40 results on '"Mottolese, Marcella"'
Search Results
2. Additional file 6 of TRF2 and VEGF-A: an unknown relationship with prognostic impact on survival of colorectal cancer patients
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Dinami, Roberto, Porru, Manuela, Amoreo, Carla Azzurra, Sperduti, Isabella, Mottolese, Marcella, Buglioni, Simonetta, Marinelli, Daniele, Maugeri-Saccà, Marcello, Sacconi, Andrea, Blandino, Giovanni, Leonetti, Carlo, Rocco, Giuliana Di, Verdina, Alessandra, Spinella, Francesca, Fiorentino, Francesco, Ciliberto, Gennaro, Biroccio, Annamaria, and Zizza, Pasquale
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Additional file 6:Supplementary Table S6. Combinatorial levels of TRF2 and VEGF-A evaluated on staged CRC patients
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- 2020
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3. Additional file 1 of TRF2 and VEGF-A: an unknown relationship with prognostic impact on survival of colorectal cancer patients
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Dinami, Roberto, Porru, Manuela, Amoreo, Carla Azzurra, Sperduti, Isabella, Mottolese, Marcella, Buglioni, Simonetta, Marinelli, Daniele, Maugeri-Saccà, Marcello, Sacconi, Andrea, Blandino, Giovanni, Leonetti, Carlo, Rocco, Giuliana Di, Verdina, Alessandra, Spinella, Francesca, Fiorentino, Francesco, Ciliberto, Gennaro, Biroccio, Annamaria, and Zizza, Pasquale
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Additional file 1:Supplementary Table S1. Type of adjuvant therapy administered to patients
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- 2020
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4. Additional file 4 of TRF2 and VEGF-A: an unknown relationship with prognostic impact on survival of colorectal cancer patients
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Dinami, Roberto, Porru, Manuela, Amoreo, Carla Azzurra, Sperduti, Isabella, Mottolese, Marcella, Buglioni, Simonetta, Marinelli, Daniele, Maugeri-Saccà, Marcello, Sacconi, Andrea, Blandino, Giovanni, Leonetti, Carlo, Rocco, Giuliana Di, Verdina, Alessandra, Spinella, Francesca, Fiorentino, Francesco, Ciliberto, Gennaro, Biroccio, Annamaria, and Zizza, Pasquale
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Additional file 4:Supplementary Table S4. Levels of TRF2 evaluated on staged CRC patients
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- 2020
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5. Additional file 1: of PLC-gamma-1 phosphorylation status is prognostic of metastatic risk in patients with early-stage Luminal-A and -B breast cancer subtypes
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Lattanzio, Rossano, Iezzi, Manuela, Sala, Gianluca, Tinari, Nicola, Falasca, Marco, Alberti, Saverio, Buglioni, Simonetta, Mottolese, Marcella, Perracchio, Letizia, Natali, Pier, and Piantelli, Mauro
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Table S1. Multivariate analyses of PLCγ1, PLCγ1-pY1253 and PLCγ1-pY783 expression in all cases (n = 414). Table S2. Multivariate analyses of PLCγ1-pY1253, pY783 and PLCγ1 expression in Luminal-A and Luminal-B subtypes. Table S3. PLCγ1-pY1253 and PLCγ1-pY783 expression in Luminal-A (LA) and Luminal-B (LB) subtypes according to menopausal status: multivariate analyses. (DOCX 49 kb)
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- 2019
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6. Additional file 2: of PLC-gamma-1 phosphorylation status is prognostic of metastatic risk in patients with early-stage Luminal-A and -B breast cancer subtypes
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Lattanzio, Rossano, Iezzi, Manuela, Sala, Gianluca, Tinari, Nicola, Falasca, Marco, Alberti, Saverio, Buglioni, Simonetta, Mottolese, Marcella, Perracchio, Letizia, Natali, Pier, and Piantelli, Mauro
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Figure S1. Immunoreactivity for PLCγ1, PLCγ1-pY1253 and PLCγ1-pY783 in wild-type (wt) and down-regulated (si) MDA-MB-231 breast cancer cells. Figure S2. All patients (n = 414): Kaplan-Meier estimates of DFS, LRFS, and DRFS according to high (solid green lines) and low (dashed blue lines) expression of PLCγ1, PLCγ1-pY1253 and PLCγ1-pY783; Figure S3. Patients with HER2 positive breast cancer subtype (n = 27): Kaplan-Meier estimates of DFS, LRFS, and DRFS according to high (solid green lines) and low (dashed blue lines) expression of PLCγ1, PLCγ1-pY1253 and PLCγ1-pY783. Figure S4. Patients with Triple Negative breast cancer subtype (n = 55): Kaplan-Meier estimates of DFS, LRFS, and DRFS according to high (solid green lines) and low (dashed blue lines) expression of PLCγ1, PLCγ1-pY1253 and PLCγ1-pY783. Figure S5. GOBO (Gene expression-based Outcome for Breast cancer Online) database (http://co.bmc.lu.se/gobo): Kaplan-Meier plot of DFS (A) and multivariate (B) analyses of PLCG1 transcript expression in lymph-node-negative HU-Luminal A tumours (n = 184). Red and grey lines represent tumours expressing high and low PLCG1 mRNA levels, respectively. Figure S6. KM-Plotter microarray database (http://kmplot.com/analysis/index.php?p=service&cancer=breast): Kaplan-Meier plot of distant metastasis-free survival (DMFS) of PLCG1 transcript expression in Luminal-A lymph-node negative breast cancer patients (n = 546). Red and black lines represent tumours expressing high and low PLCG1 mRNA levels, respectively. (PPTX 1483 kb)
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- 2019
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7. Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma
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Fianco, Giulia, Mongiardi, Maria Patrizia, Levi, Andrea, Luca, Teresa De, Desideri, Marianna, Trisciuoglio, Daniela, Bufalo, Donatella Del, Cinà, Irene, Benedetto, Anna Di, Mottolese, Marcella, Gentile, Antonietta, Centonze, Diego, Ferrè, Fabrizio, Barilà, Daniela, Fianco, Giulia, Mongiardi, Maria Patrizia, Levi, Andrea, Luca, Teresa De, Desideri, Marianna, Trisciuoglio, Daniela, Bufalo, Donatella Del, Cinã , Irene, Benedetto, Anna Di, Mottolese, Marcella, Gentile, Antonietta, Centonze, Diego, Ferrè, Fabrizio, and Barilà , Daniela
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Vascular Endothelial Growth Factor A ,0301 basic medicine ,Angiogenesis ,Immunology and Microbiology (all) ,Neovascularization ,angiogenesis ,cell biology ,Biology (General) ,cancer biology ,Caspase 8 ,Neovascularization, Pathologic ,General Neuroscience ,NF-kappa B ,General Medicine ,Prognosis ,Vascular endothelial growth factor A ,cell death ,Cytokines ,Medicine ,Settore MED/26 - Neurologia ,medicine.symptom ,signal transduction ,medicine.drug ,QH301-705.5 ,Science ,Short Report ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,Humans ,cancer ,Neoplastic transformation ,human ,mouse ,Temozolomide ,Neuroscience (all) ,Biochemistry, Genetics and Molecular Biology (all) ,General Immunology and Microbiology ,Microarray analysis techniques ,Gene Expression Profiling ,Cancer ,angiogenesi ,Microarray Analysis ,medicine.disease ,Gene expression profiling ,Settore BIO/18 - Genetica ,cell proliferation ,030104 developmental biology ,Drug Resistance, Neoplasm ,Immunology ,Cancer research ,Glioblastoma - Abstract
Caspase-8 is a key player in extrinsic apoptosis and its activity is often downregulated in cancer. However, human Caspase-8 expression is retained in some tumors, including glioblastoma (GBM), suggesting that it may support cancer growth in these contexts. GBM, the most aggressive of the gliomas, is characterized by extensive angiogenesis and by an inflammatory microenvironment that support its development and resistance to therapies. We have recently shown that Caspase-8 sustains neoplastic transformation in vitro in human GBM cell lines. Here, we demonstrate that Caspase-8, through activation of NF-kB, enhances the expression and secretion of VEGF, IL-6, IL-8, IL-1beta and MCP-1, leading to neovascularization and increased resistance to Temozolomide. Importantly, the bioinformatics analysis of microarray gene expression data derived from a set of high-grade human gliomas, shows that high Caspase-8 expression levels correlate with a worse prognosis. DOI: http://dx.doi.org/10.7554/eLife.22593.001, eLife digest Cancer cells are different to normal cells in various ways. Most cancer cells, for example, delete or switch off the gene for a protein called Caspase-8. This is because this protein is best known for promoting cell death and stopping tumor cells from growing. However, some cancers keep the gene for Caspase-8 switched on including glioblastoma, the most aggressive type of brain cancer in adults. This begged the question whether this protein may in fact promote the development of tumors under certain circumstances. Glioblastomas are often highly resistant to chemotherapy and can communicate with nearby cells using proteins called cytokines to promote the formation of new blood vessels. The new blood vessel allows the tumor to readily spread into healthy brain tissue, which in turn makes it difficult for surgeons to remove all the cancerous cells. As a result, glioblastomas almost always return after surgery, and so there is strong need for new effective treatments for this type of cancer. Fianco et al. have now investigated whether Caspase-8 helps glioblastomas to grow and form new blood vessels. One common method to study human cancer cells is to inject them into mice and watch how they grow, because these experiments mimic how tumors develop in the human body. When mice were injected with human glioblastoma cells with experimentally reduced levels of Caspase-8, the cells grew poorly and did not form as many new blood vessels as unaltered glioblastoma cells. Further experiments showed that, when grown in the laboratory, glioblastoma cells with less Caspase-8 were more sensitive to a chemotherapeutic drug called temozolomide. These findings confirm that Caspase-8 does boost the growth and drug resistance of at least one cancer. When Fianco et al. analyzed clinical data from patients affected by glioblastoma, they also observed that those patients with high levels of Caspase-8 often had the worse outcomes. Previous studies conducted in white blood cells showed that Caspase-8 activated a protein complex called NF-kB, which in turn led to the cells releasing cytokines. Fianco et al. have now verified that Caspase-8 promotes NF-kB activity also in glioblastoma cells, and that this causes the cancer cells to release more cytokines. As such, these findings reveal a clear link between Caspase-8 and the formation of new blood vessels by glioblastomas. Future studies are now needed to understand why Caspase-8 promotes cell death in some cancers but the formation of new blood vessels in others. Indeed, Caspase-8 might become a target for new anticancer drugs if it is possible to inhibit its cancer-boosting activity without interfering with its ability to promote cell death. DOI: http://dx.doi.org/10.7554/eLife.22593.002
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- 2017
8. MOESM2 of Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
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Melucci, Elisa, Casini, Beatrice, Ronchetti, Livia, Pizzuti, Laura, Sperati, Francesca, Pallocca, Matteo, Nicola, Francesca De, Goeman, Frauke, Gallo, Enzo, Amoreo, Carla, Sergi, Domenico, Terrenato, Irene, Vici, Patrizia, Lauro, Luigi Di, Diodoro, Maria, Pescarmona, Edoardo, Barba, Maddalena, Mazzotta, Marco, Mottolese, Marcella, Fanciulli, Maurizio, Ciliberto, Gennaro, Maria, Ruggero De, Buglioni, Simonetta, and Maugeri-SaccĂ, Marcello
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Additional file 2. Representative examples of immunohistochemical expression of TAZ and YAP in gastric cancer. Two cases are presented with combined nuclear expression of both TAZ and YAP (Aâ D).
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- 2018
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9. Additional file 4: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Table S2 Predictive power of ID4, CD68 and the macrophage signature (MacSig) comprising eight widely used markers (CD14, CD105, CD11b, CD68, CD93, CD33, IL4R, CD163) for the mononuclear phagocyte system [37]. Analysis was performed using datasets deposited in the KMplot database [36]. DMFS Distant metastasis-free survival, OS Overall survival. (DOCX 21 kb)
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- 2018
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10. Additional file 5: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Table S3 mRNAs modulated in an ID4-dependent manner in differentiated HL60 cells cultured with conditioned medium from control (CM EV) or ID4-overexpressing (CM ID4) MDA-MB-468 cells. The presence of HIF-1 consensus sequences on promoters was evaluated using the LASAGNA-Search web tool (http://biogrid-lasagna.engr.uconn.edu/lasagna_search/). The presence of putative binding sites for miR-107, miR-15b and miR-195 on 3′-UTR or coding (CDS) sequences of mRNAs was evaluated using the miRWalk analysis tool ( http://zmf.umm.uni-heidelberg.de/apps/zmf/mirwalk2/ ) by selecting the following databases: (1) 3′-UTR analysis = miRWalk, miRanda, miRDB, miRNAMap, Pictar2, RNA22, RNAhybrid, TargetScan; and (2) CDS analysis = miRWalk, miRanda, RNA22, RNAhybrid, TargetScan. (DOCX 22 kb)
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- 2018
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11. Additional file 9: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Figure S6 Differentiated U937 cells transfected with an empty vector (EV) or a granulin (GRN) expression vector and subsequently cultivated in the presence of CM from MDA-MB-468 cells were evaluated for their differentiation state (percentage of CD11b+ cells) (a) and for their viability (b) by, respectively, FACS analysis and ATPlite assay at the indicated time points after CM addition. c Overexpression of GRN evaluated by Western blotting. (PDF 141 kb)
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- 2018
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12. Additional file 9: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Figure S6 Differentiated U937 cells transfected with an empty vector (EV) or a granulin (GRN) expression vector and subsequently cultivated in the presence of CM from MDA-MB-468 cells were evaluated for their differentiation state (percentage of CD11b+ cells) (a) and for their viability (b) by, respectively, FACS analysis and ATPlite assay at the indicated time points after CM addition. c Overexpression of GRN evaluated by Western blotting. (PDF 141 kb)
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- 2018
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13. MOESM1 of Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
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Melucci, Elisa, Casini, Beatrice, Ronchetti, Livia, Pizzuti, Laura, Sperati, Francesca, Pallocca, Matteo, Nicola, Francesca De, Goeman, Frauke, Gallo, Enzo, Amoreo, Carla, Sergi, Domenico, Terrenato, Irene, Vici, Patrizia, Lauro, Luigi Di, Diodoro, Maria, Pescarmona, Edoardo, Barba, Maddalena, Mazzotta, Marco, Mottolese, Marcella, Fanciulli, Maurizio, Ciliberto, Gennaro, Maria, Ruggero De, Buglioni, Simonetta, and Maugeri-SaccĂ, Marcello
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Additional file 1. First-line chemotherapy regimens and schedules (NÂ =Â 86).
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- 2018
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14. Additional file 6: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Figure S2. Predictive power of ID4 mRNA expression for overall survival (OS) was evaluated by Kaplan-Meier analysis on the TCGA cohort in BLBCs showing high or low CD68 (a and b) or macrophage signature (MacSig) (c and d) levels. Macrophage signature is composed of eight widely used markers for the mononuclear phagocyte system (CD14, CD105, CD11b, CD68, CD93, CD33, IL4R and CD163 [37]). e Evaluation of association between ID4 or CD68 and the pathological variables T, N, G and TP53 status in the BLBCs from the TCGA cohort. (PDF 4464 kb)
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- 2018
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15. Additional file 1: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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fungi - Abstract
Figure S3 Growth curve of MDA-MB-468 cells depleted (si-ID4) or not (si-SCR) of ID4 expression by siRNA transfection (a). Cells were transfected for 16Â hours, and then equal numbers of cells were plated and counted at the indicated time points. Efficiency of ID4 depletion at 48Â hours and 72Â hours was evaluated by Western blotting (b). (PDF 4554 kb)
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- 2018
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16. Additional file 3: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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skin and connective tissue diseases - Abstract
Figure S1. Comparison of ID4 mRNA expression in basal-like breast cancer (BLBC) and triple-negative breast cancer (TNBC) versus all other breast cancer subtypes (Others) in the indicated representative datasets [19, 22, 60]. (PDF 143 kb)
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- 2018
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17. Additional file 7: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Figure S4 a Modulation of selected genes modulated in the TLDA was validated by RT-qPCR in differentiated HL60 cells cultured in CM from ID4-overexpressing (CM ID4-HA) or control (CM EV) MDA-MB-468 cells (left panel). The same transcripts were analysed in MDA-MB-468 cells transfected with ID4-HA expression vector (ID4-HA) or control empty vector (EV) (right panel). b Expression of EphB2, MDK and GRN protein evaluated by Western blotting on lysates from differentiated HL60 cells cultured as in (a); secreted GRN (sGRN) was evaluated on CM from differentiated HL60 cells in the same conditions. c HIF1A protein expression evaluated by Western blotting in differentiated U937 cells cultured in RPMI medium or in CM from SKBR3 cells stably interfered for ID4 expression (sh-ID4) or control cells (sh-CTR). (PDF 1320 kb)
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- 2018
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18. Additional file 6: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Figure S2. Predictive power of ID4 mRNA expression for overall survival (OS) was evaluated by Kaplan-Meier analysis on the TCGA cohort in BLBCs showing high or low CD68 (a and b) or macrophage signature (MacSig) (c and d) levels. Macrophage signature is composed of eight widely used markers for the mononuclear phagocyte system (CD14, CD105, CD11b, CD68, CD93, CD33, IL4R and CD163 [37]). e Evaluation of association between ID4 or CD68 and the pathological variables T, N, G and TP53 status in the BLBCs from the TCGA cohort. (PDF 4464 kb)
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- 2018
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19. Additional file 8: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Figure S5 a Expression of miR-107, miR-15b and miR-195 in differentiated HL60 cells cultured with CM from control (CM EV) or ID4-overexpressing (CM ID4) MDA-MB-468 cells. bâ e Expression of miR-15b and miR-195 in HL60 and U937 cells cultured with CM from control (si-SCR) or ID4-depleted (si-ID4) BC cells. f miR-107, miR-15b and miR-195 expression evaluated by RT-qPCR in differentiated U937 cells cultured with CM from MDA-MB-468 cells depleted or not of VEGFA expression. VEGFA interference efficiency is shown in Fig. 3i. g Expression levels of miR-15b and miR-195 in differentiated U937 cells cultivated in RPMI medium (CTR) or CM from MDA-MB-468 cells for the indicated time points. h and i HIF1A mRNA (h) and protein (i) expression evaluated, respectively, by RT-qPCR and immunofluorescence in differentiated U937 cells transfected with control mimic or miR-107 mimic and cultured in the presence of CM from MDA-MB-468 cells for 48 hours. (PDF 2150 kb)
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- 2018
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20. Additional file 7: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Figure S4 a Modulation of selected genes modulated in the TLDA was validated by RT-qPCR in differentiated HL60 cells cultured in CM from ID4-overexpressing (CM ID4-HA) or control (CM EV) MDA-MB-468 cells (left panel). The same transcripts were analysed in MDA-MB-468 cells transfected with ID4-HA expression vector (ID4-HA) or control empty vector (EV) (right panel). b Expression of EphB2, MDK and GRN protein evaluated by Western blotting on lysates from differentiated HL60 cells cultured as in (a); secreted GRN (sGRN) was evaluated on CM from differentiated HL60 cells in the same conditions. c HIF1A protein expression evaluated by Western blotting in differentiated U937 cells cultured in RPMI medium or in CM from SKBR3 cells stably interfered for ID4 expression (sh-ID4) or control cells (sh-CTR). (PDF 1320 kb)
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- 2018
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21. The Dilemma of HER2 Double-equivocal Breast Carcinomas
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Marchio, Caterina, Dell'Orto, Patrizia, Annaratone, Anna, Geyer, Felipe, Venesio, Tiziana, Berrino, Enrico, Verdun di Cantogno, Ludovica, Garofoli, Andrea, Rangel, Nelson, Casorzo, Laura, dell'Aglio, Carmine, Gugliotta, Patrizia, Trisolini, Elena, Beano, Alessandra, Pietribiasi, Francesca, Orlassino, Renzo, Cassoni, Paola, Pich, Achille, Montemurro, Filippo, Mottolese, Marcella, Vincent-Salomon, Anne, Penault-Llorca, Frédérique, Medico, Enzo, Ng, Charlotte, Viale, Giuseppe, Sapino, Anna, Dell’Orto, Patrizia, dell’Aglio, Carmine, Ng, Charlotte K.Y., Breakthrough Breast Cancer Centre, London Institute of Cancer, Division of Pathology and Laboratory Medicine, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), Unit of Pathology, Università degli studi di Torino = University of Turin (UNITO), Department of Biomedical Sciences and Human Oncology, University of Turin Med. School, Pathology, Regina Elena Cancer Institute, Département de Pathologie, Institut Curie [Paris], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Oncological Sciences and Laboratory of Oncogenomics, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), Institute for Cancer Research (IRCC), University of Turin Med. School, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Torino (UNITO), and University of Turin
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Adult ,Receptor, ErbB-2 ,Gene Expression Profiling ,Carcinoma ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Original Articles ,Middle Aged ,molecular subtype ,mutations ,risk of recurrence ,HER2 ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Biomarkers, Tumor ,Humans ,Female ,breast carcinoma ,skin and connective tissue diseases ,equivocal result ,neoplasms - Abstract
Supplemental Digital Content is available in the text., The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines for HER2 assessment have increased the number of HER2 equivocal breast carcinomas following in situ hybridization reflex testing, that is, HER2 “double equivocal” (equivocal protein expression and equivocal gene copy number). Forty-five double-equivocal carcinomas were subjected to Prosigna analysis. Twenty-seven cases were investigated for the expression of genes found to be differentially expressed between estrogen receptor (ER)-positive/HER2-positive (N=22) and ER-positive/HER2-negative (N=22) control cases. Twenty-nine of the 45 cases were also analyzed by targeted sequencing using a panel of 14 genes. We then explored the pathologic complete response rates in an independent series of double-equivocal carcinoma patients treated with trastuzumab-containing chemotherapy. All cases were ER-positive, with a mean Ki67 of 28%. Double-equivocal carcinomas were predominantly luminal B (76%); 9 cases (20%) were luminal A, and 2 cases (4%) HER2-enriched. The majority (73%) showed a high risk of recurrence by Prosigna, even when the carcinomas were small (
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- 2018
22. Additional file 2: of Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages
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Donzelli, Sara, Milano, Elisa, Pruszko, Magdalena, Sacconi, Andrea, Masciarelli, Silvia, Iosue, Ilaria, Melucci, Elisa, Gallo, Enzo, Terrenato, Irene, Mottolese, Marcella, Zylicz, Maciej, Zylicz, Alicja, Fazi, Francesco, Blandino, Giovanni, and Fontemaggi, Giulia
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Table S1 Characteristics of patients selected for the analysis of ID4 protein expression. (DOCX 17 kb)
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- 2018
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23. DNA damage repair and survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
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Ronchetti, Livia, Melucci, Elisa, De Nicola, Francesca, Goeman, Frauke, Casini, Beatrice, Sperati, Francesca, Pallocca, Matteo, Terrenato, Irene, Pizzuti, Laura, Vici, Patrizia, Sergi, Domenico, Di Lauro, Luigi, Amoreo, Carla Azzurra, Gallo, Enzo, Diodoro, Maria Grazia, Pescarmona, Edoardo, Vitale, Ilio, Barba, Maddalena, Buglioni, Simonetta, Mottolese, Marcella, Fanciulli, Maurizio, De Maria Marchiano, Ruggero, and Maugeri-Saccà, Marcello
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Male ,Cancer Research ,DNA Repair ,γ-H2AX ,Antineoplastic Agents ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Disease-Free Survival ,Histones ,Settore MED/04 - PATOLOGIA GENERALE ,Stomach Neoplasms ,pATM ,Biomarkers, Tumor ,DNA damage repair ,Humans ,TP53 ,Aged ,Tumor ,Settore MED/06 - ONCOLOGIA MEDICA ,gastric cancer ,Stomach ,Middle Aged ,ARID1A ,DNA-Binding Proteins ,Oncology ,Gastric Mucosa ,Female ,Protein Kinases ,Biomarkers ,DNA Damage ,Signal Transduction - Abstract
The DNA damage response (DDR) network is exploited by cancer cells to withstand chemotherapy. Gastric cancer (GC) carries deregulation of the DDR and harbors genetic defects that fuel its activation. The ATM-Chk2 and ATR-Chk1-Wee1 axes are deputed to initiate DNA repair. Overactivation of these pathways in cancer cells may represent an adaptive response for compensating genetic defects deregulating G
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- 2016
24. Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer
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Corda, Gabriele, Sala, Gianluca, Lattanzio, Rossano, Iezzi, Manuela, Sallese, Michele, Fragassi, Giorgia, Lamolinara, Alessia, Mirza, Hasan, Barcaroli, Daniela, Ermler, Sibylle, Silva, Elisabete, Yasaei, Hemad, Newbold, Robert F., Vagnarelli, Paola, Mottolese, Marcella, Natali, Pier Giorgio, Perracchio, Letizia, Quist, Jelmar, Grigoriadis, Anita, Marra, Pierfrancesco, Tutt, Andrew N., Piantelli, Mauro, Iacobelli, Stefano, De Laurenzi, Vincenzo, and Sala, Arturo
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Original Paper ,actin cytoskeleton ,mouse model ,Breast Neoplasms ,Genomics ,Prognosis ,Original Papers ,Frizzled Receptors ,Cell Movement ,Cell Line, Tumor ,Humans ,metastasis ,Female ,Neoplasm Recurrence, Local ,xenograft ,Wnt signalling ,Signal Transduction - Abstract
Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple‐negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three‐dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6‐depleted, triple‐negative MDA‐MB‐231 cells rearranged the actin cytoskeleton and restored epidermal growth factor‐mediated invasion. In patients with localized, lymph node‐negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse‐free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6–fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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- 2016
25. Additional file 3: Table S3. of Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy
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Vici, Patrizia, Ercolani, Cristiana, Benedetto, Anna Di, Pizzuti, Laura, Lauro, Luigi Di, Sperati, Francesca, Terrenato, Irene, Gamucci, Teresa, Natoli, Clara, Filippo, Franco Di, Botti, Claudio, Barba, Maddalena, Mottolese, Marcella, Maria, Ruggero De, and Maugeri-SaccĂ, Marcello
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Pattern of recurrence in the 19 TNBC patients. (DOCX 12 kb)
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- 2016
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26. Additional file 1: Table S1. of Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy
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Vici, Patrizia, Ercolani, Cristiana, Benedetto, Anna Di, Pizzuti, Laura, Lauro, Luigi Di, Sperati, Francesca, Terrenato, Irene, Gamucci, Teresa, Natoli, Clara, Filippo, Franco Di, Botti, Claudio, Barba, Maddalena, Mottolese, Marcella, Maria, Ruggero De, and Maugeri-SaccĂ, Marcello
- Abstract
Expression of TAZ and YAP in cancer cells, non-lymphocytic stromal cells, endothelial cells, and tumor-infiltrating lymphocytes. Subcellular localization of TAZ/YAP in tumors is also reported (Nâ =â 61). (DOCX 13 kb)
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- 2016
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27. Additional file 2: Table S2. of Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy
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Vici, Patrizia, Ercolani, Cristiana, Benedetto, Anna Di, Pizzuti, Laura, Lauro, Luigi Di, Sperati, Francesca, Terrenato, Irene, Gamucci, Teresa, Natoli, Clara, Filippo, Franco Di, Botti, Claudio, Barba, Maddalena, Mottolese, Marcella, Maria, Ruggero De, and Maugeri-SaccĂ, Marcello
- Abstract
associations between TAZ/YAP, assessed in the tumor and in the microenvironment, and clinical-molecular features and pCR (Nâ =â 61). (DOCX 12 kb)
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- 2016
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28. Anthropometric, metabolic and molecular determinants of human epidermal growth factor receptor 2 expression in luminal B breast cancer
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Vici, Patrizia, Crispo, Anna, Giordano, Antonio, Lauro, Luigi Di, Sperati, Francesca, Terrenato, Irene, Pizzuti, Laura, Sergi, Domenico, Mottolese, Marcella, Botti, Claudio, Grimaldi, Maria, Capasso, Immacolata, D'Aiuto, Giuseppe, Bonito, Maurizio Di, Paola, Flaviano Di, Maugeri Saccà, Marcello, Montella, Maurizio, and Barba, Maddalena
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Adult ,Blood Glucose ,Anthropometry ,Physiology ,Receptor, ErbB-2 ,Medicine (all) ,Clinical Biochemistry ,Breast Neoplasms ,Cell Biology ,Middle Aged ,Estrogen ,Immunohistochemistry ,Body Mass Index ,ErbB-2 ,Receptors, Estrogen ,Receptors ,Humans ,Aged ,Female ,Receptor - Abstract
Genomic and trascriptomic profiling has recently contributed details to the characterization of luminal B breast cancer. We explored the contribution of anthropometric, metabolic, and molecular determinants to the multifaceted heterogeneity of this breast cancer subtype, with a specific focus on the association between body mass index (BMI), pre-treatment fasting glucose, hormone receptors, and expression of human epidermal growth factor receptor 2 (HER2). Extensively annotated specimens were obtained from 154 women with luminal B breast cancer diagnosed at two Italian comprehensive cancer centres. Participants' characteristics were descriptively analyzed overall and by HER2 status (positive vs. negative). BMI (25 vs ≥25), pre-treatment fasting glucose (median value of 94 mg/dl vs. ≥94) and percentage of hormone receptors were tested for association with HER2 expression in regression models. In univariate models, BMI, fasting glucose and, at a lesser extent, percentage of estrogen receptors (ER) were significantly and inversely associated with HER2 expression (OR: 0.32, 95% CI: 0.16-0.66; 0.43, 0.23-0.82; 0.96, 0.94-0.97, respectively). The multivariate models confirmed the protective role of BMI and ER on HER2 expression, with luminal B HER2 positive patients being significantly less frequent among women within the highest category of BMI and percentage expression of ER compared with their counterparts (OR: 0.22, 95% CI: 0.09-0.53; 0.95, 0.93-0.97). In conclusions, BMI and percentage of ER representation are inversely associated with HER2 expression in luminal B breast cancers. Upon confirmatory findings, this might help identify patient subgroups who may best benefit from the use of interventions targeting insulin resistance in well depicted breast cancer scenarios.
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- 2014
29. Prognostic Impact of Cytoskeleton Regulatory Protein Human Mena (hmena) Isoforms In Resected, Node-negative, Non-smallcell Lung Cancer: Validation of A Clinic-molecular Prognostic Model
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Bria, Emilio, Mottolese, Marcella, Francesca Di Modugno, Alessandrini, Gabriele, Ludovini, Vienna, Antoniani, Barbara, Iapicca, Pierluigi, Ceribelli, Anna, Sidoni, Angelo, Crino, Lucio, Cognetti, Francesco, Facciolo, Francesco, Visca, Paolo, Pilotto, Sara, Tortora, Giampaolo, Sperduti, Isabella, Milella, Michele, and Nistico, Paola
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- 2013
30. Deregulation of Aurora kinase gene expression in human testicular germ cell tumours
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Baldini, Enke, Arlot-Bonnemains, Yannick, Mottolese, Marcella, Sentinelli, Steno, Antoniani, Barbara, Sorrenti, Salvatore, Salducci, M., Comini, E., Ulisse, Salvatore, D'Armiento, Massimino, Department of Experimental Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology, Regina Elena Cancer Institute, Department of Surgical Sciences, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), De Villemeur, Hervé, Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
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Adult ,Male ,mitosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Middle Aged ,Neoplasms, Germ Cell and Embryonal ,Protein Serine-Threonine Kinases ,genomic instability ,Seminoma ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,aneuploidy ,aurora kinases ,testicular germ cell tumour ,Testicular Neoplasms ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Testis ,Aurora Kinase B ,Humans ,Aurora Kinase C ,RNA, Messenger ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology - Abstract
International audience; The Aurora kinases regulate chromosome segregation and cytokinesis, and alterations in their expression associate with cell malignant transformation. In this study, we demonstrated by qRT-PCR analysis of 14 seminomas that Aurora-A mRNA was, with respect to control tissues, augmented in five of 14 tumour tissues by 2.17 +/- 0.30 fold (P < 0.05) and reduced in 9 to 0.38 +/- 0.10 (P < 0.01). Aurora-B mRNA was increased in 11 tumour tissues by 4.33 +/- 0.82 fold (P < 0.01) and reduced in 3 to 0.41 +/- 0.11 fold. Aurora-C mRNA was reduced to 0.20 +/- 0.32 fold (P < 0.01) in 13 seminomas and up-regulated in one case. Western blot experiments, performed on protein extracts of nine seminomas and six normal testes, showed an up-regulation of Aurora-B protein by 10.14 +/- 3.51 fold (P < 0.05), while Aurora-A protein was found increased in four seminomas by 2.16 +/- 0.43 (P < 0.05), unchanged in three and reduced in two tumour tissues. Aurora-C protein was increased by 9.2 +/- 2.90 fold (P < 0.05), suggesting that post-transcriptional mechanisms modulate its expression. In conclusion, we demonstrated that expression of Aurora kinases is deregulated in seminomas, suggesting that they may play a role in the progression of testicular cancers.
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- 2010
31. Prognostic value of HER2 and progesterone receptor expression in endometrial carcinoma with positive peritoneal washing
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Benevolo, Maria, Vocaturo, Amina, Novelli, Flavia, Mariani, Luciano, Vocaturo, Giuseppe, Cianciulli, Anna Maria, Marandino, Ferdinando, Perrone-Donnorso, Raffaele, Diana Giannarelli, Natali, Pier Giorgio, and Mottolese, Marcella
32. PROGNOSTIC ROLE OF CYTOSKELETAL PROTEIN HUMAN MENA (HMENA), ISOFORMS HMENA(+11A) AND HMENA(DELTAV6), ESTROGEN RECEPTOR-BETA (ER-BETA), EPIDERMAL GROWTH FACTOR RECEPTOR-1 AND-2 (EGFR/HER-2) IN RESECTED NODE-NEGATIVE NON-SMALL-CELL LUNG CANCER (NSCLC)
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Bria, Emilio, Mottolese, Marcella, Sperduti, Isabella, Visca, Paolo, Antoniani, Barbara, Facciolo, Francesco, Alessandrini, Gabriele, Cognetti, Francesco, Paola Nisticò, and Milella, Michele
33. IMPACT OF KRAS AND BRAF GENE MUTATION STATUS ON OUTCOMES OF CHEMOTHERAPY IN COMBINATION WITH BEVACIZUMAB IN METASTATIC COLORECTAL CANCER
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Rossi, Luigi, Veltri, Enzo, Zullo, Angelo, Zoratto, Federica, Colonna, Maria, Longo, Flavia, Mottolese, Marcella, Diana Giannarelli, Ruco, Luigi, Romiti, Adriana, Barucca, Viola, Adua, Daniela, Baiano, Giovanni, Giannini, Giuseppe, Nardi, Stefano, Lapadula, Vittoria, and Tomao, Silverio
34. Prognostic role of cytoskeletal protein human mena (hMena), estrogen receptor-beta (ER-beta), and epidermal growth factor receptor (EGFR) in resected node-negative non-small cell lung cancer (NSCLC)
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Bria, Emilio, Mottolese, Marcella, Isabella Sperduti, Visca, Paolo, Antoniani, Barbara, Facciolo, Francesco, Di Modugno, Francesca, Cognetti, Francesco, Nistico, Paola, and Milella, Michele
35. HIPK2 is a potential predictive marker of a favorable response for adjuvant chemotherapy in stage II colorectal cancer
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Marcella Mottolese, Alessandra Verdina, Isabella Sperduti, Giuliana Di Rocco, Carla Azzurra Amoreo, Simonetta Buglioni, Micol Di Segni, Silvia Soddu, Verdina, Alessandra, Di Segni, Micol, Amoreo, Carla, Sperduti, Isabella, Buglioni, Simonetta, Mottolese, Marcella, Di Rocco, Giuliana, and Soddu, Silvia
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Cancer Research ,Cell Survival ,NF-E2-Related Factor 2 ,Colorectal cancer ,Antineoplastic Agents ,Protein Serine-Threonine Kinases ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Adjuvant therapy ,Humans ,Neoplasm Staging ,Tissue microarray ,Predictive marker ,Quassins ,Oncogene ,business.industry ,Cancer ,General Medicine ,Cell cycle ,medicine.disease ,Survival Analysis ,Oxaliplatin ,Oncology ,Chemotherapy, Adjuvant ,Drug Resistance, Neoplasm ,Cancer research ,Fluorouracil ,Tumor Suppressor Protein p53 ,Carrier Proteins ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Colorectal cancer (CRC) is the third most frequently diagnosed type of cancer worldwide. Stage II CRC accounts for ~25% all CRC cases and their management after surgical resection remains a clinical dilemma due to the lack of reliable criteria for identifying patients who may benefit from adjuvant chemotherapy. Homeodomain‑interacting protein kinase 2 (HIPK2), a multifunctional kinase involved in numerous signaling pathways, serves several key roles in cell response to different types of stresses, including chemotherapy‑induced genotoxic damage. In the present study, immunohistochemistry was performed for HIPK2 on a tissue microarray of primary human tumor samples from 84 patients with stage II CRC, treated (30 patients) or not treated (54 patients) with adjuvant chemotherapy, and sequenced for the TP53 gene, a key HIPK2 target in genotoxic damage response. It was observed that, regardless of the TP53 gene status, a high percentage of HIPK2+ cells was associated with therapeutic vulnerability in stage II CRC, suggesting a contribution of HIPK2 to drug‑response in vivo. For the in vitro characterization, HIPK2 was depleted in human CRC cells by CRISPR/Cas9 or RNA interference. HIPK2‑proficient and HIPK2‑defective cells were evaluated for their response to 5‑fluorouracil (5‑FU) and oxaliplatin (OXA). The results revealed that HIPK2 depletion induced resistance to 5‑FU and OXA, and that this resistance was not overcome by brusatol, an inhibitor of the antioxidant response regulator nuclear factor erythroid 2‑related factor 2 (NRF2), which is frequently overexpressed in CRC. By contrast, cell sensitivity to 5‑FU and OXA was further induced by brusatol supplementation in HIPK2‑proficient cells, further supporting the contribution of HIPK2 in chemotherapy response. Overall, the present results suggested that HIPK2 may be a potential predictive marker for adjuvant‑treated stage II CRC and for prospective therapy with NRF2 modulators.
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- 2020
36. TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment
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Paola Ostano, Erica Salvati, Chiara Cingolani, Isabella Sperduti, Eleonora Petti, Roberto Dinami, Annamaria Biroccio, Giovanna Chiorino, Marcella Mottolese, Carmen D'Angelo, Giovanni Blandino, Eric Gilson, Manuela Porru, Carla Azzurra Amoreo, Angela Maria Rizzo, Pasquale Zizza, Rosita Russo, Angela Chambery, Carlo Leonetti, Julien Cherfils-Vicini, Andrea Sacconi, Zizza, Pasquale, Dinami, Roberto, Porru, Manuela, Cingolani, Chiara, Salvati, Erica, Rizzo, Angela, D'Angelo, Carmen, Petti, Eleonora, Amoreo, Carla Azzurra, Mottolese, Marcella, Sperduti, Isabella, Chambery, Angela, Russo, Rosita, Ostano, Paola, Chiorino, Giovanna, Blandino, Giovanni, Sacconi, Andrea, Cherfils-Vicini, Julien, Leonetti, Carlo, Gilson, Eric, Biroccio, Annamaria, Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de 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), Pathology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon
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Male ,Vascular Endothelial Growth Factor A ,Angiogenesis ,Mice, Nude ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease_cause ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Neovascularization ,03 medical and health sciences ,Mice ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,Genetics ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Telomeric Repeat Binding Protein 2 ,Neoplasm Metastasis ,[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,030304 developmental biology ,0303 health sciences ,Tumor microenvironment ,Neovascularization, Pathologic ,Heparin ,Gene regulation, Chromatin and Epigenetics ,Cancer ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Telomere ,Vascular endothelial growth factor A ,Cancer cell ,Colonic Neoplasms ,Cancer research ,medicine.symptom ,Sulfatases ,Sulfotransferases ,Carcinogenesis ,030217 neurology & neurosurgery ,Heparan Sulfate Proteoglycans - Abstract
The telomeric protein TRF2 is overexpressed in several human malignancies and contributes to tumorigenesis even though the molecular mechanism is not completely understood. By using a high-throughput approach based on the multiplexed Luminex X-MAP technology, we demonstrated that TRF2 dramatically affects VEGF-A level in the secretome of cancer cells, promoting endothelial cell-differentiation and angiogenesis. The pro-angiogenic effect of TRF2 is independent from its role in telomere capping. Instead, TRF2 binding to a distal regulatory element promotes the expression of SULF2, an endoglucosamine-6-sulfatase that impairs the VEGF-A association to the plasma membrane by inducing post-synthetic modification of heparan sulfate proteoglycans (HSPGs). Finally, we addressed the clinical relevance of our findings showing that TRF2/SULF2 expression is a worse prognostic biomarker in colorectal cancer (CRC) patients. The telomeric protein TRF2 is overexpressed in several human malignancies and contributes to tumorigenesis even though the molecular mechanism is not completely understood. By using a high-throughput approach based on the multiplexed Luminex X-MAP technology, we demonstrated that TRF2 dramatically affects VEGF-A level in the secretome of cancer cells, promoting endothelial cell-differentiation and angiogenesis. The pro-angiogenic effect of TRF2 is independent from its role in telomere capping. Instead, TRF2 binding to a distal regulatory element promotes the expression of SULF2, an endoglucosamine-6-sulfatase that impairs the VEGF-A association to the plasma membrane by inducing post-synthetic modification of heparan sulfate proteoglycans (HSPGs). Finally, we addressed the clinical relevance of our findings showing that TRF2/SULF2 expression is a worse prognostic biomarker in colorectal cancer (CRC) patients.
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- 2019
37. SIRT6 interacts with TRF2 and promotes its degradation in response to DNA damage
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Ettore Novellino, Angela Capolupo, Marcella Mottolese, Angela Maria Rizzo, Carmen D'Angelo, Eric Gilson, Erica Salvati, Salvatore Di Maro, Annamaria Biroccio, Carmen Maresca, Sandro Cosconati, Carla Azzurra Amoreo, Delphine Benarroch-Popivker, Sara Iachettini, Pasquale Zizza, Federica del Gaudio, Isabella Sperduti, Francesco Merlino, Rizzo, A., Iachettini, S., Salvati, E., Zizza, P., Maresca, C., D'Angelo, C., Benarroch-Popivker, D., Capolupo, A., Del Gaudio, F., Cosconati, S., Di Maro, S., Merlino, F., Novellino, E., Amoreo, C. A., Mottolese, M., Sperduti, I., Gilson, E., Biroccio, A., Rizzo, Angela, Iachettini, Sara, Salvati, Erica, Zizza, Pasquale, Maresca, Carmen, D'Angelo, Carmen, Benarroch Popivker, Delphine, Capolupo, Angela, Del Gaudio, Federica, Cosconati, Sandro, DI MARO, Salvatore, Merlino, Francesco, Novellino, Ettore, Amoreo, Carla Azzurra, Mottolese, Marcella, Sperduti, Isabella, Gilson, Eric, and Biroccio, Annamaria
- Subjects
0301 basic medicine ,SIRT6 ,Models, Molecular ,sirt6 ,deacetylation ,DNA damage ,Protein Conformation ,Proteolysis ,Recombinant Fusion Proteins ,Mutant ,Colorectal Neoplasm ,TRF2 ,Biology ,Genome Integrity, Repair and Replication ,medicine.disease_cause ,DNA damage response ,Cell Line ,Substrate Specificity ,03 medical and health sciences ,medicine ,Genetics ,Sirtuin ,Humans ,Sirtuins ,Telomeric Repeat Binding Protein 2 ,Proteolysi ,Poly(ADP-ribose) Polymerase ,Gene knockdown ,medicine.diagnostic_test ,Protein Stability ,Ubiquitination ,Acetylation ,Antineoplastic Agents, Phytogenic ,Immunohistochemistry ,Cell biology ,Telomere ,030104 developmental biology ,Camptothecin ,Poly(ADP-ribose) Polymerases ,Carcinogenesis ,Colorectal Neoplasms ,Human ,Recombinant Fusion Protein ,DNA Damage ,Protein Binding - Abstract
Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in telomere maintenance and DNA damage response. Here, we show that TRF2 directly binds SIRT6 in a DNA independent manner and that this interaction is increased upon replication stress. Knockdown of SIRT6 up-regulates TRF2 protein levels and counteracts its down-regulation during DNA damage response, leading to cell survival. Moreover, we report that SIRT6 deactetylates in vivo the TRFH domain of TRF2, which in turn, is ubiquitylated in vivo activating the ubiquitin-dependent proteolysis. Notably, overexpression of the TRF2(cT) mutant failed to be stabilized by SIRT6 depletion, demonstrating that the TRFH domain is required for its post-transcriptional modification. Finally, we report an inverse correlation between SIRT6 and TRF2 protein expression levels in a cohort of colon rectal cancer patients. Taken together our findings describe TRF2 as a novel SIRT6 substrate and demonstrate that acetylation of TRF2 plays a crucial role in the regulation of TRF2 protein stability, thus providing a new route for modulating its expression level during oncogenesis and damage response. Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in telomere maintenance and DNA damage response. Here, we show that TRF2 directly binds SIRT6 in a DNA independent manner and that this interaction is increased upon replication stress. Knockdown of SIRT6 upregulates TRF2 protein levels and counteracts its down-regulation during DNA damage response, leading to cell survival. Moreover, we report that SIRT6 deactetylates in vivo the TRFH domain of TRF2, which in turn, is ubiquitylated in vivo activating the ubiquitin-dependent proteolysis. Notably, overexpression of the TRF2(cT) mutant failed to be stabilized by SIRT6 depletion, demonstrating that the TRFH domain is required for its post-transcriptional modification. Finally, we report an inverse correlation between SIRT6 and TRF2 protein expression levels in a cohort of colon rectal cancer patients. Taken together our findings describe TRF2 as a novel SIRT6 substrate and demonstrate that acetylation of TRF2 plays a crucial role in the regulation of TRF2 protein stability, thus providing a new route for modulating its expression level during oncogenesis and damage response.
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- 2017
38. Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds
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Manuela Iezzi, Federica Papaccio, Diego di Bernardo, Fabrizio Loreni, Alberto Bardelli, Laura Ciolli, Francesco Sirci, Vittorio Enrico Avvedimento, Margherita Mutarelli, Marcella Mottolese, Valentina Aria, Roberta Bosotti, Luca Cardone, Carla Azzurra Amoreo, Antonella Isacchi, Rosanna Dattilo, Barbara Tumaini, Diego Carrella, Isabella Manni, Carrella, Diego, Manni, Isabella, Tumaini, Barbara, Dattilo, Rosanna, Papaccio, Federica, Mutarelli, Margherita, Sirci, Francesco, Amoreo, Carla A, Mottolese, Marcella, Iezzi, Manuela, Ciolli, Laura, Aria, Valentina, Bosotti, Roberta, Isacchi, Antonella, Loreni, Fabrizio, Bardelli, Alberto, Avvedimento, VITTORIO ENRICO, DI BERNARDO, Diego, and Cardone, Luca
- Subjects
0301 basic medicine ,Veterinary medicine ,Carcinogenesis ,oncogenes ,Ribosomal Protein S6 Kinases 70-kDa ,Phosphatidylinositol 3-Kinases ,Mice ,Drug Approval ,Phosphoinositide-3 Kinase Inhibitors ,Tumor ,Settore BIO/11 ,Ribosomal Protein S6 Kinases, 70-kDa ,Mammary Glands ,gene expression signatures ,Drug repositioning ,Oncology ,PI3K-dependent pathways ,Niclosamide ,Female ,Signal Transduction ,FDA-approved drugs ,drugs network ,Animals ,Antineoplastic Agents ,Breast Neoplasms ,Cell Line ,Humans ,Animal ,Proto-Oncogene Proteins c-akt ,Pyrvinium Compounds ,Computational Biology ,Drug Repositioning ,Mouse Mammary Gland ,gene expression signature ,PI3K-dependent pathway ,03 medical and health sciences ,Mammary Glands, Animal ,P70S6 kinase ,Cell Line, Tumor ,medicine ,Protein kinase B ,PI3K/AKT/mTOR pathway ,FDA-approved drug ,business.industry ,Cancer ,medicine.disease ,030104 developmental biology ,Cancer research ,Breast cancer cells ,business ,Signalling pathways ,Priority Research Paper - Abstract
// Diego Carrella 1 , Isabella Manni 3 , Barbara Tumaini 1 , Rosanna Dattilo 2 , Federica Papaccio 3 , Margherita Mutarelli 1 , Francesco Sirci 1 , Carla A. Amoreo 4 , Marcella Mottolese 4 , Manuela Iezzi 5 , Laura Ciolli 5 , Valentina Aria 6 , Roberta Bosotti 7 , Antonella Isacchi 7 , Fabrizio Loreni 6 , Alberto Bardelli 8,9 , Vittorio E. Avvedimento 10 , Diego di Bernardo 1,11 and Luca Cardone 3 1 Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy 2 Department of Hematology, Oncology and Molecular Medicine, Biobank Unit, Istituto Superiore di Sanita, Rome, Italy 3 Department of Research, Advanced Diagnostics, and Technological Innovations, Regina Elena National Cancer Institute, Rome, Italy 4 S.C. Anatomia Patologica, Regina Elena National Cancer Institute, Rome, Italy 5 Immuno-Oncology Laboratory, Aging Research Center, G. d’Annunzio University of Chieti, Pescara, Italy 6 Department of Biology, University of Rome Tor Vergata, Rome, Italy 7 Nerviano Medical Sciences SRL, Nerviano, Italy 8 Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy 9 Department of Oncology, University of Torino, Candiolo, Torino, Italy 10 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli “Federico II”, Naples, Italy 11 Department of Electrical Engineering and Information Technology, University of Naples “Federico II”, Naples, Italy Correspondence to: Luca Cardone, email: // Diego di Bernardo, email: // Keywords : oncogenes, PI3K-dependent pathways, gene expression signatures, drugs network, FDA-approved drugs Received : January 03, 2016 Accepted : August 03, 2016 Published : August 16, 2016 Abstract The discovery of inhibitors for oncogenic signalling pathways remains a key focus in modern oncology, based on personalized and targeted therapeutics. Computational drug repurposing via the analysis of FDA-approved drug network is becoming a very effective approach to identify therapeutic opportunities in cancer and other human diseases. Given that gene expression signatures can be associated with specific oncogenic mutations, we tested whether a “reverse” oncogene-specific signature might assist in the computational repositioning of inhibitors of oncogenic pathways. As a proof of principle, we focused on oncogenic PI3K-dependent signalling, a molecular pathway frequently driving cancer progression as well as raising resistance to anticancer-targeted therapies. We show that implementation of “reverse” oncogenic PI3K-dependent transcriptional signatures combined with interrogation of drug networks identified inhibitors of PI3K-dependent signalling among FDA-approved compounds. This led to repositioning of Niclosamide (Niclo) and Pyrvinium Pamoate (PP), two anthelmintic drugs, as inhibitors of oncogenic PI3K-dependent signalling. Niclo inhibited phosphorylation of P70S6K, while PP inhibited phosphorylation of AKT and P70S6K, which are downstream targets of PI3K. Anthelmintics inhibited oncogenic PI3K-dependent gene expression and showed a cytostatic effect in vitro and in mouse mammary gland. Lastly, PP inhibited the growth of breast cancer cells harbouring PI3K mutations. Our data indicate that drug repositioning by network analysis of oncogene-specific transcriptional signatures is an efficient strategy for identifying oncogenic pathway inhibitors among FDA-approved compounds. We propose that PP and Niclo should be further investigated as potential therapeutics for the treatment of tumors or diseases carrying the constitutive activation of the PI3K/P70S6K signalling axis.
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- 2016
39. miR-155 drives telomere fragility in human breast cancer by targeting TRF1
- Author
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Cristiana Ercolani, Reuven Agami, Andrea Sacconi, Roberta Benetti, Yari Ciani, Francesca Biagioni, Rosanna Sestito, Carlos le Sage, Stefan Schoeftner, Claudio Schneider, Silvano Piazza, Eleonora Petti, Giovanni Blandino, Marcella Mottolese, Roberto Dinami, Dinami, Roberto, Ercolani, Cristiana, Petti, Eleonora, Piazza, Silvano, Ciani, Yari, Sestito, Rosanna, Sacconi, Andrea, Biagioni, Francesca, Le Sage, Carlo, Agami, Reuven, Benetti, Roberta, Mottolese, Marcella, Schneider, Claudio, Blandino, Giovanni, and Schoeftner, Stefan
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Genome instability ,Cancer Research ,3' Untranslated Regions ,Animals ,Base Sequence ,Breast Neoplasms ,Cell Culture Techniques ,Female ,HCT116 Cells ,HeLa Cells ,Humans ,MCF-7 Cells ,MicroRNAs ,Molecular Sequence Data ,Sequence Homology, Nucleic Acid ,Telomere ,Telomeric Repeat Binding Protein 1 ,Transfection ,Sequence Homology ,Biology ,TERF1 ,miR-155 ,Breast cancer ,Telomere Homeostasis ,breast cancer ,medicine ,miR-155, breast cancer, telomeres, shelterin ,Nucleic Acid ,medicine.disease ,Shelterin ,telomeres ,Chromatin ,Oncology ,Cancer cell ,Cancer research ,shelterin - Abstract
Telomeres consist of DNA tandem repeats that recruit the multiprotein complex shelterin to build a chromatin structure that protects chromosome ends. Although cancer formation is linked to alterations in telomere homeostasis, there is little understanding of how shelterin function is limited in cancer cells. Using a small-scale screening approach, we identified miR-155 as a key regulator in breast cancer cell expression of the shelterin component TERF1 (TRF1). miR-155 targeted a conserved sequence motif in the 3′UTR of TRF1, resulting in its translational repression. miR-155 was upregulated commonly in breast cancer specimens, as associated with reduced TRF1 protein expression, metastasis-free survival, and relapse-free survival in estrogen receptor–positive cases. Modulating miR-155 expression in cells altered TRF1 levels and TRF1 abundance at telomeres. Compromising TRF1 expression by elevating miR-155 increased telomere fragility and altered the structure of metaphase chromosomes. In contrast, reducing miR-155 levels improved telomere function and genomic stability. These results implied that miR-155 upregulation antagonizes telomere integrity in breast cancer cells, increasing genomic instability linked to poor clinical outcome in estrogen receptor–positive disease. Our work argued that miRNA-dependent regulation of shelterin function has a clinically significant impact on telomere function, suggesting the existence of “telo-miRNAs” that have an impact on cancer and aging. Cancer Res; 74(15); 4145–56. ©2014 AACR.
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- 2014
40. Decrease of survivin, p53 and Bcl-2 expression in chemorefractory colorectal liver metastases may be predictive of radiosensivity radiosensivity after radioembolization with yttrium-90 resin microspheres
- Author
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Emanuela Giampalma, Cristiana Ercolani, Livio Carpanese, Francesco Fiore, Maurizio Cosimelli, Marcella Mottolese, Rita Golfieri, Elisa Melucci, R. Mancini, Maria Grazia Diodoro, Francesco Izzo, Rosa Sciuto, Carlo Garufi, Isabella Sperduti, Giuseppe Pizzi, Melucci, Elisa, Cosimelli, Maurizio, Carpanese, Livio, Pizzi, Giuseppe, Izzo, Francesco, Fiore, Francesco, Golfieri, Rita, Giampalma, Emanuela, Sperduti, Isabella, Ercolani, Cristiana, Sciuto, Rosa, Mancini, Raffaello, Garufi, Carlo, Diodoro, Maria Grazia, and Mottolese, Marcella
- Subjects
Liver metastase ,Microsphere ,Male ,p53 ,Cancer Research ,Pathology ,Proliferation index ,Colorectal cancer ,Survivin ,Colorectal Neoplasm ,Gastroenterology ,Inhibitor of Apoptosis Proteins ,Liver metastases ,Yttrium Radioisotopes ,Prospective Studies ,Neoplasm Metastasis ,Prospective cohort study ,Yttrium-90-resin microspheres ,medicine.diagnostic_test ,biology ,Liver Neoplasms ,Middle Aged ,Embolization, Therapeutic ,Microspheres ,Neoplasm Metastasi ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,Liver Neoplasm ,Liver biopsy ,Ki-67 ,Biomarker (medicine) ,Female ,Colorectal Neoplasms ,Human ,Adult ,medicine.medical_specialty ,Adolescent ,Composite Resins ,Young Adult ,Yttrium Radioisotope ,Internal medicine ,Inhibitor of Apoptosis Protein ,medicine ,Humans ,Bcl-2 ,Radioembolization ,Aged ,business.industry ,Research ,medicine.disease ,Genes, p53 ,Composite Resin ,Genes, bcl-2 ,Prospective Studie ,biology.protein ,Yttrium-90-resin microsphere ,Steatohepatitis ,Tumor Suppressor Protein p53 ,business - Abstract
In a prospective multicenter phase II trial of radioembolization with yttrium-90 (90Y-RE) in chemorefractory liver-dominant metastatic colorectal cancer (mCRC), we showed that median survival was 12.6 months (95% CI 7.0–18.3) with 48% of 50 patients achieving disease control. In this extension retrospective study, we analyzed whether a panel of biomarkers, known to be associated to an adverse clinical outcome, underwent variations in CRC liver metastases pre and post 90Y-RE. Of the 50 patients included in the study, 29 pre-90Y-RE therapy and 15 post-90Y-RE had liver biopsy specimens available. In these series we investigated survivin, p53, Bcl-2 and Ki-67 expression pre- and post-90Y-RE by immuhistochemistry (IHC). Our findings evidenced a decrease of survivin (77% vs 33%), p53 (93% vs 73%), Bcl-2 (37% vs 26%) expression as well as of Ki-67 proliferation index (62.5% vs 40%) on liver biopsies collected post-90Y-RE as compared to pre-90Y-RE. In the subset of 13 matched liver metastases we further confirmed the reduction of survivin (92.3% vs 53.8%; p = 0.06), p53 (100% vs 69.2%; p = 0.05) and Bcl-2 (69.2% vs 53.8%; p = 0.05) expression post-90Y-RE. This biomarker modulation was accompanied by morphological changes as steatohepatitis, hepatocyte necrosis, collagen deposition, proliferating and/or bile duct ectasia, focal sinusoidal dilatation and fibrosis. Although our analysis was conducted in a very limited number cases, these changes appear strictly related to the response to 90Y-RE therapy and may deserve further investigation on a larger series of patients.
- Published
- 2013
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