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Oncogene ; 37(5): 673-686, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29035390

RESUMO

Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context.


Assuntos
Proteína 4 Semelhante a Angiopoietina/genética , Carcinoma de Células de Transição/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica/genética , Microambiente Tumoral , Neoplasias da Bexiga Urinária/genética , Idoso , Idoso de 80 Anos ou mais , Proteína 4 Semelhante a Angiopoietina/sangue , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Carcinogênese/genética , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cistectomia , Metilação de DNA/genética , Regulação para Baixo , Feminino , Genes Supressores de Tumor , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Oncogenes/genética , Regiões Promotoras Genéticas/genética , Transdução de Sinais , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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