SORBS2, mediated by MEF2D, suppresses the metastasis of human hepatocellular carcinoma by inhibitiing the c-Abl-ERK signaling pathway.

The RBP sorbin and SH3 domain-containing 2 (SORBS2) has been reported to be a tumor suppressor and is dysregulated in several cancer types. Nonetheless, the exact function and mechanism of action of SORBS2 in hepatocellular carcinoma (HCC) remain unclear. In this study, we found that expression levels of SORBS2 were significantly lower in HCC tissues than that in normal tissue samples, and underexpression of SORBS2 was associated with lower overall survival tates of patients with HCC. In HCC cell lines, SORBS2 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition, whereas SORBS2 inhibition yielded the opposite results. In vivo metastasis assays confirmed that overexpression of SORBS2 markedly inhibited HCC metastasis. Mechanistically, SORBS2 exerted tumor-suppressive effects on HCC by inhibiting the c-Abl/ERK signaling pathway. Furthermore, MEF2D, which binds to the promoter of SORBS2, was identified as an upstream regulator of SORBS2 and reduced SORBS2 expression. Our data suggest that SORBS2, downregulated by MEF2D, suppresses HCC metastasis through the c-Abl/ERK signaling pathway and has the potential to serve as a novel prognostic marker or therapeutic target in HCC. AJCR