Abstract

Seven in absentia homologue 2 (SIAH2) has been shown to contribute to the progression of various human tumors, including hepatocellular carcinoma (HCC). However, the precise mechanisms by which SIAH2 promotes HCC cell migration remain to be fully elucidated. In this study, we demonstrate that SIAH2 accelerates the invasion and migration of HCC cells by promoting K48-linked polyubiquitination and degradation of EPH receptor B6 (EPHB6). Notably, the invasion and migration of HCC cells regulated by the SIAH2-EPHB6 axis in association with enhanced filopodia formation, a critical early step in cell motility. Furthermore, our findings indicate that the SIAH2-EPHB6 axis promotes filopodia formation in HCC cells by modulating Ras homolog family member F (RHOF). Finally, we investigated the expression correlations among SIAH2, EPHB6, and RHOF using clinical tissue specimens. In summary, SIAH2 accelerates K48-linked polyubiquitination and degradation of EPHB6 to regulate filopodia formation in HCC cells.