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Atypical lipomatous tumors (ALTs)/well-differentiated liposarcomas represent a distinctive subset of mesenchymal neoplasms featuring mature adipocytic proliferation. These tumors are characterized cytogenetically by the presence of supernumerary ring and/or long marker chromosomes that contain several copies of the chromosomal region 12q13-15, in which the HMGA2 gene is located. Deregulation of the HMGA2 gene is a common molecular alteration implicated in the development of a variety of benign tumors, such as lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. In this study, we observed HMGA2 overexpression in 7 of 12 ALT primary cell cultures examined. Subsequently, we generated an adenovirus containing the HMGA2 gene in the antisense orientation (Ad-A2as) to study the effect of HMGA2 protein suppression in ALT cells. The infection of six ALT cells, three of which were positive for HMGA2 expression, resulted in growth inhibition coupled with a significant increase in apoptosis. In addition, the growth of the ALT cells negative for HMGA2 expression was not affected by the infection with either the Ad-A2as or the control virus. On the basis of these findings, the targeting of the HMGA2 protein expression may represent a promising approach for treating the well-differentiated liposarcomas resistant to conventional therapies.

The high mobility group (HMG) proteins (HMGA1a, HMGA1b, and HMGA2) bind to DNA and interact with various transcriptional factors. Therefore, they play an important role in chromatin organization. HMGA protein expression is low in normal adult tissues, but abundant during embryonic development and in several experimental and human tumors. Blockage of HMGA expression inhibits the transformation of rat thyroid PC Cl 3 cells treated with oncogene-carrying retroviruses, thus implicating HMGA in rat thyroid transformation. To better understand the role of HMGA and to establish whether its up-regulated expression is sufficient to induce the transformed phenotype, we generated PC Cl 3 cells that overexpress the protein. We demonstrate that HMGA1b protein overexpression does not transform normal rat thyroid PC Cl 3 cells, but it deregulates their cell cycle: cells enter S-phase earlier and the G(2)-M transition is delayed. HMGA1-overexpressing cells undergo apoptosis through a pathway involving caspase-3 activation, probably consequent to the conflict between mitogenic pressure and the inability to proceed through the cell cycle. Using various HMGA1b gene mutations, we found that the third AT-hook domain and the acetylation site K60 are the protein regions required for induction of apoptosis in PC Cl 3 cells. In conclusion, although HMGA1 protein overexpression is associated with the malignant phenotype of rat and human thyroid cells, it does not transform normal thyroid cells in culture but leads them to programmed cell death.

[This article][1] ([1][2]) has been retracted at the request of the editors. The editors were made aware of concerns regarding potential manipulation of data in the article. An internal review by the editors determined that multiple γ-tubulin Western blot bands appear to be duplicated in Figs. 1A

[This article][1] ([1][2]) has been retracted at the request of the editors. The editors were made aware of concerns regarding potential manipulation of data in the article. An internal review by the editors determined that multiple duplicated electrophoretic mobility shift assay–free probe bands

Chromobox protein homologue 7 (CBX7) is a chromobox family protein encoding a novel polycomb protein, the expression of which shows a progressive reduction, well related with the malignant grade of the thyroid neoplasias. Indeed, CBX7 protein levels decreased in an increasing percentage of cases going from benign adenomas to papillary, follicular, and anaplastic thyroid carcinomas. To elucidate the function of CBX7 in carcinogenesis, we searched for CBX7 interacting proteins by a proteomic analysis. By this approach, we identified several proteins. Among these proteins, we selected histone deacetylase 2 (HDAC2), which is well known to play a key role in neoplastic cell transformation and down-regulation of E-cadherin expression, the loss of which is a critical event in the epithelial-to-mesenchymal transition. We confirmed by coimmunoprecipitation that CBX7 physically interacts with the HDAC2 protein and is able to inhibit its activity. Then, we showed that both these proteins bind the E-cadherin promoter and that CBX7 up-regulates E-cadherin expression. Consistent with these data, we found a positive statistical correlation between CBX7 and E-cadherin expression in human thyroid carcinomas. Finally, we showed that the expression of CBX7 increases the acetylation status of the histones H3 and H4 on the E-cadherin promoter. Therefore, the ability of CBX7 to positively regulate E-cadherin expression by interacting with HDAC2 and inhibiting its activity on the E-cadherin promoter would account for the correlation between the loss of CBX7 expression and a highly malignant phenotype. [Cancer Res 2009;69(17):7079–87]

RET/papillary thyroid carcinoma (RET/PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC stimulates the β-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal–regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3β (GSK3β) phosphorylation, thereby reducing GSK3β-mediated NH2-terminal β-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with β-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)β-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3β complex and activates the transcription factor T-cell factor/lymphoid enhancer factor. Moreover, through the ERK pathway, RET/PTC stimulates cyclic AMP–responsive element binding protein (CREB) phosphorylation and promotes the formation of a β-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing β-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC–expressing cells. Silencing of β-catenin by small interfering RNA inhibits proliferation of RET/PTC–transformed PC Cl3 thyrocytes, whereas a constitutively active form of β-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on β-catenin to stimulate cell proliferation. [Cancer Res 2009;69(5):1867–76]

Various studies have shown that the insulin receptor (IR) is increased in most human breast cancers, and both ligand-dependent malignant transformation and increased cell growth occur in cultured breast cells overexpressing the IR. However, although numerous in vivo and in vitro observations have indicated an important contributory role for the IR in breast cancer cell biology, the molecular mechanisms accounting for increased IR expression in breast tumors have not previously been elucidated. Herein, we did immunoblot analyses of nuclear protein from cultured breast cancer cells and normal and tumoral tissues from breast cancer patients combined with promoter studies by using a series of human wild-type and mutant IR promoter constructs. We provide evidence that IR overexpression in breast cancer is dependent on the assembly of a transcriptionally active multiprotein-DNA complex, which includes the high-mobility group A1 (HMGA1) protein, the developmentally regulated activator protein-2 (AP-2) transcription factor and the ubiquitously expressed transcription factor Sp1. In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression. However, AP-2 DNA-binding activity was undetectable with the IR gene promoter, suggesting that transactivation of this gene by AP-2 might occur indirectly through physical and functional cooperation with HMGA1 and Sp1. Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis. (Cancer Res 2006; 66(10): 5085-93)

The phosphatidylinositol 3′-kinase (PI3K) pathway is frequently activated in thyroid carcinomas through the constitutive activation of stimulatory molecules (e.g., Ras) and/or the loss of expression and/or function of the inhibitory PTEN protein that results in Akt activation. Recently, it has been reported that somatic mutations within the PI3K catalytic subunit, PIK3CA, are common (25-40%) among colorectal, gastric, breast, ovarian cancers, and high-grade brain tumors. Moreover, PIK3CA mutations have a tendency to cluster within the helical (exon 9) and the kinase (exon 20) domains. In this study, 13 thyroid cancer cell lines, 80 well-differentiated thyroid carcinomas of follicular (WDFC) and papillary (WDPC) type, and 70 anaplastic thyroid carcinomas (ATC) were investigated, by PCR-direct sequencing, for activating PIK3CA mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 ATC (23%), two WDFC (8%), and one WDPC (2%). In 18 of the 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component and located primarily within the kinase domain. Three cell lines of papillary and follicular lineage (K1, K2, and K5) were also found mutated. In addition, activation of Akt was observed in most of the ATC harboring PIK3CA mutations. These findings indicate that mutant PIK3CA is likely to function as an oncogene among ATC and less frequently well-differentiated thyroid carcinomas. The data also argue for a role of PIK3CA targeting in the treatment of ATC patients.

High mobility group A (HMGA) proteins are chromatinic proteins that do not have transcriptional activity per se, however, by interacting with the transcription machinery, they regulate, negatively or positively, the expression of several genes. We searched for genes regulated by HMGA1 proteins using microarray analysis in embryonic stem (ES) cells bearing one or two disrupted hmga1 alleles. We identified 87 transcripts increased and 163 transcripts decreased of at least 4-fold in hmga1−/− ES cells. For some of them, a HMGA1-dose dependency was observed, because an intermediate level was observed in the heterozygous ES cells. When the expression analysis of these genes was extended to embryonic fibroblasts and adult tissues such as heart, spleen, and liver from hmga1-knockout mice, contrasting results were obtained. In fact, aside some genes showing the same HMGA1 regulation observed in ES cells, there were some genes that did not modify their expression, and others showing a HMGA1-mediated regulation but in an opposite direction. These results clearly indicate that HMGA1-mediated gene regulation depends on the cellular context. Finally for a couple of analyzed HMGA1-regulated genes, electrophoretic mobility shift assay and chromatin immunoprecipitation revealed a direct binding of HMGA1 proteins to their promoters, suggesting a HMGA1-direct regulation of their expression.

The high mobility group A (HMGA) non-histone chromosomal proteins constitute a subgroup of HMG accessory factors that play key roles in chromatin architecture and orchestrate the assembly of nucleoprotein complexes involved in gene transcription, replication, and chromatin structure through a complex network of protein-DNA and protein-protein interactions. HMGA overexpression and gene rearrangements are frequent events in human cancer, but the molecular basis of HMGA oncogenic activity remains partially unclear. Recently, we have defined a new physical and functional interaction between HMGA1 and p53. This interaction modulates the transcription of p53 target genes such as Mdm2, p21waf1, Bax, and inhibits p53-mediated apoptosis. Moreover, we have described a new mechanism through which HMGA1 inhibits p53-mediated apoptosis by counteracting the p53 proapoptotic activator homeodomain-interacting protein kinase 2 (HIPK2), which binds to and activates p53 by phosphorylating it at Ser46. We found that HMGA1 overexpression promoted HIPK2 relocalization from the nucleus to the cytoplasm, with consequent inhibition of p53 apoptotic function. During my doctorate course, I looked for other target genes that could be regulated by the HMGA1-p53 complex. So, I focused my attention on the apoptosis inhibitor gene Bcl-2, because this gene belongs to Bax family, is regulated by p53, and its promoter has several possible target regions for the HMGA1 proteins binding. I demonstrated that HMGA1 binds Bcl-2 promoter in vitro and in vivo, and that this binding exerts regulatory effects on Bcl-2 transcription. In fact, HMGA1 is able to abolish the repression promoted by p53 on Bcl-2 expression. This effect, as for the Bax promoter regulation, is due to HIPK2 delocalization, from the nucleus to the cytoplasm. Therefore, also Bcl-2 is a gene regulated by HMGA1-p53-HIPK2 complex. Subsequently, my studies were focalized in finding other possible components of this multiprotein complex. Using the neuronal cell line ND7, I found that the transcription factor Brn-3a belongs to this complex. Brn-3a is one of the most important activators of Bcl-2 transcription but, when p53 is overexpressed, it acts as a corepressor for this gene. Moreover, the binding of Brn-3a to its consensus sequences is positively regulated by HIPK2. I demonstrated that HMGA1 overexpression, in this cellular context, promotes not only HIPK2 delocalization from nucleus to the cytoplasm, but also the reduction of Brn-3a binding to the Bcl-2 promoter, removing Brn-3a from its role of corepressor following p53 overexpression. These data support the causal role suggested for the HMGA1 proteins in the neoplastic transformation and provide another mechanism of inactivation of p53 apoptotic function

El pdf del artículo es la versión de autor.-- et al., RET/papillary thyroid carcinoma (PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC1 activates the Rap1 small GTPase. The activation of Rap1 was dependent on the phosphorylation of RET Tyr1062. RET/PTC1 recruited a complex containing growth factor receptor binding protein 2-associated binding protein 1 (Gab1), CrkII (v-erk sarcoma virus CT10 oncogene homologue II), and C3G (Rap guanine nucleotide exchange factor 1). By using dominant-negative and small interfering duplex (small interfering RNA) oligonucleotides, we show that RET/PTC1-mediated Rap1 activation was dependent on CrkII, C3G, and Gab1. Activation of Rap1 was involved in the RET/PTC1-mediated stimulation of the BRAF kinase and the p42/p44 mitogen-activated protein kinases. Proliferation and stress fiber formation of RET/PTC1-expressing PC C1 3 thyroid follicular cells were inhibited by the dominant-negative Rap1(N17) and by Rap1-specific GTPase-activating protein. Thus, Rap1 is a downstream effector of RET/PTC and may contribute to the transformed phenotype of RET/PTC-expressing thyrocytes. ©2007 American Association for Cancer Research., Associazione Italiana per la Ricerca sul Cancro (AIRC) and the Italian Ministero per l’Istruzione, Universitaè Ricerca Scientifica (MIUR). G. De Vita and M.D. Castellone were recipient of AIRC fellowships.

Thyroid cancer is frequently associated with the oncogenic conversion of the RET receptor tyrosine kinase. RET gene rearrangements, which lead to the generation of chimeric RET/papillary thyroid carcinoma (PTC) oncogenes, occur in PTC, whereas RET point mutations occur in familial multiple endocrine neoplasia type 2 (MEN2) and sporadic medullary thyroid carcinomas (MTC). We showed previously that the expression of the receptor-type protein tyrosine phosphatase J (PTPRJ) is suppressed in neoplastically transformed follicular thyroid cells. We now report that PTPRJ coimmunoprecipitates with wild-type RET and with the MEN2A-associated RET(C634R) oncoprotein but not with the RET/PTC1 and RET-MEN2B isoforms. Using mutated forms of PTPRJ and RET-MEN2A, we show that the integrity of the respective catalytic domains is required for the PTPRJ/RET-MEN2A interaction. PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels. In line with this finding, adoptive PTPRJ expression reduced the oncogenic activity of RET(C634R) in an in vitro focus formation assay of NIH3T3 cells. As expected from the coimmunoprecipitation results, the RET(M918T) oncoprotein, which is associated to MEN2B and sporadic MTC, was resistant to the dephosphorylating activity of PTPRJ. Taken together, these findings identify RET as a novel substrate of PTPRJ and suggest that PTPRJ expression levels may affect tumor phenotype associated with RET/PTC1 and RET(C634R) mutants. On the other hand, resistance to PTPRJ may be part of the mechanism of RET oncogenic conversion secondary to the M918T mutation. (Cancer Res 2006; 66(12): 6280-7)

Atypical lipomatous tumors (ALTs)/well-differentiated liposarcomas represent a distinctive subset of mesenchymal neoplasms featuring mature adipocytic proliferation. These tumors are characterized cytogenetically by the presence of supernumerary ring and/or long marker chromosomes that contain several copies of the chromosomal region 12q13-15, in which the HMGA2 gene is located. Deregulation of the HMGA2 gene is a common molecular alteration implicated in the development of a variety of benign tumors, such as lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. In this study, we observed HMGA2 overexpression in 7 of 12 ALT primary cell cultures examined. Subsequently, we generated an adenovirus containing the HMGA2 gene in the antisense orientation (Ad-A2as) to study the effect of HMGA2 protein suppression in ALT cells. The infection of six ALT cells, three of which were positive for HMGA2 expression, resulted in growth inhibition coupled with a significant increase in apoptosis. In addition, the growth of the ALT cells negative for HMGA2 expression was not affected by the infection with either the Ad-A2as or the control virus. On the basis of these findings, the targeting of the HMGA2 protein expression may represent a promising approach for treating the well-differentiated liposarcomas resistant to conventional therapies.

Trisomy of chromosome 12 is a nonrandom chromosomal change in pituitary adenomas, particularly prolactinomas. This and the finding that prolactin-secreting pituitary adenomas develop in transgenic mice overexpressing the wild-type HMGA2 gene (which maps to 12q14-15) prompted us to investigate HMGA2 rearrangements and expression in human prolactinomas. By dual-color interphase fluorescence in situ hybridization analysis using HMGA2-specific PACs and BACs, we found that the HMGA2 locus was amplified in seven of the eight prolactinoma samples examined. The cytogenetic manifestations of elevated HMGA2 concentrations ranged from simple trisomy to tetrasomy 12 and der(12) chromosomes to marker chromosomes bearing 12q14-15-derived regions. Reverse transcription-PCR, Western blot and immunohistochemical analysis showed HMGA2 overexpression in a number of prolactinomas bearing rearrangement of regions 12q14-15. These data suggest a critical role of the HMGA2 overexpression in the generation of prolactin-secreting pituitary adenomas in humans.

Angiogenesis and increased vessel permeability play key roles during tumor growth and cancer progression. Therefore, much current effort in the field aims at understanding the molecular mechanisms underlying the formation and remodeling of blood vessels as a way to identify new approaches to harness these processes. In this context, we have been focusing our efforts on the protein tyrosine phosphatase DEP-1 (also named PTPRJ or CD148), which was initially identified as a negative regulator of cell proliferation and VEGFR2 phosphorylation when highly expressed in quiescent endothelial cells. However, using an RNAi knockdown approach, we demonstrated for the first time that through its ability to dephosphorylate the Src inhibitory Y529, DEP-1 was also a positive regulator of Src activation in VEGF-stimulated endothelial cells. As Src plays key roles in the promotion of angiogenesis and vascular permeability, we further demonstrated that DEP-1 was indeed a promoter of these vascular functions in vitro, and that the tyrosine phosphorylation of its C-terminal tail, allowing Src interaction and activation, was required for this. Interestingly, the catalytic inactivation of DEP-1 in mice led to increased endothelial cell proliferation, but also disorganized vascular structures, in contrast with the apparent absence of phenotype in DEP-1 knock-out (KO) mice models. In this study, we evaluated the biological consequences of the loss of DEP-1 expression on normal and pathological angiogenesis using a complete KO mouse model. We first confirmed that DEP-1 was required for Src activation and the phosphorylation of its substrates VE-cadherin and FAK in mice lung lysates upon systemic VEGF stimulation. Consistent with these observations, VEGF-induced vascular leakage was abrogated in the DEP-1 KO mice, as determined using a modified Miles assay. Capillary formation from mouse aortic rings ex vivo and in Matrigel plugs was also impaired, demonstrating the key positive role of DEP-1 in permeability and angiogenesis. Ischemia-induced angiogenesis was also deficient in KO mice, as demonstrated by reduced limb blood flow and capillary formation in a hind limb ischemia model. To assess tumor-associated angiogenesis, the highly metastatic Mvt-1 mouse mammary tumor cells were orthotopically injected in WT and DEP-1 KO mice. The growth of tumors in DEP-1 KO mice was reduced by about 50% compared to those grown in WT animals, due to inhibition of tumor angiogenesis. As tumor-associated and leaky blood vessels contribute to dissemination of cancer cells, a 50-60% decrease in the number and size of spontaneous and experimental metastases were also observed in the lungs of DEP-1 KO mice. Altogether, these results demonstrate for the first time that DEP-1 is an essential driver of VEGF-dependent Src activation, permeability, and angiogenesis in vivo, therefore acting as a promoter of tumor cell growth and dissemination. Citation Format: Patrick Fournier, Sylvie Dussault, Alfredo Fusco, Alain Rivard, Isabelle Royal. The protein tyrosine phosphatase DEP-1/PTPRJ is an essential promoter of vascular permeability, angiogenesis and tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 8. doi:10.1158/1538-7445.AM2014-8

Background and aim: Mounting evidence suggest that hepatocellular carcinoma (HCC) contains a subset of cells possessing some functional properties similar to normal tissue stem cells, usually referred as cancer stem cells (CSCs). THY1 (aka CD90) is involved in tumor-genesis and is commonly acknowledged as a maker of CSC in HCC. HMGA1, an HMG (high mobility group) chromatin-remodelling protein, has been recently highlighted as a key player in stem cell biology. HMGA1 overexpression induces malignant transformation in vitro and is deregulated in many cancer entities. This study aims to address the interrelated role of HMGA1 and THY1 in HCC. Methods: Using a global transcriptomic profiling (Affymetrix), validated by RT-qPCR, we analysed HMGA1 and THY1 expression levels in a cohort of HCC needle biopsy matched with corresponding non-neoplastic liver (total n=118) and normal liver (n=5). Using tissue microarray (TMA) technology, we evaluated by immunohistochemical staining HMGA1 and THY1 protein levels in a large collective of liver specimens (n=434, of which n=216 were HCCs). Results: We observed that both HMGA1 and THY1 expression is significantly up regulated in a subset of HCC specimens, correlating with metastatic disease and histological grading. Additionally, we demonstrate that high HMGA1 protein levels along with THY1 positivity in HCC samples results in unfavorable patients' outcome and disease progression. Conclusion: With this work we provide new evidence for HMGA1 and THY1 involvement in HCC progression and disease outcome and set the basis for further studies aiming to address their role in CSC biology of HCC. Citation Format: Mariacarla Andreozzi, Luca Quagliata, David Benz, Francesca Trapani, Serenella Eppenberger-Castori, Christian Ruiz, Pierlorenzo Pallante, Markus Heim, Luigi Tornillo, Alfredo Fusco, Salvatore Piscuoglio, Luigi Maria Terracciano. Enhanced expression of HMGA1 and THY1 in human hepatocellular carcinoma correlates with poor prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1386. doi:10.1158/1538-7445.AM2014-1386

The proteins of the Ets family are transcription factors involved in signal transduction, cell cycle progression, and differentiation. In this study, we report that thyroid cell neoplastic transformation is associated with a dramatic increase in ETS transcriptional activity, which is dependent on the accumulation of Ets-1, Ets-2, and other Ets-related proteins. Inhibition of ETS transactivation activity by the Ets-dominant negative construct (Ets-Z) induced programmed cell death in human thyroid carcinoma cell lines but not in normal thyroid cells. Apoptotic cell death induced by Ets-Z was dependent on the reduction of c-MYC protein levels, because it was prevented by overexpressinn of c-myc. Taken together, these data indicate that the induction of Ets-l and Ets-2 transcription factors plays a pivotal role in thyroid cell neoplastic transformation.

Background: Colorectal cancer is the result of the accumulation of different genetic modifications including critical genes involved in the control of cell proliferation. In a large number of carcinomas with worst prognosis, lesions are not diagnosed until the disease is at an advanced stage. To diagnose cancer at an early stage and to establish more effective therapies featuring of key molecules in carcinogenesis is a critical steps. UBCH10 (also known as E2C or UBE2C) is a cell cycle-related protein involved in mitosis completion. UbcH10 participates in proper metaphase to anaphase transition, and abrogation of UbcH10 results in the premature separation of sister chromatids. Thus, UbcH10 is essential for cell cycle progression, and his expression is cell-cycle dependent and related to proliferation Aims: The aim of this study is to investigate the association of UbcH10 gene expression with clinicopathological features and tumor progression of colorectal cancer. Materials and methods: We investigated the expression of the UBCH10 genes in a tissue microarray platform consisting of normal and neoplastic colorectal cancers (CRC) tissues by immunohistochemistry. UBCH10 was detectable in 889 patients. Immunoreactivity was scored semi-quantitatively by evaluating the number of positive tumor cells over the total number of tumor cells. Scores were assigned using 5% intervals and ranged from 0% to 100%. Median protein expression levels were used as cut-off scores to define protein marker positivity and the findings were associated with clinical-pathological parameters. Results: Our results demonstrated that UBCH10 is over-expressed in CRCs tissues compared to normal colon (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4496. doi:1538-7445.AM2012-4496

Background: Lung cancer is the leading cause of cancer death worldwide with an overall 5-year survival rate of only 15%. Therefore, research focusing on lung carcinogenesis is strongly needed. High mobility group A (HMGA) proteins play an important role in the regulation of transcription, differentiation, and neoplastic transformation. The HMGA gene family includes HMGA1, which encodes the HMGA1a and HMGA1b protein isoforms, and HMGA2, which encodes HMGA2. These chromatin-binding proteins function in transcriptional regulation and recent studies also suggest a role in cellular senescence. HMGA1 proteins also appear to participate in cell cycle regulation and malignant transformation, whereas HMGA2 has been implicated primarily in the pathogenesis of benign mesenchymal tumors. Aims: The aim of this study was to investigate on the potential role of HMGA 1 and 2 in lung carcinogenesis. Materials and methods: A tissue microarray (TMA) including normal and neoplastic non-small cell lung cancer (NSCLC; n=454) tissues was constructed and HMGA1 and 2 analyzed by immunohistochemistry. HMGA1 was detectable in a 454 patients and HMGA2 in 409 patients, respectively. Immunoreactivity was scored semi-quantitatively by evaluating the number of positive tumor cells over the total number of tumor cells. Scores were assigned using 5% intervals and ranged from 0% to 100%. Median protein expression levels were used as cut-off scores to define protein marker positivity and the findings were associated with clinical-pathological parameters. Results: HMGA1 and A2 are over-expressed in NSCLC tissues compared to normal lung (p Conclusion: HMGA1 and A2 over-expression seems to play an important role in lung carcinogenesis and additional studies are needed to demonstrate a potential prognostic impact of HMGA1 and HMGA2 expression in NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3195. doi:10.1158/1538-7445.AM2011-3195