RESUMEN
The epigenetic dysregulation of tumor suppressor genes plays an important role in many cancers, including hepatocellular carcinoma (HCC). In this study, we identified a new gene, family with sequence similarity 43, member B (FAM43B), based on a previous genome-wide approach. FAM43B was significantly downregulated in 60% (24/40) HCC specimens as compared to non-HCC livers. Enforced FAM43B overexpression could suppress cell growth and colony formation in vitro, and induce cell cycle delay, whereas FAM43B knockdown enhanced cell growth. The expression level of FAM43B was found related to the methylation level of FAM43B promoter in HCC cell lines and HCC specimens. The collective data suggest that the expression of FAM43B was regulated by methylation and the epigenetic silencing of FAM43B could contribute to HCC tumorigenesis by regulating cell proliferation.
Asunto(s)
Carcinoma Hepatocelular/genética , Proliferación Celular , Metilación de ADN , Epigénesis Genética , Genes Supresores de Tumor , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/metabolismo , Ciclo Celular/genética , Línea Celular Tumoral , Núcleo Celular/metabolismo , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/metabolismo , Especificidad de Órganos , Filogenia , Regiones Promotoras Genéticas , Interferencia de ARNRESUMEN
The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Here, in a human genome-wide survey, we identified scavenger receptor class A, member 5 (SCARA5) as a candidate tumor suppressor gene located on chromosome 8p. We found that SCARA5 expression was frequently downregulated as a result of promoter hypermethylation and allelic imbalance and was associated with vascular invasion in human hepatocellular carcinoma (HCC). Furthermore, SCARA5 knockdown via RNAi markedly enhanced HCC cell growth in vitro, colony formation in soft agar, and invasiveness, tumorigenicity, and lung metastasis in vivo. By contrast, SCARA5 overexpression suppressed these malignant behaviors. Interestingly, SCARA5 was found to physically associate with focal adhesion kinase (FAK) and inhibit the tyrosine phosphorylation cascade of the FAK-Src-Cas signaling pathway. Conversely, silencing SCARA5 stimulated the signaling pathway via increased phosphorylation of certain tyrosine residues of FAK, Src, and p130Cas; it was also associated with activation of MMP9, a tumor metastasis-associated enzyme. Taken together, these data suggest that the plasma membrane protein SCARA5 can contribute to HCC tumorigenesis and metastasis via activation of the FAK signaling pathway.
Asunto(s)
Carcinoma Hepatocelular/etiología , Proteína-Tirosina Quinasas de Adhesión Focal/fisiología , Neoplasias Hepáticas/etiología , Receptores Depuradores de Clase A/fisiología , Transducción de Señal/fisiología , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Cromosomas Humanos Par 8 , Metilación de ADN , Silenciador del Gen , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Pérdida de Heterocigocidad , Ratones , Ratones SCID , Invasividad Neoplásica , Regiones Promotoras Genéticas , Receptores Depuradores de Clase A/antagonistas & inhibidores , Receptores Depuradores de Clase A/genéticaRESUMEN
This study reported that all three human BolA proteins (hBolA1, hBolA2, and hBolA3) are novel non-classical secreted proteins identified with bioinformatics and molecular biology experiments. The three BolA fusion proteins with c-Myc tag could be secreted into the culture medium of the transfected Cos-7 cells, although they could not be colocalized with Golgi apparatus. And the secretion of three BolA proteins could not be inhibited after BFA treatment. Furthermore, the secretion was not dependent on its predicted signal peptide. All the experiment results suggested that the secretion was a non-classical export. Phylogenetic analysis showed that the human BolAs belong to three different groups with functional divergence of BolA subfamily, where the different helix-turn-helix motif among hBolA1, hBolA2, and hBolA3 could be responsible for their functional divergence. Our data provided a basis for functional studies of BolA protein family.
