Abstract
The hepatitis B virus (HBV) X protein (HBX), a viral macromolecule, plays a vital role in the development of HBV-related hepatocellular carcinoma (HCC). Increased expression of HER2 is linked to HBV infection, and HBX is responsible for HER2 upregulation in HCC. Nevertheless, the underlying molecular mechanisms are not yet fully understood. In the study, we discovered that HBX promoted HER2 expression to facilitate the sensitization of the insulin signaling pathway and enhance the growth and migration of HCC cells. Mechanistically, the viral protein enhanced the stability of HER2 by preventing its ubiquitination-mediated proteasomal degradation through LASP1, which could bind to HER2. Furthermore, increased SUMOylation of LASP1 contributed to the upregulation of HER2 and the interaction of LASP1 with HER2. In addition, RANBP2 and RANGAP1 were found to interact with LASP1 and promote SUMOylation of LASP1 to upregulate HER2 expression in HBX-associated hepatoma cells. In summary, our work provides a novel insight into hepatocarcinogenesis mediated by HBX and estimates the detailed mechanisms related to the increase in HER2 regulated by the viral protein, which might help provide a theoretical basis for identifying novel targets for HBV-positive HCC treatment.