Hepatitis B Virus Pre-S Mutants as Biomarkers and Targets for the Development and Recurrence of Hepatocellular Carcinoma

Abstract

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), the leading cause of cancer-related death worldwide. Despite progress in the prevention and therapy of HCC, high incidence and recurrence rates of HCC remain big threats, resulting in poor patient survival. Effective biomarkers and targets of HCC are therefore urgently needed for better management and to improve patient outcomes. Pre-S mutants have been well demonstrated as HBV oncoproteins that play important roles in HCC development through activation of multiple oncogenic signal pathways in hepatocytes, in vitro and in vivo. The presence of pre-S mutants in patients with chronic HBV infection and HBV-related HCC has been associated with a significantly higher risk of HCC development and recurrence after curative surgical resection, respectively. In this review, we summarize the roles of pre-S mutants as biomarkers for predicting HBV-related HCC development and recurrence, and highlight the pre-S mutants-activated oncogenic signal pathways as potential targets for preventing HBV-related HCC development.

Keywords: biomarkers; hepatitis B virus; hepatocellular carcinoma; pre-S mutants; targets.

Figure 1

Schematic representation of HBV pre-S mutants-activated mTOR signal pathways as potential targets for HCC chemoprevention. In chronic HBV infection, pre-S mutants can upregulate the expression of vascular endothelial growth factor-A (VEGF-A) in GHHs. Through binding to its cognate receptor, the upregulated VEGF-A functions in either autocrine or paracrine manners to activate mTOR via mediation of Akt activation. The activated mTOR can promote hepatocyte proliferation directly or indirectly, by initiating two metabolic pathways, one involving Yin Yang 1 (YY1)/MYC/solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) to induce aerobic glycolysis, and another involving sterol regulatory element-binding factor 1 (SREBF1)/adenosine triphosphate citrate lyase (ACLY)/fatty acid desaturase 2 (FADS2) to stimulate lipid synthesis. Combined effects of hepatocyte proliferation, aerobic glycolysis, and lipid synthesis will potentially result in HCC development. By means of blocking the pre-S mutants-activated mTOR signal pathways, treatment of either the resveratrol combined with silymarin or the phytosome-formulated curcumin exhibits potential efficacy in preventing HCC development. Abbreviations: HBV, hepatitis B virus; VEGF-A, vascular endothelial growth factor-A; mTOR, mammalian target of rapamycin; YY1, Yin Yang 1; SLC2A1, solute carrier family 2 (facilitated glucose transporter) member 1; SREBF1, sterol regulatory element-binding factor 1; ACLY, adenosine triphosphate citrate lyase; FADS2, fatty acid desaturase 2; HCC, hepatocellular carcinoma.