RESUMO
The p53 target gene WIG-1 (ZMAT3) is located in chromosomal region 3q26, that is frequently amplified in human tumors, including cervical cancer. We have examined the status of WIG-1 and the encoded Wig-1 protein in cervical carcinoma cell lines and tumor tissue samples. Our analysis of eight cervical cancer lines (Ca Ski, ME-180, MS751, SiHa, SW756, C-4I, C-33A, and HT-3) by spectral karyotype, comparative genomic hybridization and Southern blotting revealed WIG-1 is not the primary target for chromosome 3 gains. However, WIG-1/Wig-1 were readily expressed and WIG-1 mRNA expression was higher in the two HPV-negative cervical cell lines (C33-A, HT-3) than in HPV-positive lines. We then assessed Wig-1 expression by immunohistochemistry in 38 cervical tumor samples. We found higher nuclear Wig-1 expression levels in HPV-negative compared to HPV positive cases (p = 0.002) and in adenocarcinomas as compared to squamous cell lesions (p<0.0001). Cases with moderate nuclear Wig-1 staining and positive cytoplasmic Wig-1 staining showed longer survival than patients with strong nuclear and negative cytoplasmic staining (p = 0.042). Nuclear Wig-1 expression levels were positively associated with age at diagnosis (p = 0.023) and histologic grade (p = 0.034). These results are consistent with a growth-promoting and/or anti-cell death function of nuclear Wig-1 and suggest that Wig-1 expression can serve as a prognostic marker in cervical carcinoma.
Assuntos
Proteínas de Transporte/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Papillomaviridae/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Cromossomos Humanos Par 3/genética , Feminino , Loci Gênicos/genética , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Proteínas Nucleares/metabolismo , Prognóstico , Proteínas de Ligação a RNA , Análise de Sobrevida , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologiaRESUMO
The demonstration of the PAX8-PPAR(gamma) fusion oncogene in a subset of follicular thyroid tumors provides a new and promising starting point to dissect the molecular genetic events involved in the development of this tumor form. In the present study, we compared the gene expression profiles of follicular thyroid carcinomas (FTCs) bearing a PAX8-PPAR(gamma) fusion against FTCs that lack this fusion. Using unsupervised clustering and multidimensional scaling analyses, we show that FTCs possessing a PAX8-PPAR(gamma) fusion have a highly uniform and distinct gene expression signature that clearly distinguishes them from FTCs without the fusion. The PAX8-PPAR(gamma)(+) FTCs grouped in a defined cluster, where highly ranked genes were mostly associated with signal transduction, cell growth and translation control. Notably, a large number of ribosomal protein and translation-associated genes were concurrently underexpressed in the FTCs with the fusion. Taken together, our findings further support that follicular carcinomas with a PAX8-PPAR(gamma) rearrangement constitute a distinct biological entity. The current data represent one step to elucidate the molecular pathways in the development of FTCs with the specific PAX8-PPAR(gamma) fusion.
Assuntos
Adenocarcinoma Folicular/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/diagnóstico , Oxirredutases do Álcool , Proteínas Correpressoras , Biologia Computacional , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Regulação para Baixo/genética , Proteínas do Olho/genética , Perfilação da Expressão Gênica , Humanos , Proteínas do Tecido Nervoso , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Fusão Oncogênica/biossíntese , Fator de Transcrição PAX8 , PPAR gama/genética , Fatores de Transcrição Box Pareados , Biossíntese de Proteínas/genética , Proteínas Ribossômicas/genética , Neoplasias da Glândula Tireoide/diagnóstico , Transativadores/genética , Transcrição Gênica , Regulação para Cima/genéticaRESUMO
To further delineate the role of chromosomal aberrations in non-medullary thyroid tumors, we performed cytogenetic analyses of established thyroid cancer cell lines and primary tumors using spectral karyotyping (SKY), G-banding and comparative genomic hybridization (CGH). Five of the primary thyroid tumors revealed an abnormal karyotype. In a follicular thyroid carcinoma, we observed two translocations t(2;10), t(2;5) and losses of chromosomes 10p and 22. In a papillary thyroid carcinoma (PTC), a balanced translocation t(3;15) was revealed, while a case of metastatic PTC carried several clonal translocations involving ten different chromosomes. Numerical aberrations were observed in two of the five follicular adenomas analyzed, both leading to gain of chromosome 7 material. Furthermore, we cytogenetically characterized the three established thyroid cancer cell lines CGTH W-1, ARO and DRO. SKY, in combination with G-banding, revealed structural and numerical karyotypic abnormalities in all three cell lines and the breakpoint regions partly overlapped those of the primary tumors. The copy number changes detected by CGH correlated well with the karyotypic findings and demonstrated high-level amplifications in chromosomes 1, 5, 7, 8, 9, 11 and 19. The results provide evidence of chromosomal regions involved in non-medullary thyroid tumorigenesis, while further characterization of the observed translocations may lead to the identification of novel fusion oncogenes for thyroid cancer.
Assuntos
Aberrações Cromossômicas , Neoplasias da Glândula Tireoide/genética , Adulto , Linhagem Celular Tumoral , Feminino , Amplificação de Genes/genética , Humanos , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites/genética , Cariotipagem Espectral , Neoplasias da Glândula Tireoide/patologia , Translocação Genética/genética , Células Tumorais CultivadasRESUMO
Recently, a translocation t(2; 3)(q13;p25), involving the fusion of PAX8 and peroxisome proliferator-activated receptor gamma (PPAR gamma) was suggested to arise only in follicular thyroid carcinomas. In this study, a group of 87 thyroid tumors were analyzed to determine the involvement of the PAX8/PPAR gamma fusion gene in these tumors, and also to determine whether this rearrangement can be used as a diagnostic marker for the differentiation between follicular thyroid carcinoma and adenoma. The PAX8/PPAR gamma rearrangement was detected by RT-PCR, fluorescence in situ hybridization, and/or Western analysis in 10 of 34 (29%) follicular thyroid carcinomas and in one of 20 (5%) atypical follicular thyroid adenomas, but not in any of the 20 follicular thyroid adenomas or 13 anaplastic thyroid carcinomas studied. In addition, seven of the 87 thyroid tumors exhibited involvement of PPAR gamma alone. Our findings suggest that PAX8/PPAR gamma occurs frequently in follicular thyroid carcinomas, and the presence of this rearrangement is likely to prove highly suggestive of a malignant tumor. Lack of the PAX8/PPAR gamma rearrangement in the anaplastic thyroid carcinoma group suggests that the tumorigenic pathway in these tumors is likely to be independent of this fusion. Furthermore, the results suggest that other rearrangements, involving PPAR gamma and other unidentified genes, may be involved in follicular thyroid tumorigenesis.
