, Emilio Rojas, Eun-Yi Moon, Lin Li, Silvana Papagerakis, Nik van Larebeke, Adela Lopez de Cerain Salsamendi, Staffan Eriksson, Simona Romano, Dean W. Felsher, Paramita M. Ghosh, Karine A. Cohen-Solal, Paul Dent, Jun Sun, Carmen Blanco-Aparicio, Riccardo Di Fiore, Chia-Wen Hsu, Mahin Khatami, Kannan Badri Narayanan, Francis Martin, Colleen S. Curran, Dale W. Laird, William H. Goodson, Abdul Manaf Ali, Valerie Odero-Marah, Michael J. Gonzalez, Renza Vento, Liang Tzung Lin, Clement G. Yedjou, Hosni Salem, Hsue-Yin Hsu, Zhenbang Chen, Nuzhat Ahmed, Gerard Wagemaker, Sandra Ryeom, Stefano Forte, Debasish Roy, Nancy B. Kuemmerle, Robert C. Castellino, Po Sing Leung, Wilhelm Engström, National Institute of Environmental Health Sciences (US), Research Council of Norway, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Cáncer (España), European Commission, Junta de Andalucía, Ministerio de Educación y Ciencia (España), Ministero dell'Istruzione, dell'Università e della Ricerca, University of Oslo, Regione Emilia Romagna, National Institutes of Health (US), Consejo Nacional de Ciencia y Tecnología (México), Associazione Italiana per la Ricerca sul Cancro, National Research Foundation of Korea, Ministry of Education, Science and Technology (South Korea), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), Ministry of Education, Culture, Sports, Science and Technology (Japan), Japan Science and Technology Agency, Ministry of Science and Technology (Taiwan), Arkansas Biosciences Institute, Czech Science Foundation, Fundación Fero, Swim Across America, American Cancer Society, Research Foundation - Flanders, Austrian Science Fund, Institut National de la Santé et de la Recherche Médicale (France), Natural Sciences and Engineering Research Council of Canada, Farmacologie en Toxicologie, RS: NUTRIM - R4 - Gene-environment interaction, Goodson, William H, Lowe, Leroy, Carpenter, David O, Gilbertson, Michael, Manaf Ali, Abdul, Lopez de Cerain Salsamendi, Adela, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K, Collins, Andrew R, Ward, Andrew, Salzberg, Anna C, Colacci, Annamaria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J, Zhou, Binhua P, Blanco Aparicio, Carmen, Baglole, Carolyn J, Dong, Chenfang, Mondello, Chiara, Hsu, Chia Wen, Naus, Christian C, Yedjou, Clement, Curran, Colleen S, Laird, Dale W, Koch, Daniel C, Carlin, Danielle J, Felsher, Dean W, Roy, Debasish, Brown, Dustin G, Ratovitski, Edward, Ryan, Elizabeth P, Corsini, Emanuela, Rojas, Emilio, Moon, Eun Yi, Laconi, Ezio, Marongiu, Fabio, Al Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L, Van Schooten, Frederik J, Goldberg, Gary S, Wagemaker, Gerard, Nangami, Gladys N, Calaf, Gloria M, Williams, Graeme, Wolf, Gregory T, Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K, Hsu, Hsue Yin, Park, Hyun Ho, Koturbash, Igor, Miousse, Isabelle R, Scovassi, A. Ivana, Klaunig, James E, Vondráček, Jan, Raju, Jayadev, Roman, Jesse, Wise, John Pierce, Whitfield, Jonathan R, Woodrick, Jordan, Christopher, Joseph A, Ochieng, Josiah, Martinez Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Sun, Jun, Prudhomme, Kalan R, Narayanan, Kannan Badri, Cohen Solal, Karine A, Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D'Abronzo, Leandro S, Lin, Liang Tzung, Li, Lin, Gulliver, Linda, Mccawley, Lisa J, Memeo, Lorenzo, Vermeulen, Loui, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, MARIA FIAMMETTA, Chapellier, Marion, Williams, Marc A, Wade, Mark, Manjili, Masoud H, Lleonart, Matilde E, Xia, Menghang, Gonzalez, Michael J, Karamouzis, Michalis V, Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B, Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, van Larebeke, Nik, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K, Vadgama, Pankaj, Marignani, Paola A, Ghosh, Paramita M, Ostrosky Wegman, Patricia, Thompson, Patricia A, Dent, Paul, Heneberg, Petr, Darbre, Philippa, Sing Leung, Po, Nangia Makker, Pratima, Cheng, Qiang Shawn, Robey, R. Brook, Al Temaimi, Rabeah, Roy, Rabindra, Andrade Vieira, Rafaela, Sinha, Ranjeet K, Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce Cusi, Richard, Dornetshuber Fleiss, Rita, Nahta, Rita, Castellino, Robert C, Palorini, Roberta, Abd Hamid, Roslida, Langie, Sabine A. S, Eltom, Sakina E, Brooks, Samira A, Ryeom, Sandra, Wise, Sandra S, Bay, Sarah N, Harris, Shelley A, Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Eriksson, Staffan, Forte, Stefano, Casey, Stephanie C, Luanpitpong, Sudjit, Lee, Tae Jin, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thoma, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Marah, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K, Bisson, William H, Rojanasakul, Yon, Luqmani, Yunu, Chen, Zhenbang, Hu, Zhiwei, Goodson, W., Lowe, L., Carpenter, D., Gilbertson, M., Ali, A., de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A., Collins, A., Ward, A., Salzberg, A., Colacci, A., Olsen, A., Berg, A., Barclay, B., Zhou, B., Blanco-Aparicio, C., Baglole, C., Dong, C., Mondello, C., Hsu, C., Naus, C., Yedjou, C., Curran, C., Laird, D., Koch, D., Carlin, D., Felsher, D., Roy, D., Brown, D., Ratovitski, E., Ryan, E., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F., Van Schooten, F., Goldberg, G., Wagemaker, G., Nangami, G., Calaf, G., Williams, G., Wolf, G., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H., Hsu, H., Park, H., Koturbash, I., Miousse, I., Ivana Scovassi, A., Klaunig, J., Vondráček, J., Raju, J., Roman, J., Wise, J., Whitfield, J., Woodrick, J., Christopher, J., Ochieng, J., Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K., Narayanan, K., Cohen-Solal, K., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L., Lin, L., Li, L., Gulliver, L., Mccawley, L., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M., Chapellier, M., Williams, M., Wade, M., Manjili, M., Lleonart, M., Xia, M., Gonzalez, M., Karamouzis, M., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P., Vadgama, P., Marignani, P., Ghosh, P., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Leung, P., Nangia-Makker, P., Cheng, Q., Brooks Robey, R., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R., Palorini, R., Hamid, R., Langie, S., Eltom, S., Brooks, S., Ryeom, S., Wise, S., Bay, S., Harris, S., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Kimryn Rathmell, W., Engström, W., Decker, W., Bisson, W., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z., Goodson, W.H., Carpenter, D.O., Ali, A.M., de Cerain Salsamendi, A.L., Charles, A.K., Collins, A.R., Salzberg, A.C., Olsen, A.-K., Barclay, B.J., Zhou, B.P., Baglole, C.J., Hsu, C.-W., Naus, C.C., Curran, C.S., Laird, D.W., Koch, D.C., Carlin, D.J., Felsher, D.W., Brown, D.G., Ryan, E.P., Moon, E.-Y., Martin, F.L., Van Schooten, F.J., Goldberg, G.S., Calaf, G.M., Wolf, G.T., Hamid, H.A., Salem, H.K., Hsu, H.-Y., Park, H.H., Miousse, I.R., Klaunig, J.E., Vondracek, J., Wise, J.P., Whitfield, J.R., Christopher, J.A., Martinez-Leal, J.F., Prudhomme, K.R., Narayanan, K.B., Cohen-Solal, K.A., D'Abronzo, L.S., Lin, L.-T., Mccawley, L.J., Romano, M.F., Williams, M.A., Manjili, M.H., Gonzalez, M.J., Karamouzis, M.V., Kuemmerle, N.B., Krishnakumar, P.K., Marignani, P.A., Ghosh, P.M., Leung, P.S., Cheng, Q.S., Sinha, R.K., Castellino, R.C., Hamid, R.A., Langie, S.A.S., Brooks, S.A., Wise, S.S., Bay, S.N., Harris, S.A., Casey, S.C., Lee, T.-J., Engstrom, W., Decker, W.K., Bisson, W.H., sans affiliation, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276), Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript, William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation, Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia, Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey, Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012), Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support, Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012), Andrew R.Collins was supported by the University of Oslo, Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy, Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S), Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370), Christian C.Naus holds a Canada Research Chair, Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581), Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151, Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964), Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS), Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea, Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06), Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro, IG 15364), Francis L.Martin acknowledges funding from Rosemere Cancer Foundation, he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years, Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation, Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA), Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium, Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697), Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST, Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002), Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449), Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S), Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health, Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain, Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology, Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback, Jun Sun is supported by a Swim Across America Cancer Research Award, Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE), Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07), Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain, Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19), Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand, Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164), Mahara Valverde would like to thank CONACyT support 153781, Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India, Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C), P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association, Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774), Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y, Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021, Qiang Cheng was supported in part by grant NSF IIS-1218712, R. Brooks Robey is supported by the United States Department of Veterans Affairs, Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447), Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007, Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013), Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung, Roberta Palorini is supported by a SysBioNet fellowship, Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165, Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013, Sakina Eltom is supported by NIH grant SC1CA153326, Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship, Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation, Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg, Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR, MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC, 313313) and the California Breast Cancer Research Program (CBCRP, 17UB-8703), Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy, W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society, William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas, William H.Bisson was supported with funding from the NIH P30 ES000210, Yon Rojanasakul was supported with NIH grant R01-ES022968, Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593), Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program., Sans affiliation, Courcelles, Michel, Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, and Hu, Z
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Cancer Research ,Carcinogenesis ,[SDV]Life Sciences [q-bio] ,METHOXYCHLOR-INDUCED ALTERATIONS ,Review ,Pharmacology ,MESH: Carcinogens, Environmental ,Carcinogenic synergies ,Chemical mixtures ,Neoplasms ,MESH: Animals ,MESH: Neoplasms ,Carcinogenesi ,Risk assessment ,Cancer ,ACTIVATED PROTEIN-KINASES ,Medicine (all) ,Low dose ,1. No poverty ,Cumulative effects ,BREAST-CANCER CELLS ,General Medicine ,Environmental exposure ,MESH: Carcinogenesis ,BIO/10 - BIOCHIMICA ,EPITHELIAL-MESENCHYMAL TRANSITION ,3. Good health ,[SDV] Life Sciences [q-bio] ,Environmental Carcinogenesis ,ESTROGEN-RECEPTOR-ALPHA ,Human ,MESH: Environmental Exposure ,ENDOCRINE-DISRUPTING CHEMICALS ,TARGETING TISSUE FACTOR ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Prototypical chemical disruptors ,Exposure ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Environmental health ,medicine ,[SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health ,Carcinogen ,Environmental carcinogenesis ,[SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health ,MESH: Humans ,Animal ,POLYBROMINATED DIPHENYL ETHERS ,Environmental Exposure ,medicine.disease ,MESH: Hazardous Substances ,Carcinogens, Environmental ,MIGRATION INHIBITORY FACTOR ,VASCULAR ENDOTHELIAL-CELLS ,Hazardous Substance ,Neoplasm - Abstract
Goodson, William H. et al., © The Author 2015. Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology., We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276); Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript; William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation; Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia; Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey; Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012); Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support; Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012); Andrew R.Collins was supported by the University of Oslo; Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy; Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S); Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370); Christian C.Naus holds a Canada Research Chair; Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581); Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151; Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964); Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS); Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea; Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06); Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro; IG 15364); Francis L.Martin acknowledges funding from Rosemere Cancer Foundation; he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years; Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation; Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA); Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium; Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697); Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST; Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002); Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449); Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000; Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S); Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health; Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain; Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology; Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback; Jun Sun is supported by a Swim Across America Cancer Research Award; Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE); Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07); Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain; Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19); Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand; Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164); Mahara Valverde would like to thank CONACyT support 153781; Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India; Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C); P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia; Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association; Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774); Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y; Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021; Qiang Cheng was supported in part by grant NSF IIS-1218712; R. Brooks Robey is supported by the United States Department of Veterans Affairs; Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447); Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007; Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013); Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung; Roberta Palorini is supported by a SysBioNet fellowship; Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165; Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013; Sakina Eltom is supported by NIH grant SC1CA153326; Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship; Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation; Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg; Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR; MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC; 313313) and the California Breast Cancer Research Program (CBCRP; 17UB-8703); Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy; W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society; William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas; William H.Bisson was supported with funding from the NIH P30 ES000210; Yon Rojanasakul was supported with NIH grant R01-ES022968; Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593); Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program.
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- 2015
11. A loop involving NRF2, miR‐29b‐1‐5p and AKT, regulates cell fate of MDA‐MB‐231 triple‐negative breast cancer cells
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Giovanni Tesoriere, Shawn Baldacchino, Anna De Blasio, Renza Vento, Riccardo Di Fiore, Giovanni Pratelli, Christian Scerri, Godfrey Grech, Rosa Drago-Ferrante, Christian Saliba, and De Blasio A, Di Fiore R, Pratelli G, Drago-Ferrante R, Saliba C, Baldacchino S, Grech G, Scerri C, Vento R, Tesoriere G.
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DNA (Cytosine-5-)-Methyltransferase 1 ,0301 basic medicine ,NF-E2-Related Factor 2 ,Physiology ,Clinical Biochemistry ,Triple Negative Breast Neoplasms ,AKT, DNMTs, miR‐29b‐1‐5p, NRF2, parthenolide, tumor suppressor genes ,Cell fate determination ,environment and public health ,DNA Methyltransferase 3A ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Settore BIO/10 - Biochimica ,Cell Line, Tumor ,Cyclin D2 ,Humans ,Parthenolide ,DNA (Cytosine-5-)-Methyltransferases ,Protein kinase B ,Triple-negative breast cancer ,Cell Proliferation ,chemistry.chemical_classification ,Reactive oxygen species ,Cell growth ,Tumor Suppressor Proteins ,Cell Biology ,DNA Methylation ,respiratory system ,Cell biology ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,DNMT1 ,Female ,Reactive Oxygen Species ,Proto-Oncogene Proteins c-akt ,Sesquiterpenes ,Signal Transduction - Abstract
The present study shows that nuclear factor erythroid 2-related factor 2 (NRF2) and miR-29b-1-5p are two opposite forces which could regulate the fate of MDA-MB-231 cells, the most studied triple-negative breast cancer (TNBC) cell line. We show that NRF2 activation stimulates cell growth and markedly reduces reactive oxygen species (ROS) generation, whereas miR-29b-1-5p overexpression increases ROS generation and reduces cell proliferation. Moreover, NRF2 downregulates miR-29b-1-5p expression, whereas miR-29b-1-5p overexpression decreases p-AKT and p-NRF2. Furthermore, miR-29b-1-5p overexpression induces both inhibition of DNA N-methyltransferases (DNMT1, DNMT3A, and DNMT3B) expression and re-expression of HIN1, RASSF1A and CCND2. Conversely, NRF2 activation induces opposite effects. We also show that parthenolide, a naturally occurring small molecule, induces the expression of miR-29b-1-5p which could suppress NRF2 activation via AKT inhibition. Overall, this study uncovers a novel NRF2/miR-29b-1-5p/AKT regulatory loop that can regulate the fate (life/death) of MDA-MB-231 cells and suggests this loop as therapeutic target for TNBC.
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- 2019
12. Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels
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Christian Saliba, Giovanni Pratelli, Giovanni Tesoriere, Shawn Baldacchino, Rosa Drago-Ferrante, Christian Scerri, Riccardo Di Fiore, Anna De Blasio, Godfrey Grech, Renza Vento, De Blasio A., Pratelli G., Drago-Ferrante R., Saliba C., Baldacchino S., Grech G., Tesoriere G., Scerri C., Vento R., and Di Fiore R.
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0301 basic medicine ,cancer stem cell ,Indoles ,Physiology ,Cell Survival ,Clinical Biochemistry ,Cell ,Population ,Apoptosis ,TNF-Related Apoptosis-Inducing Ligand ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,Settore BIO/10 - Biochimica ,Cell Line, Tumor ,medicine ,rh-TRAIL ,Biomarkers, Tumor ,Gene silencing ,Humans ,Viability assay ,Gene Silencing ,education ,Cell Shape ,Cell Proliferation ,Membrane Potential, Mitochondrial ,education.field_of_study ,Sulfonamides ,Chemistry ,Cell growth ,Cell Cycle ,Cell Biology ,Cell cycle ,Recombinant Proteins ,Gene Expression Regulation, Neoplastic ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,030104 developmental biology ,medicine.anatomical_structure ,MCL1 ,DR4 receptor ,030220 oncology & carcinogenesis ,Cancer research ,triple-negative breast cancer ,Myeloid Cell Leukemia Sequence 1 Protein - Abstract
Triple-negative breast cancer (TNBC) is a form of BC characterized by highaggressiveness and therapy resistance probably determined by cancer stem cells. MCL1 is an antiapoptotic Bcl-2 family member that could limit the efficacy of anticancer agents as recombinant human tumor necrosis factor related apoptosis-inducing ligand (rh-TRAIL). Here, we investigated MCL1 expression in TNBC tissues and cells. We found MCL1 differentially expressed (upregulated or downregulated) in TNBC tissues. Furthermore, in comparison to the human mammary epithelial cells, we found that MDA-MB-231 cells show similar messenger RNA levels but higher MCL1 protein levels, whereas it resulted downregulated in MDA-MB-436 and BT-20 cells. We evaluated the effects of rh-TRAIL and A-1210477, a selective MCL1 inhibitor, on cell viability and growth of MDA-MB-231 cells. We demonstrated that the drug combination reduced the cell growth and activated the apoptotic pathway. Similar effects were observed on three-dimensional cultures and tertiary mammospheres of MDA-MB-231 cells. In MDA-MB-231 cells, after MCL1 silencing, rh-TRAIL confined the cell population in the sub-G0/G1 phase and induced a drop in the mitochondrial transmembrane potential. To understand themolecular mechanism by which the loss of MCL1 function sensitizes the MDA-MB-231 cells to rh-TRAIL, we analyzed by real-time reverse transcription polymerase chain reaction, the expression of genes related to apoptosis, stemness, cell cycle, and those involved in epigenetic regulation. Interestingly, among the upregulated genes through MCL1 silencing or inhibition, there was TNFRSF10A (DR4). Moreover, MCL1 inhibition increased DR4 protein levels and its cell surface expression. Finally, we demonstrated MCL1-DR4 interaction and dissociation of this complex after A-1210477 treatment. Overall, our findings highlight the potential MCL1-roles in MDA-MB-231 cells and suggest that MCL1 targeting could be an effective strategy to overcome TNBC's rh-TRAIL resistance.
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- 2018
13. Mcl-1 targeting could be an intriguing perspective to cure cancer
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Renza Vento, Anna De Blasio, Riccardo Di Fiore, and De Blasio A, Vento R, Di Fiore R
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0301 basic medicine ,Carcinogenesis ,Physiology ,Clinical Biochemistry ,Apoptosis ,Biology ,medicine.disease_cause ,cancer care ,03 medical and health sciences ,Mcl-1 in cancer ,0302 clinical medicine ,Bcl-2 family ,immune system diseases ,Cancer stem cell ,hemic and lymphatic diseases ,Neoplasms ,medicine ,cancer-stem-cell ,Humans ,Post-translational regulation ,Molecular Targeted Therapy ,neoplasms ,Cellular Senescence ,Oncogene ,Autophagy ,Cancer ,Cell Biology ,medicine.disease ,Mcl-1 isoform ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,USP9X ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,Cancer research ,targeting Mcl-1 ,Myeloid Cell Leukemia Sequence 1 Protein ,Protein Processing, Post-Translational - Abstract
The Bcl-2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl-1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl-2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl-1 expression is regulated independent of Bcl-2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy is apoptosis. Mcl-1 is a potent oncogene that is regulated at the transcriptional, posttranscriptional, and posttranslational levels. Mcl-1 is a short-lived protein that, in the NH2 terminal region, contains sites for posttranslational regulation that can lead to proteasomal degradation. The USP9X Mcl-1 deubiquitinase regulates Mcl-1 and the levels of these two proteins are strongly correlated. Mcl-1 has three splicing variants (the antiapoptotic protein Mcl-1L and the proapoptotic proteins Mcl-1S and Mcl-1ES), each contributing toward apoptosis regulation. In cancers responsible for the most deaths in the world, the presence of Mcl-1 is associated with malignant cell growth and evasion of apoptosis. Mcl-1 is also one of the key regulators ofcancer stem cells’ self-renewal that contributes to tumor survival. A great number of indirect and selective Mcl-1 inhibitors have been produced and some of these have shown efficacy in several clinical trials. Thus, therapeutic manipulation of Mcl-1 can be a useful strategy to combat cancer.
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- 2018
14. Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression
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Lorenzo Memeo, Jayadev Raju, Amedeo Amedei, Dustin G. Brown, Rafaela Andrade-Vieira, Jordan Woodrick, Dale W. Laird, Fahd Al-Mulla, Neetu Singh, Gary S. Goldberg, Debasish Roy, Rabeah Al-Temaimi, Paul Dent, William H. Bisson, Paola A. Marignani, Jan Vondráček, Gloria M. Calaf, Richard Ponce-Cusi, Karine A. Cohen-Solal, Riccardo Di Fiore, Rita Nahta, Annamaria Colacci, Hosni Salem, Robert C. Castellino, Elizabeth P. Ryan, Nichola Cruickshanks, Harini Krishnan, Chiara Mondello, Christian C. Naus, Mark Wade, Rabindra Roy, Monica Vaccari, Stefano Forte, Sarah N Bay, Roslida Abd Hamid, Ahmed Lasfar, A. Ivana Scovassi, Renza Vento, Nahta, R., Al-Mulla, F., Al-Temaimi, R., Amedei, A., Andrade-Vieira, R., Bay, S., Brown, D., Calaf, G., Castellino, R., Cohen-Solal, K., Colacci, A., Cruickshanks, N., Dent, P., Di Fiore, R., Forte, S., Goldberg, G., Hamid, R., Krishnan, H., Laird, D., Lasfar, A., Marignani, P., Memeo, L., Mondello, C., Naus, C., Ponce-Cusi, R., Raju, J., Roy, D., Roy, R., Ryan, E., Salem, H., Ivana Scovassi, A., Singh, N., Vaccari, M., Vento, R., Vondráček, J., Wade, M., Woodrick, J., and Bisson, W.
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Cancer Research ,Review ,Hazardous Substances ,chemistry.chemical_compound ,Neoplasms ,Animals ,Humans ,Medicine ,biology ,Animal ,business.industry ,Medicine (all) ,Retinoblastoma protein ,Contact inhibition ,Cancer ,Environmental Exposure ,General Medicine ,Environmental exposure ,Evasion (ethics) ,medicine.disease ,Cell biology ,chemistry ,Hazardous Substance ,Immunology ,Cancer cell ,biology.protein ,Neoplasm ,Signal transduction ,Growth inhibition ,business ,Human ,Signal Transduction - Abstract
As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.
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- 2015
15. Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation
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Godfrey Grech, Giovanni Tesoriere, Shawn Baldacchino, Daniela Carlisi, Anna De Blasio, Antonio Giordano, James DeGaetano, Renza Vento, Christian Scerri, Rosa Drago-Ferrante, Joseph Debono, Gordon Caruana-Dingli, Christian Saliba, Francesca Pentimalli, Riccardo Di Fiore, Drago-Ferrante, R., Pentimalli, F., Carlisi, D., De Blasio, A., Saliba, C., Baldacchino, S., Degaetano, J., Debono, J., Caruana-Dingli, G., Grech, G., Scerri, C., Tesoriere, G., Giordano, A., Vento, R., and Di Fiore, R.
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0301 basic medicine ,Oncology ,cancer stem cells ,Carcinogenesis ,Cell Cycle Proteins ,Triple Negative Breast Neoplasms ,MicroRNA 29b ,0302 clinical medicine ,Cell Movement ,Settore BIO/10 - Biochimica ,Cancer stem cells ,MiR-29b-1 ,SPIN1 ,Triple-negative breast cancer ,Wnt/β-catenin and Akt signaling pathways ,Medicine ,Breast ,Breast -- Cancer ,Wnt signaling pathway ,MicroRNA ,Nanog Homeobox Protein ,Gene Expression Regulation, Neoplastic ,Wnt/β-catenin and Akt signaling pathway ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,triple-negative breast cancer ,Female ,Microtubule-Associated Proteins ,Signal Transduction ,Research Paper ,medicine.medical_specialty ,cancer stem cell ,Paclitaxel ,Down-Regulation ,03 medical and health sciences ,Breast cancer ,SOX2 ,Cancer stem cell ,Internal medicine ,Cell Line, Tumor ,microRNA ,Humans ,Neoplasm Invasiveness ,Cell Proliferation ,business.industry ,SOXB1 Transcription Factors ,medicine.disease ,Phosphoproteins ,Molecular medicine ,Antineoplastic Agents, Phytogenic ,MicroRNAs ,030104 developmental biology ,Drug Resistance, Neoplasm ,business ,Octamer Transcription Factor-3 - Abstract
MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR- 29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/βcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b- 1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR-29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC., This study was partially funded by the European Regional Development Fund, European Territorial Cooperation 2007-2013, CCI 2007 CB 163 PO 037, OP Italia-Malta 2007-2013; the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2013; R. Di Fiore and R. Drago-Ferrante were recipients of fellowships granted by the European Regional Development Fund, European Territorial Cooperation 2007-2013, CCI 2007 CB 163 PO 037, OP Italia-Malta 2007-2013; D. Carlisi was a recipient of a fellowship granted by MIUR (contract no. 82, January 23, 2014)., peer-reviewed
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- 2017
16. Let-7d miRNA Shows Both Antioncogenic and Oncogenic Functions in Osteosarcoma-Derived 3AB-OS Cancer Stem Cells
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Di Fiore, Riccardo, Drago Ferrante, Rosa, Pentimalli, Francesca, Di Marzo, Domenico, Forte, Iris Maria, Carlisi, Daniela, De Blasio, Anna, Tesoriere, Giovanni, Giordano, Antonio, Vento, Renza, Di Fiore, R., Drago-Ferrante, R., Pentimalli, F., Di Marzo, D., Forte, I., Carlisi, D., De Blasio, A., Tesoriere, G., Giordano, A., and Vento, R.
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Time Factors ,Epithelial-Mesenchymal Transition ,Time Factor ,Transcription Factor ,Physiology ,Clinical Biochemistry ,Drug Resistance ,Antineoplastic Agents ,Apoptosis ,Bone Neoplasms ,Cell Cycle Proteins ,Bone Neoplasm ,Transfection ,Cell Line ,Antineoplastic Agent ,Cell Movement ,Cell Line, Tumor ,Cell Cycle Protein ,Humans ,Neoplasm Invasiveness ,Cell Self Renewal ,Apoptosis Regulatory Proteins ,Cell Cycle ,Drug Resistance, Neoplasm ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Neoplastic Stem Cells ,Osteosarcoma ,Phenotype ,Signal Transduction ,Transcription Factors ,Medicine (all) ,Cell Biology ,Neoplasm Invasivene ,Neoplastic ,Tumor ,Apoptosis Regulatory Protein ,Apoptosi ,MicroRNA ,Gene Expression Regulation ,Neoplasm ,Neoplastic Stem Cell ,Human - Abstract
Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B, and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. J. Cell. Physiol. 231: 1832-1841, 2016. © 2015 Wiley Periodicals, Inc.
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- 2016
17. Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231
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Marco Morreale, Rosa Drago-Ferrante, Daniela Carlisi, Riccardo Di Fiore, Anna De Blasio, Giovanni Tesoriere, Mauro Montalbano, Renza Vento, Christian Scerri, De Blasio, A., Di Fiore, R., Morreale, M., Carlisi, D., Drago-Ferrante, R., Montalbano, M., Scerri, C., Tesoriere, G., and Vento, R.
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0301 basic medicine ,MDA-MB-231 cell ,Cancer Research ,Down-Regulation ,Triple Negative Breast Neoplasms ,Transfection ,Resting Phase, Cell Cycle ,03 medical and health sciences ,Kruppel-Like Factor 4 ,0302 clinical medicine ,HMGA2 ,Breast cancer ,Cell Line, Tumor ,medicine ,Humans ,RNA, Small Interfering ,Caspase-8 unusual role ,Triple-negative breast cancer ,Caspase 8 ,Triple-negative breast cancer cell ,biology ,Oncogene ,Caspase-8 knockdown ,Cell Cycle ,G1 Phase ,Cancer ,Cell cycle ,medicine.disease ,Molecular medicine ,KLF4 ,Invasivity and metastasi ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Cell cycle regulator - Abstract
Triple-negative breast cancer (TNBC) is a clinically aggressive form of breast cancer that is unresponsive to endocrine agents or trastuzumab. TNBC accounts for ~10-20% of all breast cancer cases and represents the form with the poorest prognosis. Patients with TNBC are at higher risk of early recurrence, mainly in the lungs, brain and soft tissue, therefore, there is an urgent need for new therapies. The present study was carried out in MDA-MB-231 cells, where we assessed the role of caspase-8 (casp-8), a critical effector of death receptors, also involved in non‑apoptotic functions. Analysis of casp-8 mRNA and protein levels indicated that they were up-regulated with respect to the normal human mammalian epithelial cells. We demonstrated that silencing of casp-8 by small interfering-RNA, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypo-phosphorylated/active form of pRb levels. Surprisingly, casp-8-knockdown, also potently increased both the migratory and metastatic capacity of MDA-MB‑231 cells, as shown by both wound healing and Matrigel assay, and by the expression of a number of related-genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2. Among these, KLF4, a transcriptional factor with a dual role (activator and repressor), seemed to play critical roles. We suggest that in MDA-MB‑231 cells, the endogenous expression of casp-8 might keep the cells perpetually cycling through downregulation of KLF4, the subsequent lowering of p21 and p27, and the inactivation by hyperphosphorylation of pRb. Simultaneously, by lowering the expression of some migratory and invasive genes, casp-8 might restrain the metastatic ability of the cells. Overall, our findings showed that, in MDA-MB-231 cells, casp-8 might play some unusual roles which should be better explored, in order to understand whether it might be identified as a molecular therapeutic target.
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- 2016
18. The synergistic effect of SAHA and parthenolide in MDA-MB231 breast cancer cells
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CARLISI, Daniela, LAURICELLA, Marianna, D'ANNEO, Antonella, BUTTITTA, Giuseppina, EMANUELE, Sonia, DI FIORE, Riccardo, MARTINEZ, Roberta, Rolfo, Christian Diego, VENTO, Renza, TESORIERE, Giovanni, Carlisi, D., Lauricella, M., D'Anneo, A., Buttitta, G., Emanuele, S., di Fiore, R., Martinez, R., Rolfo, C., Vento, R., and Tesoriere, G.
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Sesquiterpene ,Physiology ,Clinical Biochemistry ,Down-Regulation ,Apoptosis ,Breast Neoplasms ,Autophagy ,Cell Line, Tumor ,Drug Synergism ,Female ,Histone Deacetylase Inhibitors ,Humans ,Hydroxamic Acids ,NF-kappa B ,Sesquiterpenes ,Cell Biology ,Medicine (all) ,Hydroxamic Acid ,Settore BIO/10 - Biochimica ,Histone Deacetylase Inhibitor ,Biology ,Vorinostat ,Apoptosi ,Human medicine ,Breast Neoplasm ,Human - Abstract
The sesquiterpene lactone Parthenolide (PN) exerted a cytotoxic effect on MDA-MB231 cells, a triple-negative breast cancer (TNBC) cell line, but its effectiveness was scarce when employed at low doses. This represents an obstacle for a therapeutic utilization of PN. In order to overcome this difficulty we associated to PN the suberoylanilide hydroxamic acid (SAHA), an histone deacetylase inhibitor. Our results show that SAHA synergistically sensitized MDA-MB231 cells to the cytotoxic effect of PN. It is noteworthy that treatment with PN alone stimulated the survival pathway Akt/mTOR and the consequent nuclear translocation of Nrf2, while treatment with SAHA alone induced autophagic activity. However, when the cells were treated with SAHA/PN combination, SAHA suppressed PN effect on Akt/mTOR/Nrf2 pathway, while PN reduced the prosurvival autophagic activity of SAHA. In addition SAHA/PN combination induced GSH depletion, fall in m, release of cytochrome c, activation of caspase 3 and apoptosis. Finally we demonstrated that combined treatment maintained both hyperacetylation of histones H3 and H4 induced by SAHA and down-regulation of DNMT1 expression induced by PN. Inhibition of the DNA-binding activity of NF-kB, which is determined by PN, was also observed after combined treatment. In conclusion, combination of PN to SAHA inhibits the cytoprotective responses induced by the single compounds, but does not alter the mechanisms leading to the cytotoxic effects. Taken together our results suggest that this combination could be a candidate for TNBC therapy. J. Cell. Physiol. 230: 1276-1289, 2015. (c) 2014 Wiley Periodicals, Inc., A Wiley Company
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- 2015
19. The cytotoxic effect exerted by parthenolide and DMAPT on breast cancer stem-like cells
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BUTTITTA, Giuseppina, CARLISI, Daniela, DI FIORE, Riccardo, SCERRI, CHRISTIAN, VENTO, Renza, TESORIERE, Giovanni, Buttitta, G., Carlisi, D., DI FIORE, R., Scerri, C., Vento, R., and Tesoriere, G.
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Parthenolide, DMAPT, Breast cancer ,stem cells - Abstract
Triple-negative breast cancers (TNBCs) are aggressive forms of breast carcinoma associated with a high rate of recidivism. It is known that a small proportion of tumour cells, termed cancer stem cells (CSCs), is responsible for tumour formation, progression and recurrence. The sesquiterpene lactone parthenolide (PN) was identified as the first small molecule capable of killing CSCs.1 Previously we have shown2 that PN and its soluble analogue DMAPT induce a strong cytotoxic effect in MDA-MB231 cells, the most studied line of TNBCs. In the present research we investigated about the effects exerted by both PN and DMAPT on breast cancer stem-like cells derived from three lines of TNBCs (MDA-MB231, BT20 and MDA-MB436). The two compounds inhibited both the production of mammospheres from the three lines of cells and the viability of breast cancer stem-like cells derived from dissociation of mammospheres. This effect was suppressed by NAC, while z-VAD, a general inhibitor of caspase activity, was ineffective. PN and DMAPT induced in stem-like cells, in the first hours of treatment, a strong production of hydrogen peroxide. Prolonging the time of treatment (12-24h) the levels of both superoxide anion and hROS (hydroxyl radicals and peroxynitrite) increased in concomitance with down-regulation of MnSOD and catalase, dissipation of mitochondrial membrane potential and cell necrosis. It is noteworthy that treatment with PN and DMAPT also caused a rapid and remarkable decrement of the level of Nrf-2, which is a critical regulator of the intracellular antioxidant response. In conclusion PN and DMAPT markedly inhibited viability of stem-like cells derived from three lines of TNBCs by inducing ROS generation, mitochondrial dysfunction and cell necrosis.
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- 2015
20. Janus-Faced role of microRNA let-7d in osteosarcoma 3AB-OS cancer stem cells
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DRAGO FERRANTE, Rosa, DI FIORE, Riccardo, PENTIMALLI, F, DI MARZO, D, FORTE, I. M, CARLISI, Daniela, DE BLASIO, Anna, TESORIERE, Giovanni, GIORDANO, A, VENTO, Renza, DRAGO-FERRANTE, R, DI FIORE, R, PENTIMALLI, F, DI MARZO, D, FORTE, I. M, CARLISI, D, DE BLASIO, A, TESORIERE, G, GIORDANO, A, and VENTO, R
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Cancer stem cells, osteosarcoma, microRNA - Abstract
Osteosarcoma (OS) is the most common malignancy of bone in children and adolescent. It is a highly invasive and metastatic bone-malignancy because of which, despite therapeutic advances, 30%-50% of patients still die of pulmonary metastasis. As a consequence, there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of the patients. Advances in OS treatment are inconceivable without better understanding of molecular mechanism of osteosarmagenesis and, especially, metastatic processes. Growing evidence suggests that cancer stem cells (CSCs), which have self-renewing and malignant potential, are at the root of tumor growth and relapse. Thus, a challenge for innovative therapy is their identification and eradication. Here, we have used the 3AB-OS CSCs, a cell line previously produced in our laboratory from the OS-MG63 cells, which was genetically, molecularly and functionally characterized. This study was focused on the role of let-7d miRNA-previously found by us to be downregulated in 3AB-OS-CSCs- in managing their stemness properties. We have found that let-7d-overesperession reduces cell proliferation by both decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also reduces sarcosphere and colony-forming ability and the expression of Oct3/4, Sox2, Nanog, Lin28B and HMGA2, key regulators of cancer cell stemness. Moreover, let-7d induces mesenchymal-to-epithelium-transition, as shown by both N-Cadherin-E-cadherin-switch and vimentin decrease. Surprisingly, this swich was accompanied by enhanced migratory/invasive capacities and by increases in MMP9, CXCR4 and VersicanV1. Let-7d also reduced the resistance to serum starvation and chemotherapy. A decrease in caspase-3 with an increase in Bcl-2 was also observed. Overall, this study shows that let-7d displaying both suppressor and oncogenic functions behaves as a Janus-Faced miRNA. Thus, we suggest that, before prospecting new therapeutic strategies by let-7d modulation, it is urgent to better understand its functions.
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- 2015
21. Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis
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Daniela Carlisi, Rosa Drago-Ferrante, Renza Vento, Christian Scerri, Giuseppina Buttitta, Giovanni Tesoriere, R Di Fiore, Carlisi, D., Buttitta, G., Di Fiore, R., Scerri, C., Drago-Ferrante, R., Vento, R., and Tesoriere, G.
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0301 basic medicine ,Cancer Research ,Necrosis ,medicine.disease_cause ,Cancer -- Treatment ,chemistry.chemical_compound ,Onium Compounds ,Medicine ,Cytotoxic T cell ,Breast -- Cancer ,Membrane Potential, Mitochondrial ,chemistry.chemical_classification ,Superoxide ,Mitochondrial DNA ,Mitochondria ,Neoplastic Stem Cells ,Female ,Original Article ,medicine.symptom ,Oligopeptides ,Sesquiterpenes ,Cell Survival ,NF-E2-Related Factor 2 ,Immunology ,Breast Neoplasms ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Downregulation and upregulation ,Cell Line, Tumor ,Humans ,Parthenolide ,parthenolide, cancer stem cell, triple-negative breast cancer, reactive oxygen species, nuclear factor erythroid 2-related factor 2 ,Fluorescent Dyes ,Reactive oxygen species ,business.industry ,Acetophenones ,NADPH Oxidases ,Cell Biology ,Cell nuclei -- Abnormalities ,Oxidative Stress ,030104 developmental biology ,chemistry ,Apocynin ,Cancer research ,Reactive Oxygen Species ,business ,Oxidative stress ,Transcription Factors - Abstract
Triple-negative breast cancers (TNBCs) are aggressive forms of breast carcinoma associated with a high rate of recidivism. In this paper, we report the production of mammospheres from three lines of TNBC cells and demonstrate that both parthenolide (PN) and its soluble analog dimethylaminoparthenolide (DMAPT) suppressed this production and induced cytotoxic effects in breast cancer stem-like cells, derived from dissociation of mammospheres. In particular, the drugs exerted a remarkable inhibitory effect on viability of stem-like cells. Such an effect was suppressed by N-acetylcysteine, suggesting a role of reactive oxygen species (ROS) generation in the cytotoxic effect. Instead z-VAD, a general inhibitor of caspase activity, was ineffective. Analysis of ROS generation, performed using fluorescent probes, showed that both the drugs stimulated in the first hours of treatment a very high production of hydrogen peroxide. This event was, at least in part, a consequence of activation of NADPH oxidases (NOXs), as it was reduced by apocynin and diphenylene iodinium, two inhibitors of NOXs. Moreover, both the drugs caused downregulation of Nrf2 (nuclear factor erythroid 2-related factor 2), which is a critical regulator of the intracellular antioxidant response. Prolonging the treatment with PN or DMAPT we observed between 12 and 24 h that the levels of both superoxide anion and hROS increased in concomitance with the downregulation of manganese superoxide dismutase and catalase. In addition, during this phase dissipation of mitochondrial membrane potential occurred together with necrosis of stem-like cells. Finally, our results suggested that the effect on ROS generation found in the first hours of treatment was, in part, responsible for the cytotoxic events observed in the successive phase. In conclusion, PN and DMAPT markedly inhibited viability of stem-like cells derived from three lines of TNBCs by inducing ROS generation, mitochondrial dysfunction and cell necrosis., peer-reviewed
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- 2016
22. The role of microRNA-9 in ovarian and cervical cancers: An updated overview.
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Di Fiore R, Drago-Ferrante R, Suleiman S, Calleja N, and Calleja-Agius J
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Ovarian and cervical cancers are the two most frequent kind of gynaecological cancers (GCs). In spite of advances in prevention, screening and treatment, cervical cancer still leads to an increased morbidity and mortality worldwide. Ovarian cancer is often detected at a late stage, which significantly reduces the effectiveness of available treatments. Therefore, novel methods are desperately needed to improve the clinical care of GC patients. MicroRNAs, also known as short noncoding RNAs (miRNAs/miRs), are a diverse group of RNAs with a length of 22 nucleotides. These typically cause translational repression and mRNA degradation by interacting with target mRNAs' 3' untranslated region (3'-UTR), together with other regions and gene promoters. Under certain conditions, they are also able to activate translation or regulate transcription. It has been demonstrated that miRNAs are crucial to several biological processes leading to tumorigenesis, including GCs. Recent research has shown that miR-9 affects carcinogenesis. In this review, we will provide an overview of current research on the potential utility of miR-9 in the diagnosis, prognosis, and therapy of ovarian and cervical malignancies., Competing Interests: Conflict of interest None., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)
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- 2024
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23. Sarcopenia in gynaecological cancers.
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Di Fiore R, Drago-Ferrante R, Suleiman S, Veronese N, Pegreffi F, and Calleja-Agius J
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Gynaecological cancers (GCs) comprise a group of cancers that originate in the female reproductive organs. Each GC is unique, with different signs and symptoms, risk factors and therapeutic strategies. Worldwide, the majority of GCs are still associated with high mortality rates, especially ovarian, due to difficulty in early detection. Despite numerous studies on the underlying pathophysiology, research in the field of GCs poses unique scientific and technological challenges. These challenges require a concerted multi- and inter-disciplinary effort by the clinical, scientific and research communities to accelerate the advancement of prognostic, diagnostic, and therapeutic approaches. Sarcopenia is a multifactorial disease which leads to the systemic loss of skeletal muscle mass and function. It can be caused by malignancies, as well as due to malnutrition, physical inactivity, ageing and neuromuscular, inflammatory, and/or endocrine diseases. Anorexia and systemic inflammation can shift the metabolic balance of patients with cancer cachexia towards catabolism of skeletal muscle, and hence sarcopenia. Therefore, sarcopenia is considered as an indicator of poor general health status, as well as the possible indicator of advanced cancer. There is a growing body of evidence showing the prognostic significance of sarcopenia in various cancers, including GCs. This review will outline the clinical importance of sarcopenia in patients with GCs., Competing Interests: Declaration of competing interest None., (© 2024 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)
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- 2024
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24. Role of Flex-Dose Delivery Program in Patients Affected by HCC: Advantages in Management of Tare in Our Experience.
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Paladini A, Spinetta M, Matheoud R, D'Alessio A, Sassone M, Di Fiore R, Coda C, Carriero S, Biondetti P, Laganà D, Minici R, Semeraro V, Sacchetti GM, Carrafiello G, and Guzzardi G
- Abstract
Background : Introduced in the latest BCLC 2022, endovascular trans-arterial radioembolization (TARE) has an important role in the treatment of unresectable hepatocellular carcinoma (HCC) as a "bridge" or "downstaging" of disease. The evolution of TARE technology allows a more flexible and personalized target treatment, based on the anatomy and vascular characteristics of each HCC. The flex-dose delivery program is part of this perspective, which allows us to adjust the dose and its radio-embolizing power in relation to the size and type of cancer and to split the therapeutic dose of Y90 in different injections (split-bolus). Methods : From January 2020 to January 2022, we enrolled 19 patients affected by unresectable HCC and candidates for TARE treatment. Thirteen patients completed the treatment following the flex-dose delivery program. Response to treatment was assessed using the mRECIST criteria with CT performed 6 and 9 months after treatment. Two patients did not complete the radiological follow-up and were not included in this retrospective study. The final cohort of this study counts eleven patients. Results : According to mRECIST criteria, six months of follow-up were reported: five cases of complete response (CR, 45.4% of cases), four cases of partial response (PR, 36.4%), and two cases of progression disease (PD, 18.2%). Nine months follow-up reported five cases of complete response (CR, 45.4%), two cases of partial response (PR, 18.2%), and four cases of progression disease (PD, 36.4%). No intra and post-operative complications were described. The average absorbed doses to the hepatic lesion and to the healthy liver tissue were 319 Gy (range 133-447 Gy) and 9.5 Gy (range 2-19 Gy), respectively. Conclusions : The flex-dose delivery program represents a therapeutic protocol capable of "saving" portions of healthy liver parenchyma by designing a "custom-made" treatment for the patient.
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- 2024
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25. The Role of FBXW7 in Gynecologic Malignancies.
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Di Fiore R, Suleiman S, Drago-Ferrante R, Subbannayya Y, Suleiman S, Vasileva-Slaveva M, Yordanov A, Pentimalli F, Giordano A, and Calleja-Agius J
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- Female, Humans, F-Box-WD Repeat-Containing Protein 7 genetics, F-Box-WD Repeat-Containing Protein 7 metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Ubiquitins metabolism, F-Box Proteins genetics, F-Box Proteins metabolism, Genital Neoplasms, Female genetics
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The F-Box and WD Repeat Domain Containing 7 (FBXW7) protein has been shown to regulate cellular growth and act as a tumor suppressor. This protein, also known as FBW7, hCDC4, SEL10 or hAGO, is encoded by the gene FBXW7. It is a crucial component of the Skp1-Cullin1-F-box (SCF) complex, which is a ubiquitin ligase. This complex aids in the degradation of many oncoproteins, such as cyclin E, c-JUN, c-MYC, NOTCH, and MCL1, via the ubiquitin-proteasome system (UPS). The FBXW7 gene is commonly mutated or deleted in numerous types of cancer, including gynecologic cancers (GCs). Such FBXW7 mutations are linked to a poor prognosis due to increased treatment resistance. Hence, detection of the FBXW7 mutation may possibly be an appropriate diagnostic and prognostic biomarker that plays a central role in determining suitable individualized management. Recent studies also suggest that, under specific circumstances, FBXW7 may act as an oncogene. There is mounting evidence indicating that the aberrant expression of FBXW7 is involved in the development of GCs. The aim of this review is to give an update on the role of FBXW7 as a potential biomarker and also as a therapeutic target for novel treatments, particularly in the management of GCs.
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- 2023
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26. Cancer of the Cervix in Bulgaria: Epidemiology of a Crisis.
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Yordanov A, Vasileva-Slaveva M, Galai N, Faraggi D, Kubelac MP, Tripac-Iacovleva I, Calleja N, Di Fiore R, and Calleja-Agius J
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Eastern Europe continues to have the highest rates of cancer of the uterine cervix (CUC) and human papillomavirus (HPV) infection in Europe., Aim: The aim of this study was to investigate CUC trends in Bulgaria in the context of a lack of a population-based screening program and a demographic crisis., Methodology: This was a retrospective study of 7861 CUC patients who were registered in the Bulgarian National Cancer Registry (BNCR) between 2013 and 2020 and followed up with until March 2022. We used descriptive statistics and modeling to assess temporal trends in new CUC incidence rates and identify factors associated with survival., Results: Bulgaria's population has decreased by 11.5% between 2011 and 2021. The CUC incidence rate decreased from 29.5/100,000 in 2013 to 23.2/100,000 in 2020 but remains very high. The proportion of patients diagnosed in earlier stages of CUC has decreased over time. Up to 19% of patients with CUC in Bulgaria are diagnosed between the age of 35 and 44 years. The median survival was 101.5 months, with some improvement in later years (adjusted HR = 0.83 for 2017-2020)., Conclusions: In countries with well-established population-based screening, CUC is nowadays considered a rare disease. However, it is not considered rare in Bulgaria. Population-based screening starting at an earlier age is the fastest way to improve outcomes.
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- 2023
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27. Endometrial carcinoma in patients under 40 years of age: insights from the Bulgarian Cancer Registry.
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Yordanov A, Kostov S, Kornovski Y, Slavchev S, Ivanova Y, Calleja-Agius J, Di Fiore R, Suleiman S, Piciu A, Hasan I, and Vasileva-Slaveva M
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- Humans, Female, Bulgaria epidemiology, Retrospective Studies, Uterus, Registries, Endometrial Neoplasms epidemiology, Endometrial Neoplasms therapy
- Abstract
Objectives: We aimed to investigate the overall survival (OS) of young women with endometrial cancer (EC) in Bulgaria and the impact of histological type on survival., Material and Methods: This is a population-wide retrospective study of patients with EC (≤ 40 years at diagnosis) registered at Bulgarian National Cancer Registry (BNCR) between 1993 and 2020. Patients were re-classified according to the 8th edition of the TNM classification., Results: In total, 30 597 patients were registered and histologically confirmed with malignant tumors of the uterine body. From that, 29 065 of them (95%) had ECs, and the rest had sarcomas. Around 1.64% of all malignant tumors of the uterine body are diagnosed in women under the age of 40. Most of them are diagnosed in the early stage. There was no significant difference in median OS for patients diagnosed before or after 2003. In recent years there was a slight improvement in survival and patients from the last cohort of this study had a 5-year survival rate of 92.5%. Patients with favorable pathology (T1, G1/2) had no lymph node involvement at the time of diagnosis and their 10-year survival rate was 94%., Conclusions: EC in young women is a rare disease. In most cases, patients are diagnosed in early stageT1, G1/2, N0 and their prognosis is excellent. However, the lack of improvement of OS of young patients with EC in the last three decades shows the need for treatment optimization.
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- 2023
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28. Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review.
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Drago-Ferrante R, Di Fiore R, Karouia F, Subbannayya Y, Das S, Aydogan Mathyk B, Arif S, Guevara-Cerdán AP, Seylani A, Galsinh AS, Kukulska W, Borg J, Suleiman S, Porterfield DM, Camera A, Christenson LK, Ronca AE, Steller JG, Beheshti A, and Calleja-Agius J
- Subjects
- Astronauts, Female, Humans, Male, Gynecology, Neoplasms, Radiation-Induced, Space Flight, Weightlessness adverse effects
- Abstract
Outer space is an extremely hostile environment for human life, with ionizing radiation from galactic cosmic rays and microgravity posing the most significant hazards to the health of astronauts. Spaceflight has also been shown to have an impact on established cancer hallmarks, possibly increasing carcinogenic risk. Terrestrially, women have a higher incidence of radiation-induced cancers, largely driven by lung, thyroid, breast, and ovarian cancers, and therefore, historically, they have been permitted to spend significantly less time in space than men. In the present review, we focus on the effects of microgravity and radiation on the female reproductive system, particularly gynecological cancer. The aim is to provide a summary of the research that has been carried out related to the risk of gynecological cancer, highlighting what further studies are needed to pave the way for safer exploration class missions, as well as postflight screening and management of women astronauts following long-duration spaceflight.
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- 2022
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29. Cancer Stem Cells and Their Possible Implications in Cervical Cancer: A Short Review.
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Di Fiore R, Suleiman S, Drago-Ferrante R, Subbannayya Y, Pentimalli F, Giordano A, and Calleja-Agius J
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- Cell Transformation, Neoplastic metabolism, Female, Humans, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells metabolism, Nerve Tissue Proteins metabolism, RNA-Binding Proteins metabolism, Signal Transduction, Uterine Cervical Neoplasms pathology
- Abstract
Cervical cancer (CC) is the fourth most common type of gynecological malignancy affecting females worldwide. Most CC cases are linked to infection with high-risk human papillomaviruses (HPV). There has been a significant decrease in the incidence and death rate of CC due to effective cervical Pap smear screening and administration of vaccines. However, this is not equally available throughout different societies. The prognosis of patients with advanced or recurrent CC is particularly poor, with a one-year relative survival rate of a maximum of 20%. Increasing evidence suggests that cancer stem cells (CSCs) may play an important role in CC tumorigenesis, metastasis, relapse, and chemo/radio-resistance, thus representing potential targets for a better therapeutic outcome. CSCs are a small subpopulation of tumor cells with self-renewing ability, which can differentiate into heterogeneous tumor cell types, thus creating a progeny of cells constituting the bulk of tumors. Since cervical CSCs (CCSC) are difficult to identify, this has led to the search for different markers (e.g., ABCG2, ITGA6 (CD49f), PROM1 (CD133), KRT17 (CK17), MSI1, POU5F1 (OCT4), and SOX2). Promising therapeutic strategies targeting CSC-signaling pathways and the CSC niche are currently under development. Here, we provide an overview of CC and CCSCs, describing the phenotypes of CCSCs and the potential of targeting CCSCs in the management of CC.
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- 2022
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30. Epithelioid Trophoblastic Tumour: A Case with Genetic Linkage to a Child Born over Seventeen Years Prior, Successfully Treated with Surgery and Pembrolizumab.
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Pisani D, Calleja-Agius J, Di Fiore R, O'Leary JJ, Beirne JP, O'Toole SA, Felix A, and Said-Huntingford I
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- Antibodies, Monoclonal, Humanized, Female, Genetic Linkage, Humans, Middle Aged, Neoplasm Recurrence, Local, Pregnancy, Gestational Trophoblastic Disease drug therapy, Gestational Trophoblastic Disease genetics, Gestational Trophoblastic Disease surgery, Uterine Neoplasms drug therapy, Uterine Neoplasms genetics, Uterine Neoplasms surgery
- Abstract
Epithelioid trophoblastic tumours are rare neoplasms showing differentiation towards the chorion leave-type intermediate cytotrophoblast, with only a handful of cases being reported in the literature. These tumours are slow-growing and are typically confined to the uterus for extended periods of time. While the pathogenesis is unclear, they are thought to arise from a remnant intermediate trophoblast originating from prior normal pregnancies or, less frequently, gestational trophoblastic tumours. A protracted time period between the gestational event and tumour development is typical. This case describes a 49-year-old previously healthy female who presented with a completely asymptomatic uterine mass, discovered incidentally during a routine gynaecological assessment. The pathological analysis of the hysterectomy specimen confirmed an epithelioid trophoblastic tumour, involving the uterus and cervix. This is a rare gynaecological tumour. A comparative short tandem repeat analysis revealed genetic similarities to a previous healthy gestation seventeen years prior. She was successful treated with adjuvant pembrolizumab, with no evidence of disease recurrence to date.
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- 2021
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31. The Role of Omics Approaches to Characterize Molecular Mechanisms of Rare Ovarian Cancers: Recent Advances and Future Perspectives.
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Subbannayya Y, Di Fiore R, Urru SAM, and Calleja-Agius J
- Abstract
Rare ovarian cancers are ovarian cancers with an annual incidence of less than 6 cases per 100,000 women. They generally have a poor prognosis due to being delayed diagnosis and treatment. Exploration of molecular mechanisms in these cancers has been challenging due to their rarity and research efforts being fragmented across the world. Omics approaches can provide detailed molecular snapshots of the underlying mechanisms of these cancers. Omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, can identify potential candidate biomarkers for diagnosis, prognosis, and screening of rare gynecological cancers and can aid in identifying therapeutic targets. The integration of multiple omics techniques using approaches such as proteogenomics can provide a detailed understanding of the molecular mechanisms of carcinogenesis and cancer progression. Further, omics approaches can provide clues towards developing immunotherapies, cancer recurrence, and drug resistance in tumors; and form a platform for personalized medicine. The current review focuses on the application of omics approaches and integrative biology to gain a better understanding of rare ovarian cancers.
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- 2021
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32. (In)Distinctive Role of Long Non-Coding RNAs in Common and Rare Ovarian Cancers.
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Sabol M, Calleja-Agius J, Di Fiore R, Suleiman S, Ozcan S, Ward MP, and Ozretić P
- Abstract
Rare ovarian cancers (ROCs) are OCs with an annual incidence of fewer than 6 cases per 100,000 women. They affect women of all ages, but due to their low incidence and the potential clinical inexperience in management, there can be a delay in diagnosis, leading to a poor prognosis. The underlying causes for these tumors are varied, but generally, the tumors arise due to alterations in gene/protein expression in cellular processes that regulate normal proliferation and its checkpoints. Dysregulation of the cellular processes that lead to cancer includes gene mutations, epimutations, non-coding RNA (ncRNA) regulation, posttranscriptional and posttranslational modifications. Long non-coding RNA (lncRNA) are defined as transcribed RNA molecules, more than 200 nucleotides in length which are not translated into proteins. They regulate gene expression through several mechanisms and therefore add another level of complexity to the regulatory mechanisms affecting tumor development. Since few studies have been performed on ROCs, in this review we summarize the mechanisms of action of lncRNA in OC, with an emphasis on ROCs.
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- 2021
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33. LncRNA MORT (ZNF667-AS1) in Cancer-Is There a Possible Role in Gynecological Malignancies?
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Di Fiore R, Suleiman S, Drago-Ferrante R, Felix A, O'Toole SA, O'Leary JJ, Ward MP, Beirne J, Yordanov A, Vasileva-Slaveva M, Subbannayya Y, Pentimalli F, Giordano A, and Calleja-Agius J
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- Animals, Female, Genital Neoplasms, Female genetics, Humans, Genital Neoplasms, Female pathology, RNA, Long Noncoding genetics
- Abstract
Gynecological cancers (GCs) are currently among the major threats to female health. Moreover, there are different histologic subtypes of these cancers, which are defined as 'rare' due to an annual incidence of <6 per 100,000 women. The majority of these tend to be associated with a poor prognosis. Long non-coding RNAs (lncRNAs) play a critical role in the normal development of organisms as well as in tumorigenesis. LncRNAs can be classified into tumor suppressor genes or oncogenes, depending on their function within the cellular context and the signaling pathways in which they are involved. These regulatory RNAs are potential therapeutic targets for cancer due to their tissue and tumor specificity. However, there still needs to be a deeper understanding of the mechanisms by which lncRNAs are involved in the regulation of numerous biological functions in humans, both in normal health and disease. The lncRNA Mortal Obligate RNA Transcript ( MORT ; alias ZNF667-AS1 ) has been identified as a tumor-related lncRNA. ZNF667-AS1 gene, located in the human chromosome region 19q13.43, has been shown to be silenced by DNA hypermethylation in several cancers. In this review, we report on the biological functions of ZNF667-AS1 from recent studies and describe the regulatory functions of ZNF667-AS1 in human disease, including cancer. Furthermore, we discuss the emerging insights into the potential role of ZNF667-AS1 as a biomarker and novel therapeutic target in cancer, including GCs (ovarian, cervical, and endometrial cancers).
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- 2021
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34. Adenosquamous Carcinoma of the Uterine Cervix - Impact of Histology on Clinical Management.
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Yordanov A, Kostov S, Slavchev S, Strashilov S, Konsoulova A, Calleja-Agius J, Di Fiore R, Suleiman S, Kubelac P, Vlad C, Achimas-Cadariu P, and Vasileva-Slaveva M
- Abstract
Introduction: Historically, the incidence rate of cervical cancer (CC) in Eastern Europe and particularly in Bulgaria has constantly been higher than that in the other European countries. Adenosquamous carcinoma (ASC) is a rare histological subtype of CC with incidence rate of less than 6 per 100,000. We aimed to analyze the epidemiology and prognosis of all Bulgarian patients with ASC, registered at the Bulgarian National Cancer Registry (BNCR), and to compare patients' characteristics and outcomes with those of patients, treated at a large specialized institution - the Department of Gynecologic Oncology, University Hospital in Pleven, Bulgaria., Materials and Methods: This is a retrospective study of all cases of ASC, registered at the BNCR for a 10-year period of time. The Kaplan-Meier analysis with Log rank test was used to estimate the significant differences., Results: The incidence rate of ASC was calculated as 3.2% of all CC registered in BNCR and 4.97% of all stage I patients, treated in our department. The 5-year overall survival (OS) rate of all patients with ASC tumors from the registry was 50.5%. A total of 171 (48.4%) of the patients had T1 tumors and a 5-year OS of 67.1%. Lymph node status was a significant prognostic factor for OS (p=0.001). Thirty-one patients with T1 tumors and ASC histology were treated in our department for the same period of time. Lymph node metastases were found in 10 of them (32.2%). The 5-year observed OS in ASC group was 74.19%., Conclusion: The histological subtype of cancer of the uterine cervix has an impact on prognosis and should not be simply considered as a descriptive characteristic but a poor prognostic feature and should be an integral part of the decision-making in clinical management of patients., Competing Interests: The authors declare no competing interests in this work., (© 2021 Yordanov et al.)
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- 2021
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35. An Overview of the Role of Long Non-Coding RNAs in Human Choriocarcinoma.
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Di Fiore R, Suleiman S, Felix A, O'Toole SA, O'Leary JJ, Ward MP, Beirne J, Sabol M, Ozretić P, Yordanov A, Vasileva-Slaveva M, Kostov S, Nikolova M, Said-Huntingford I, Ayers D, Ellul B, Pentimalli F, Giordano A, and Calleja-Agius J
- Subjects
- Biomarkers, Tumor, Choriocarcinoma diagnosis, Choriocarcinoma metabolism, Female, Humans, Molecular Diagnostic Techniques, Molecular Targeted Therapy, Neoplasm Grading, Neoplasm Staging, Pregnancy, Uterine Neoplasms diagnosis, Uterine Neoplasms metabolism, Choriocarcinoma genetics, Disease Susceptibility, Gene Expression Regulation, Neoplastic, RNA, Long Noncoding genetics, Uterine Neoplasms genetics
- Abstract
Choriocarcinoma (CC), a subtype of trophoblastic disease, is a rare and highly aggressive neoplasm. There are two main CC subtypes: gestational and non-gestational, (so called when it develops as a component of a germ cell tumor or is related to a somatic mutation of a poorly differentiated carcinoma), each with very diverse biological activity. A therapeutic approach is highly effective in patients with early-stage CC. The advanced stage of the disease also has a good prognosis with around 95% of patients cured following chemotherapy. However, advancements in diagnosis and treatment are always needed to improve outcomes for patients with CC. Long non-coding (lnc) RNAs are non-coding transcripts that are longer than 200 nucleotides. LncRNAs can act as oncogenes or tumor suppressor genes. Deregulation of their expression has a key role in tumor development, angiogenesis, differentiation, migration, apoptosis, and proliferation. Furthermore, detection of cancer-associated lncRNAs in body fluids, such as blood, saliva, and urine of cancer patients, is emerging as a novel method for cancer diagnosis. Although there is evidence for the potential role of lncRNAs in a number of cancers of the female genital tract, their role in CC is poorly understood. This review summarizes the current knowledge of lncRNAs in gestational CC and how this may be applied to future therapeutic strategies in the treatment of this rare cancer.
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- 2021
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36. Could MicroRNAs Be Useful Tools to Improve the Diagnosis and Treatment of Rare Gynecological Cancers? A Brief Overview.
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Di Fiore R, Suleiman S, Pentimalli F, O'Toole SA, O'Leary JJ, Ward MP, Conlon NT, Sabol M, Ozretić P, Erson-Bensan AE, Reed N, Giordano A, Herrington CS, and Calleja-Agius J
- Subjects
- Circulating MicroRNA, Clinical Decision-Making, Disease Management, Female, Gene Expression Regulation, Neoplastic, Genital Neoplasms, Female therapy, Humans, Molecular Diagnostic Techniques methods, Molecular Diagnostic Techniques standards, Pregnancy, Prognosis, RNA Interference, RNA, Messenger, Treatment Outcome, Biomarkers, Tumor, Genital Neoplasms, Female diagnosis, Genital Neoplasms, Female genetics, MicroRNAs genetics
- Abstract
Gynecological cancers pose an important public health issue, with a high incidence among women of all ages. Gynecological cancers such as malignant germ-cell tumors, sex-cord-stromal tumors, uterine sarcomas and carcinosarcomas, gestational trophoblastic neoplasia, vulvar carcinoma and melanoma of the female genital tract, are defined as rare with an annual incidence of <6 per 100,000 women. Rare gynecological cancers (RGCs) are associated with poor prognosis, and given the low incidence of each entity, there is the risk of delayed diagnosis due to clinical inexperience and limited therapeutic options. There has been a growing interest in the field of microRNAs (miRNAs), a class of small non-coding RNAs of ∼22 nucleotides in length, because of their potential to regulate diverse biological processes. miRNAs usually induce mRNA degradation and translational repression by interacting with the 3' untranslated region (3'-UTR) of target mRNAs, as well as other regions and gene promoters, as well as activating translation or regulating transcription under certain conditions. Recent research has revealed the enormous promise of miRNAs for improving the diagnosis, therapy and prognosis of all major gynecological cancers. However, to date, only a few studies have been performed on RGCs. In this review, we summarize the data currently available regarding RGCs.
- Published
- 2021
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37. GYNOCARE Update: Modern Strategies to Improve Diagnosis and Treatment of Rare Gynecologic Tumors—Current Challenges and Future Directions
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Di Fiore R, Suleiman S, Ellul B, O'Toole SA, Savona-Ventura C, Felix A, Napolioni V, Conlon NT, Kahramanoglu I, Azzopardi MJ, Dalmas M, Calleja N, Brincat MR, Muscat-Baron Y, Sabol M, Dimitrievska V, Yordanov A, Vasileva-Slaveva M, von Brockdorff K, Micallef RA, Kubelac P, Achimaș-Cadariu P, Vlad C, Tzortzatou O, Poka R, Giordano A, Felice A, Reed N, Herrington CS, Faraggi D, and Calleja-Agius J
- Abstract
More than 50% of all gynecologic tumors can be classified as rare (defined as an incidence of ≤6 per 100,000 women) and usually have a poor prognosis owing to delayed diagnosis and treatment. In contrast to almost all other common solid tumors, the treatment of rare gynecologic tumors (RGT) is often based on expert opinion, retrospective studies, or extrapolation from other tumor sites with similar histology, leading to difficulty in developing guidelines for clinical practice. Currently, gynecologic cancer research, due to distinct scientific and technological challenges, is lagging behind. Moreover, the overall efforts for addressing these challenges are fragmented across different European countries and indeed, worldwide. The GYNOCARE, COST Action CA18117 (European Network for Gynecological Rare Cancer Research) programme aims to address these challenges through the creation of a unique network between key stakeholders covering distinct domains from concept to cure: basic research on RGT, biobanking, bridging with industry, and setting up the legal and regulatory requirements for international innovative clinical trials. On this basis, members of this COST Action, (Working Group 1, “Basic and Translational Research on Rare Gynecological Cancer”) have decided to focus their future efforts on the development of new approaches to improve the diagnosis and treatment of RGT. Here, we provide a brief overview of the current state-of-the-art and describe the goals of this COST Action and its future challenges with the aim to stimulate discussion and promote synergy across scientists engaged in the fight against this rare cancer worldwide.
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- 2021
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38. Anticancer effects of an extract from a local planarian species on human acute myeloid leukemia HL-60 cells in vitro.
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Suleiman S, Di Fiore R, Cassar A, Formosa MM, Calleja-Agius J, and Schembri-Wismayer P
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- Animals, Apoptosis drug effects, Cell Differentiation drug effects, Cell Division drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Gene Expression drug effects, HL-60 Cells, Humans, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Tissue Extracts pharmacology, Antineoplastic Agents pharmacology, Leukemia, Myeloid, Acute drug therapy, Planarians metabolism
- Abstract
Current anti-cancer drugs can cause many undesirable side effects to patients. Thus, there is a constant need to develop alternative therapeutic drugs. Bioactive compounds derived from natural products including animals, plants and microorganisms are being actively studied as sources for anticancer treatments. Freshwater planarians are important models for stem cell research and regeneration. However, to date, no studies on the biological activities of planaria extracts on cancer have been published. The aim of this study was to examine the potential antitumoral activity of the extract from planaria species-Malta (PSM) on human acute myeloid leukemia (AML) HL-60 cells. Antiproliferative activity was studied in terms of proliferation, apoptosis and differentiation. The expression of genes involved in the regulation of these important cellular processes was also analyzed using real-time PCR. PSM extract exhibited a selective cytotoxic effect on HL-60 cells when compared to normal lymphocytes. Furthermore, cell cycle analysis and Annexin V/PI assay showed that the extract induced apoptosis in HL-60 cells. The PSM extract induced myeloid differentiation with HL-60 cells showing a decreased nucleo/cytoplasmic ratio, an increase in nitroblue tetrazolium-positive cells, and CD11b- and CD14-positive cells. Finally, we also found that the PSM extract increased the expression of CEBPA, CEBPB, CEBPE, SPI1, BAX, CDKN1A and CDKN2C; whereas it reduced the expression of c-MYC and BCL2. This is the first study to reveal the antiproliferative, cytotoxic, and differentiation potential of PSM on HL-60 cells and suggests that it may have considerable potential for development as a novel natural product-based anticancer agent against AML., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2020
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39. Axolotl Ambystoma mexicanum extract induces cell cycle arrest and differentiation in human acute myeloid leukemia HL-60 cells.
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Suleiman S, Di Fiore R, Cassar A, Formosa MM, Schembri-Wismayer P, and Calleja-Agius J
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- Animals, CCAAT-Enhancer-Binding Protein-beta genetics, CCAAT-Enhancer-Binding Proteins genetics, Cell Cycle Checkpoints drug effects, Cell Differentiation drug effects, Cyclin-Dependent Kinase Inhibitor p18 genetics, Cyclin-Dependent Kinase Inhibitor p21 genetics, Gene Expression Regulation, Neoplastic drug effects, HL-60 Cells, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Proto-Oncogene Proteins c-myc genetics, Ambystoma mexicanum, Cell Proliferation drug effects, Complex Mixtures pharmacology, Leukemia, Myeloid, Acute drug therapy
- Abstract
Acute myeloid leukemia is the most common form of acute leukemia in adults, constituting about 80% of cases. Although remarkable progress has been made in the therapeutic scenario for patients with acute myeloid leukemia, research and development of new and effective anticancer agents to improve patient outcome and minimize toxicity is needed. In this study, the antitumor activity of axolotl (AXO) Ambystoma mexicanum crude extract was assessed in vitro on the human acute myeloid leukemia HL-60 cell line. The anticancer activity was evaluated in terms of ability to influence proliferative activity, cell viability, cell cycle arrest, and differentiation. Moreover, gene expression analysis was performed to evaluate the genes involved in the regulation of these processes. The AXO crude extract exhibited antiproliferative but not cytotoxic activities on HL-60 cells, with cell cycle arrest in the G0/G1 phase. Furthermore, the AXO-treated HL-60 cells showed an increase in both the percentage of nitroblue tetrazolium positive cells and the expression of CD11b, whereas the proportion of CD14-positive cells did not change, suggesting that extract is able to induce differentiation toward the granulocytic lineage. Finally, the treatment with AXO extract caused upregulation of CEBPA, CEBPB, CEBPE, SPI1, CDKN1A , and CDKN2C , and downregulation of c-MYC . Our data clearly show the potential anticancer activity of Ambystoma mexicanum on HL-60 cells and suggest that it could help develop promising therapeutic agents for the treatment of acute myeloid leukemia.
- Published
- 2020
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40. A loop involving NRF2, miR-29b-1-5p and AKT, regulates cell fate of MDA-MB-231 triple-negative breast cancer cells.
- Author
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De Blasio A, Di Fiore R, Pratelli G, Drago-Ferrante R, Saliba C, Baldacchino S, Grech G, Scerri C, Vento R, and Tesoriere G
- Subjects
- Cell Line, Tumor, Cell Proliferation genetics, Cyclin D2 metabolism, DNA (Cytosine-5-)-Methyltransferase 1 metabolism, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation genetics, DNA Methyltransferase 3A, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Reactive Oxygen Species metabolism, Sesquiterpenes pharmacology, Signal Transduction genetics, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms pathology, Tumor Suppressor Proteins metabolism, DNA Methyltransferase 3B, MicroRNAs genetics, NF-E2-Related Factor 2 genetics, Proto-Oncogene Proteins c-akt genetics, Triple Negative Breast Neoplasms genetics
- Abstract
The present study shows that nuclear factor erythroid 2-related factor 2 (NRF2) and miR-29b-1-5p are two opposite forces which could regulate the fate of MDA-MB-231 cells, the most studied triple-negative breast cancer (TNBC) cell line. We show that NRF2 activation stimulates cell growth and markedly reduces reactive oxygen species (ROS) generation, whereas miR-29b-1-5p overexpression increases ROS generation and reduces cell proliferation. Moreover, NRF2 downregulates miR-29b-1-5p expression, whereas miR-29b-1-5p overexpression decreases p-AKT and p-NRF2. Furthermore, miR-29b-1-5p overexpression induces both inhibition of DNA N-methyltransferases (DNMT1, DNMT3A, and DNMT3B) expression and re-expression of HIN1, RASSF1A and CCND2. Conversely, NRF2 activation induces opposite effects. We also show that parthenolide, a naturally occurring small molecule, induces the expression of miR-29b-1-5p which could suppress NRF2 activation via AKT inhibition. Overall, this study uncovers a novel NRF2/miR-29b-1-5p/AKT regulatory loop that can regulate the fate (life/death) of MDA-MB-231 cells and suggests this loop as therapeutic target for TNBC., (© 2019 Wiley Periodicals, Inc.)
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- 2020
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41. Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels.
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De Blasio A, Pratelli G, Drago-Ferrante R, Saliba C, Baldacchino S, Grech G, Tesoriere G, Scerri C, Vento R, and Di Fiore R
- Subjects
- Apoptosis drug effects, Biomarkers, Tumor metabolism, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Shape drug effects, Cell Survival drug effects, Gene Expression Regulation, Neoplastic drug effects, Gene Silencing drug effects, Humans, Indoles pharmacology, Membrane Potential, Mitochondrial drug effects, Sulfonamides pharmacology, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Recombinant Proteins pharmacology, TNF-Related Apoptosis-Inducing Ligand pharmacology
- Abstract
Triple-negative breast cancer (TNBC) is a form of BC characterized by high aggressiveness and therapy resistance probably determined by cancer stem cells. MCL1 is an antiapoptotic Bcl-2 family member that could limit the efficacy of anticancer agents as recombinant human tumor necrosis factor related apoptosis-inducing ligand (rh-TRAIL). Here, we investigated MCL1 expression in TNBC tissues and cells. We found MCL1 differentially expressed (upregulated or downregulated) in TNBC tissues. Furthermore, in comparison to the human mammary epithelial cells, we found that MDA-MB-231 cells show similar messenger RNA levels but higher MCL1 protein levels, whereas it resulted downregulated in MDA-MB-436 and BT-20 cells. We evaluated the effects of rh-TRAIL and A-1210477, a selective MCL1 inhibitor, on cell viability and growth of MDA-MB-231 cells. We demonstrated that the drug combination reduced the cell growth and activated the apoptotic pathway. Similar effects were observed on three-dimensional cultures and tertiary mammospheres of MDA-MB-231 cells. In MDA-MB-231 cells, after MCL1 silencing, rh-TRAIL confined the cell population in the sub-G0/G1 phase and induced a drop in the mitochondrial transmembrane potential. To understand the molecular mechanism by which the loss of MCL1 function sensitizes the MDA-MB-231 cells to rh-TRAIL, we analyzed by real-time reverse transcription polymerase chain reaction, the expression of genes related to apoptosis, stemness, cell cycle, and those involved in epigenetic regulation. Interestingly, among the upregulated genes through MCL1 silencing or inhibition, there was TNFRSF10A (DR4). Moreover, MCL1 inhibition increased DR4 protein levels and its cell surface expression. Finally, we demonstrated MCL1-DR4 interaction and dissociation of this complex after A-1210477 treatment. Overall, our findings highlight the potential MCL1-roles in MDA-MB-231 cells and suggest that MCL1 targeting could be an effective strategy to overcome TNBC's rh-TRAIL resistance., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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42. Mcl-1 targeting could be an intriguing perspective to cure cancer.
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De Blasio A, Vento R, and Di Fiore R
- Subjects
- Apoptosis genetics, Cellular Senescence genetics, Gene Expression Regulation, Neoplastic genetics, Humans, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein therapeutic use, Neoplasms therapy, Protein Processing, Post-Translational genetics, Proto-Oncogene Proteins c-bcl-2 genetics, Carcinogenesis genetics, Molecular Targeted Therapy, Myeloid Cell Leukemia Sequence 1 Protein genetics, Neoplasms genetics
- Abstract
The Bcl-2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl-1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl-2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl-1 expression is regulated independent of Bcl-2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy is apoptosis. Mcl-1 is a potent oncogene that is regulated at the transcriptional, posttranscriptional, and posttranslational levels. Mcl-1 is a short-lived protein that, in the NH2 terminal region, contains sites for posttranslational regulation that can lead to proteasomal degradation. The USP9X Mcl-1 deubiquitinase regulates Mcl-1 and the levels of these two proteins are strongly correlated. Mcl-1 has three splicing variants (the antiapoptotic protein Mcl-1L and the proapoptotic proteins Mcl-1S and Mcl-1ES), each contributing toward apoptosis regulation. In cancers responsible for the most deaths in the world, the presence of Mcl-1 is associated with malignant cell growth and evasion of apoptosis. Mcl-1 is also one of the key regulators of cancer stem cells' self-renewal that contributes to tumor survival. A great number of indirect and selective Mcl-1 inhibitors have been produced and some of these have shown efficacy in several clinical trials. Thus, therapeutic manipulation of Mcl-1 can be a useful strategy to combat cancer., (© 2018 Wiley Periodicals, Inc.)
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- 2018
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43. Parthenolide prevents resistance of MDA-MB231 cells to doxorubicin and mitoxantrone: the role of Nrf2.
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Carlisi D, De Blasio A, Drago-Ferrante R, Di Fiore R, Buttitta G, Morreale M, Scerri C, Vento R, and Tesoriere G
- Abstract
Triple-negative breast cancer is a group of aggressive cancers with poor prognosis owing to chemoresistance, recurrence and metastasis. New strategies are required that could reduce chemoresistance and increases the effectiveness of chemotherapy. The results presented in this paper, showing that parthenolide (PN) prevents drug resistance in MDA-MB231 cells, represent a contribution to one of these possible strategies. MDA-MB231 cells, the most studied line of TNBC cells, were submitted to selection treatment with mitoxantrone (Mitox) and doxorubicin (DOX). The presence of resistant cells was confirmed through the measurement of the resistance index. Cells submitted to this treatment exhibited a remarkable increment of NF-E2-related factor 2 (Nrf2) level, which was accompanied by upregulation of catalase, MnSOD, HSP70, Bcl-2 and P-glycoprotein. Moreover, as a consequence of overexpression of Nrf2 and correlated proteins, drug-treated cells exhibited a much lower ability than parental cells to generate ROS in response to a suitable stimulation. The addition of PN (2.0 μ M) to Mitox and DOX, over the total selection time, prevented both the induction of resistance and the overexpression of Nrf2 and correlated proteins, whereas the cells showed a good ability to generate ROS in response to adequate stimulation. To demonstrate that Nrf2 exerted a crucial role in the induction of resistance, the cells were transiently transfected with a specific small interfering RNA for Nrf2. Similarly to the effects induced by PN, downregulation of Nrf2 was accompanied by reductions in the levels of catalase, MnSOD, HSP70 and Bcl-2, prevention of chemoresistance and increased ability to generate ROS under stimulation. In conclusion, our results show that PN inhibited the development of the resistance toward Mitox and DOX, and suggest that these effects were correlated with the prevention of the overexpression of Nrf2 and its target proteins, which occurred in the cells submitted to drug treatment., Competing Interests: The authors declare no conflict of interest.
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- 2017
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44. Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation.
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Drago-Ferrante R, Pentimalli F, Carlisi D, De Blasio A, Saliba C, Baldacchino S, Degaetano J, Debono J, Caruana-Dingli G, Grech G, Scerri C, Tesoriere G, Giordano A, Vento R, and Di Fiore R
- Subjects
- Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Agents, Phytogenic therapeutic use, Breast pathology, Carcinogenesis genetics, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, Down-Regulation, Drug Resistance, Neoplasm genetics, Female, Humans, MicroRNAs genetics, Microtubule-Associated Proteins metabolism, Nanog Homeobox Protein metabolism, Neoplasm Invasiveness genetics, Neoplastic Stem Cells metabolism, Octamer Transcription Factor-3 metabolism, Paclitaxel pharmacology, Paclitaxel therapeutic use, Phosphoproteins metabolism, SOXB1 Transcription Factors metabolism, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms pathology, Cell Cycle Proteins genetics, Gene Expression Regulation, Neoplastic, MicroRNAs metabolism, Microtubule-Associated Proteins genetics, Phosphoproteins genetics, Signal Transduction genetics, Triple Negative Breast Neoplasms genetics
- Abstract
MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR-29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/βcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b-1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR-29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC.
- Published
- 2017
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45. Let-7d miRNA Shows Both Antioncogenic and Oncogenic Functions in Osteosarcoma-Derived 3AB-OS Cancer Stem Cells.
- Author
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Di Fiore R, Drago-Ferrante R, Pentimalli F, Di Marzo D, Forte IM, Carlisi D, De Blasio A, Tesoriere G, Giordano A, and Vento R
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, Bone Neoplasms drug therapy, Bone Neoplasms genetics, Bone Neoplasms pathology, Cell Cycle, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Movement, Cell Self Renewal, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs genetics, Neoplasm Invasiveness, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Osteosarcoma drug therapy, Osteosarcoma genetics, Osteosarcoma pathology, Phenotype, Signal Transduction, Time Factors, Transcription Factors genetics, Transcription Factors metabolism, Transfection, Bone Neoplasms metabolism, MicroRNAs metabolism, Neoplastic Stem Cells metabolism, Osteosarcoma metabolism
- Abstract
Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B, and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. J. Cell. Physiol. 231: 1832-1841, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2016
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46. Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231.
- Author
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De Blasio A, Di Fiore R, Morreale M, Carlisi D, Drago-Ferrante R, Montalbano M, Scerri C, Tesoriere G, and Vento R
- Subjects
- Caspase 8 genetics, Cell Cycle physiology, Cell Line, Tumor, Down-Regulation, Female, G1 Phase physiology, Humans, Kruppel-Like Factor 4, RNA, Small Interfering administration & dosage, RNA, Small Interfering genetics, Resting Phase, Cell Cycle physiology, Transfection, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Caspase 8 metabolism, Triple Negative Breast Neoplasms enzymology
- Abstract
Triple-negative breast cancer (TNBC) is a clinically aggressive form of breast cancer that is unresponsive to endocrine agents or trastuzumab. TNBC accounts for ~10-20% of all breast cancer cases and represents the form with the poorest prognosis. Patients with TNBC are at higher risk of early recurrence, mainly in the lungs, brain and soft tissue, therefore, there is an urgent need for new therapies. The present study was carried out in MDA-MB-231 cells, where we assessed the role of caspase-8 (casp-8), a critical effector of death receptors, also involved in non‑apoptotic functions. Analysis of casp-8 mRNA and protein levels indicated that they were up-regulated with respect to the normal human mammalian epithelial cells. We demonstrated that silencing of casp-8 by small interfering-RNA, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypo-phosphorylated/active form of pRb levels. Surprisingly, casp-8-knockdown, also potently increased both the migratory and metastatic capacity of MDA-MB‑231 cells, as shown by both wound healing and Matrigel assay, and by the expression of a number of related-genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2. Among these, KLF4, a transcriptional factor with a dual role (activator and repressor), seemed to play critical roles. We suggest that in MDA-MB‑231 cells, the endogenous expression of casp-8 might keep the cells perpetually cycling through downregulation of KLF4, the subsequent lowering of p21 and p27, and the inactivation by hyperphosphorylation of pRb. Simultaneously, by lowering the expression of some migratory and invasive genes, casp-8 might restrain the metastatic ability of the cells. Overall, our findings showed that, in MDA-MB-231 cells, casp-8 might play some unusual roles which should be better explored, in order to understand whether it might be identified as a molecular therapeutic target.
- Published
- 2016
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47. Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression.
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Nahta R, Al-Mulla F, Al-Temaimi R, Amedei A, Andrade-Vieira R, Bay SN, Brown DG, Calaf GM, Castellino RC, Cohen-Solal KA, Colacci A, Cruickshanks N, Dent P, Di Fiore R, Forte S, Goldberg GS, Hamid RA, Krishnan H, Laird DW, Lasfar A, Marignani PA, Memeo L, Mondello C, Naus CC, Ponce-Cusi R, Raju J, Roy D, Roy R, Ryan EP, Salem HK, Scovassi AI, Singh N, Vaccari M, Vento R, Vondráček J, Wade M, Woodrick J, and Bisson WH
- Subjects
- Animals, Humans, Signal Transduction drug effects, Environmental Exposure adverse effects, Hazardous Substances adverse effects, Neoplasms chemically induced, Neoplasms etiology
- Abstract
As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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48. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.
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Goodson WH 3rd, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci A, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams G, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi AI, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP Sr, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D'Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, Manjili MH, Lleonart ME, Xia M, Gonzalez MJ, Karamouzis MV, Kirsch-Volders M, Vaccari M, Kuemmerle NB, Singh N, Cruickshanks N, Kleinstreuer N, van Larebeke N, Ahmed N, Ogunkua O, Krishnakumar PK, Vadgama P, Marignani PA, Ghosh PM, Ostrosky-Wegman P, Thompson PA, Dent P, Heneberg P, Darbre P, Sing Leung P, Nangia-Makker P, Cheng QS, Robey RB, Al-Temaimi R, Roy R, Andrade-Vieira R, Sinha RK, Mehta R, Vento R, Di Fiore R, Ponce-Cusi R, Dornetshuber-Fleiss R, Nahta R, Castellino RC, Palorini R, Abd Hamid R, Langie SA, Eltom SE, Brooks SA, Ryeom S, Wise SS, Bay SN, Harris SA, Papagerakis S, Romano S, Pavanello S, Eriksson S, Forte S, Casey SC, Luanpitpong S, Lee TJ, Otsuki T, Chen T, Massfelder T, Sanderson T, Guarnieri T, Hultman T, Dormoy V, Odero-Marah V, Sabbisetti V, Maguer-Satta V, Rathmell WK, Engström W, Decker WK, Bisson WH, Rojanasakul Y, Luqmani Y, Chen Z, and Hu Z
- Subjects
- Animals, Humans, Carcinogenesis chemically induced, Carcinogens, Environmental adverse effects, Environmental Exposure adverse effects, Hazardous Substances adverse effects, Neoplasms chemically induced, Neoplasms etiology
- Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology., (© The Author 2015. Published by Oxford University Press.)
- Published
- 2015
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49. A novel polymorphism in the PAI-1 gene promoter enhances gene expression. A novel pro-thrombotic risk factor?
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Liguori R, Quaranta S, Di Fiore R, Elce A, Castaldo G, and Amato F
- Subjects
- Adult, Base Sequence, Female, Humans, Molecular Sequence Data, Mutation genetics, Risk Factors, Gene Expression Regulation genetics, Genetic Predisposition to Disease genetics, Plasminogen Activator Inhibitor 1 genetics, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Thrombosis genetics
- Abstract
Introduction: Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of tissue-type plasminogen activator in plasma and the most important regulator of the fibrinolytic pathway. The 4G/5G polymorphism (rs1799889) in the PAI-1 promoter is associated with altered PAI-1 transcription. We have identified a new 4G/5G allele, in which a T is inserted near the 4G tract or replaces a G in the 5G tract, forming a T plus 4G (T4G) region., Materials and Methods: This new variant was first identified in two women, one had experienced juvenile myocardial infarction, the other repeated miscarriage; both had increased PAI-1 plasma activity. In view of the important influence of this promoter region on PAI-1 protein plasma level, we performed in vitro evaluation of the effects of the T4G variant on the transcription activity of the PAI-1 gene promoter., Results and Conclusions: In silico prediction analysis showed that presence of the T4G allele disrupts the E-Box region upstream of the T4G variant, altering the affinity of the target sequence for E-Box binding factors like upstream stimulatory factor-1 (USF-1). Basal T4G promoter activity was 50% higher compared to 4G and 5G variants, but it was less stimulated by USF-1 overexpression. We also analyzed the effects of IL-1β and IL-6 on the PAI-1 promoter activity of our three constructs and showed that the T4G variant was less affected by IL-1β than the other variants. These findings indicate that the T4G variant may be a novel risk factor for thrombotic events., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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50. MicroRNA-29b-1 impairs in vitro cell proliferation, self‑renewal and chemoresistance of human osteosarcoma 3AB-OS cancer stem cells.
- Author
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Di Fiore R, Drago-Ferrante R, Pentimalli F, Di Marzo D, Forte IM, D'Anneo A, Carlisi D, De Blasio A, Giuliano M, Tesoriere G, Giordano A, and Vento R
- Subjects
- Bone Neoplasms pathology, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation genetics, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs genetics, Neoplasm Invasiveness genetics, Osteosarcoma pathology, Bone Neoplasms genetics, Drug Resistance, Neoplasm genetics, MicroRNAs biosynthesis, Osteosarcoma genetics
- Abstract
Osteosarcoma (OS) is the most common type of bone cancer, with a peak incidence in the early childhood. Emerging evidence suggests that treatments targeting cancer stem cells (CSCs) within a tumor can halt cancer and improve patient survival. MicroRNAs (miRNAs) have been implicated in the maintenance of the CSC phenotype, thus, identification of CSC-related miRNAs would provide information for a better understanding of CSCs. Downregulation of miRNA-29 family members (miR-29a/b/c; miR‑29s) was observed in human OS, however, little is known about the functions of miR-29s in human OS CSCs. Previously, during the characterization of 3AB-OS cells, a CSC line selected from human OS MG63 cells, we showed a potent downregulation of miR-29b. In this study, after stable transfection of 3AB-OS cells with miR-29b-1, we investigated the role of miR-29b-1 in regulating cell proliferation, sarcosphere-forming ability, clonogenic growth, chemosensitivity, migration and invasive ability of 3AB-OS cells, in vitro. We found that, miR-29b-1 overexpression consistently reduced both, 3AB-OS CSCs growth in two- and three-dimensional culture systems and their sarcosphere- and colony-forming ability. In addition, while miR-29b-1 overexpression sensitized 3AB-OS cells to chemotherapeutic drug-induced apoptosis, it did not influence their migratory and invasive capacities, thus suggesting a context-depending role of miR-29b-1. Using publicly available databases, we proceeded to identify potential miR-29b target genes, known to play a role in the above reported functions. Among these targets we analyzed CD133, N-Myc, CCND2, E2F1 and E2F2, Bcl-2 and IAP-2. We also analyzed the most important stemness markers as Oct3/4, Sox2 and Nanog. Real-time RT-PCR and western-blot analyses showed that miR-29b-1 negatively regulated the expression of these markers. Overall, the results show that miR-29b-1 suppresses stemness properties of 3AB-OS CSCs and suggest that developing miR-29b-1 as a novel therapeutic agent might offer benefits for OS treatment.
- Published
- 2014
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