Hepatitis B Virus X Protein Up-Regulates Alpha-Fetoprotein to Promote Hepatocellular Carcinoma by Targeting miR-1236 and miR-1270

Abstract

HBV infection is the most common cause of hepatocellular carcinoma (HCC) worldwide, in which process expression of alpha-fetoprotein (AFP) is reactivated to promote tumorgenesis. The HBx protein has been implicated in hepatocarcinogenesis and considered to be oncogenic. However, the relationship between HBx and abnormal AFP expression in HCC hasn't been fully established. To explore the potential regulation of HBx on AFP re-expression in HCC, 97 HCC samples of different etiology were analyzed, and extremely higher AFP levels are found in HBsAg+ patients. Analyses of HBV-related HCC specimens show that up-regulation of AFP is associated with down-regulation of miR-1236 and miR-1270. Further analyses indicate that HBx promotes AFP expression by orchestrating the expression of miR-1236 and miR-1270 both in vitro and in vivo. Specifically, miR-1236 and miR-1270 bind to potential target sequences in AFP-mRNA-3'-UTR to suppress its expression. HBx transfection results in apparent decrement of these miRNAs and increment of AFP expression. Moreover, AFP promotes the proliferation of hepatoma cells and attenuates the pro-apoptotic effect of chemotherapy agents. These findings reveal a novel regulatory mechanism of HBx on abnormal AFP expression in HCC and might provide a therapeutic approach for combating HBV-related HCC by targeting regulation of AFP expression.

Keywords: Alpha-fetoprotein, microRNAs, hepatitis B virus X protein, post-transcriptional regulation, hepatocellular carcinoma