Interferon-induced transmembrane protein 3 (IFITM3) has been shown to be overexpressed in multiple cancers. However, the role of IFITM3 in metastasis of hepatocellular carcinoma (HCC) is still poorly understood. In this study, we showed that IFITM3 was frequently overexpressed in HCC tissues compared with adjacent nontumor tissues. Overexpression of IFITM3 was significantly correlated with tumor metastasis and poor prognosis in HCC. Knockdown of IFITM3 dramatically decreased MMP9 expression and inhibited the invasion and metastasis of HCC in vitro and in vivo. Moreover, the upregulation of MMP9 rescued the decreased migration and invasion induced by the knockdown of IFITM3, whereas the knockdown of MMP9 decreased IFITM3-enhanced HCC migration and invasion. Mechanistically, we found that IFITM3 regulates MMP9 expression through the p38/MAPK pathway. Taken together, we identified a novel IFITM3-p38/MAPK-MMP9 regulatory circuitry, the dysfunction of which drives invasive and metastatic character in HCC.
Keywords: IFITM3; MMP9; hepatocellular carcinoma; metastasis; p38/MAPK pathway.