The cancer/testis antigen MAGEC2 promotes amoeboid invasion of tumor cells by enhancing STAT3 signaling

The biological function of MAGEC2, a cancer/testis antigen highly expressed in various cancers, remains largely unknown. Here we demonstrate that expression of MAGEC2 induces rounded morphology and amoeboid-like movement of tumor cells in vitro and promotes tumor metastasis in vivo. The pro-metastasis effect of MAGEC2 was mediated by signal transducer and activator of transcription 3 (STAT3) activation. Mechanistically, MAGEC2 interacts with STAT3 and inhibits the polyubiquitination and proteasomal degradation of STAT3 in the nucleus of tumor cells, resulting in accumulation of phosphorylated STAT3 and enhanced transcriptional activity. Notably, expression levels of MAGEC2 and phosphorylated STAT3 are positively correlated and both are associated with incidence of metastasis in human hepatocellular carcinoma. This study not only reveals a previously unappreciated role of MAGEC2 in promoting tumor metastasis, but also identifies a new molecular mechanism by which MAGEC2 sustains hyperactivation of STAT3 in the nucleus of tumor cells. Thus, MAGEC2 may represent a new antitumor metastasis target for treatment of cancer.