Canonical WNT Signaling Activated by WNT7B Contributes to L-HBs-Mediated Sorafenib Resistance in Hepatocellular Carcinoma by Inhibiting Mitophagy

SIMPLE SUMMARY: Hepatitis B virus (HBV) is the main cause of hepatocellular carcinoma (HCC) morbidity and mortality. Because of chemoresistance, sorafenib, the first-line systemic therapy for advanced HCC, has minimal advantages. According to recent research, HBV plays a role in sorafenib resistance. However, the mechanisms remain unknown. WNT signaling is one of the critical signal pathways connected to cancer chemoresistance. We found that WNT7B was overexpressed in HBV-associated HCC tissues. Large hepatitis B surface antigens (L-HBs) increased canonical WNT signaling in HCC cells through WNT7B/frizzled-4 (FZD4). In HCC, WNT7B increased cell proliferation and metastasis. By decreasing mitophagy, L-HBs produced sorafenib resistance via WNT7B. The findings suggest a potential molecular target for HBV-related HCC development and chemoresistance. ABSTRACT: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, with hepatitis B virus (HBV) infection accounting for over half of all cases. HBV leads to the development of HCC according to a body of literature. Our previous research and other studies also suggest that HBV causes chemotherapeutic treatment resistance, however, the mechanism is uncertain. The WNT family, which encodes secreted signaling molecules, has been linked to carcinogenesis in a variety of malignancies, including HCC. However, little is known regarding WNT7B, a WNT ligand, in the development of HCC and HBV-induced chemoresistance. In this study, the bioinformatics analysis and immunohistochemistry (IHC) staining of clinical samples revealed that WNT7B was overexpressed in HBV-associated HCC tissues versus nontumor liver tissues, which was related to HCC patient survival. Further study in vitro showed that WNT7B and its receptor frizzled-4 (FZD4) were upregulated in response to large hepatitis B surface antigens (L-HBs). L-HBs increased canonical WNT signaling in HCC cells through WNT7B/FZD4. According to functional experiments, WNT7B enhanced the cell proliferation and metastasis in HCC. In vivo and in vitro studies investigated whether L-HBs induced sorafenib resistance by WNT7B in HCC. Interestingly, L-HBs suppressed sorafenib-induced mitophagy by increasing WNT7B/CTNNB1 signaling, resulting in chemoresistance. The findings revealed that WNT7B could be a promising molecular therapeutic target as well as a predictor of sorafenib resistance in HBV-related HCC. The suppression of HBV structural proteins such as L-HBs may play a crucial role in systemic chemotherapy resistance in HBV-associated HCC.