Hepatitis B virus pre-S2 mutant stimulates aerobic glycolysis through mammalian target of rapamycin signaling in tumorigenesis

[[abstract]]Hepatitis B virus (HBV) pre-S2 mutant identified in ground glass hepatocytes (GGHs) in patients with chronic HBV infection has been proposed as viral oncoprotein and can induce hepatocellular carcinoma (HCC). Previously, we observed the activation of mammalian target of rapamycin (mTOR) by HBV pre-S2 mutant in GGHs and HCCs. The frequent association of metabolic syndrome with HCC raises the possibility that pre-S2 mutant-induced mTOR activation plays a driving role in the development of metabolic disorders in HBV-related HCC patients. To address this issue, we developed transgenic mice harboring pre-S2 mutant and analyzed gene expression profiles of the transgenic livers. In support of our hypothesis, the pre-S2 mutant transgenic mice showed glycogen depletion and glycolysis elevation in HCCs, a phenotype that has been implicated in highly proliferative malignancy. We identified that pre-S2 mutant could initiate an mTOR-dependent glycolytic pathway, involving Yin Yang 1, c-Myc, and glucose transporter 1 to upregulate aerobic glycolysis. This mTOR-mediated signaling pathway was significantly activated in the pre-S2 mutant transgenic livers and HCCs and contributed to aberrant glucose uptake and lactate production in vitro. Furthermore, we demonstrated that pre-S2 mutant could promote proliferation and invasion of HCC cells by sustaining the aerobic glycolysis. Activation of this glycolysis-associated mTOR signaling cascade was also observed in human HBV-related HCCs. Collectively, our results support the role of mTOR activation in the metabolic reprogramming of hepatocytes in chronic HBV infection and tumorigenesis, which should be valuable for chemoprevention design for HC