HBx promotes tumorigenicity through RRM2-mediated autophagy in hepatocellular carcinoma

Abstract

HBV infection can exacerbate liver disease progression through multiple mechanisms, eventually leading to hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key regulatory protein of HBV infection, serves as a positive regulator of hepatocarcinogenesis. Ribonucleotide-diphosphate reductase M2 subunit (RRM2), which is indispensable for DNA replication and repair, has been shown overexpressed in a range of malignancies. Our previous studies clarified that RRM2 expression is highly elevated in HCC, particularly in HBV-related HCC. Given the robust RRM2 expression is strongly associated with poor survival rate of the patients with HCC, while the specific functions and underlying mechanisms of RRM2 in HBV-related HCC remain elusive; the present study was performed to elucidate whether HBx increases RRM2 expression, and whether RRM2 engages in interaction with HBx in vivo and in vitro. Autophagy is a crucial step in the oncogenic process of HBx, while autophagy inhibition attenuates HBx-initiated proliferation response. We further demonstrated that RRM2 interference lowered HBx-induced autophagy, inhibited the production of autophagic vesicles and lysosomes, and caused G1/S blockage, thereby inhibiting HBx-stimulated hepatocellular carcinogenesis. Our findings indicate that RRM2 may play a tumor-promoting role in HBV-associated HCC by modulating autophagy, suggesting that RRM2 may be a potential therapeutic target for HCC.