Hepatitis B surface antigen inhibits MICA and MICB expression via induction of cellular miRNAs in hepatocellular carcinoma cells

Hepatitis B surface antigen (HBsAg) seropositivity is an important risk factor for hepatocellular carcinoma (HCC), and HBsAg transgenic mice have been reported to spontaneously develop HCC. The major histocompatibility complex (MHC) class I-related molecules A and B (MICA and MICB) are NKG2D ligands that play important roles in tumor immune surveillance. In the present study, we found that HBsAg overexpression in HepG2 cells led to up-regulation of 133 and down-regulation of 9 miRNAs. Interestingly, several HBsAg-induced miRNAs repressed the expression of MICA and MICB via targeting their 3′-untranslated regions (3′-UTRs). In addition, the expression of MICA and MICB was significantly reduced upon HBsAg overexpression, which was partially restored by inhibiting the activities of HBsAg-induced miRNAs. Moreover, HBsAg-overexpressing HCC cells exhibited reduced sensitivity to NK cell-mediated cytolysis. Taken together, our data suggest that HBsAg represses the expression of MICA and MICB via induction of cellular miRNAs, thereby preventing NKG2D-mediated elimination of HCC cells.