Abstract
Chronic hepatitis B virus (HBV) infection can cause hepatocellular carcinoma (HCC). Several hypotheses have been proposed to explain the mechanisms of HBV tumorigenesis, including inflammation and liver regeneration associated with cytotoxic immune injuries and transcriptional activators of mutant HBV gene products. The mutant viral oncoprotein-driven tumorigenesis is prevailed at the advanced stage or anti-HBe-positive phase of chronic HBV infection. Besides HBx, the pre-S2 (deletion) mutant protein represents a newly recognized oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGH). The retention of pre-S2 mutant protein in ER can induce ER stress and initiate an ER stress-dependent VEGF/Akt/mTOR and NFκB/COX-2 signal pathway. Additionally, the pre-S2 mutant large surface protein can induce an ER stress-independent pathway to transactivate JAB-1/p27/RB/cyclin A,D pathway, leading to growth advantage of type II GGH. The pre-S2 mutant protein-induced ER stress can also cause DNA damage, centrosome overduplication, and genomic instability. In 5-10% of type II GGHs, there is co-expression of pre-S2 mutant protein and HBx antigen which exhibited enhanced oncogenic effects in transgenic mice. The mTOR signal cascade is consistently activated throughout the course of pre-S2 mutant transgenic livers and in human HCC tissues, leading to metabolic disorders and HCC tumorigenesis. Clinically, the presence of pre-S2 deletion mutants in sera frequently develop resistance to nucleoside analogues anti-virals and predict HCC development. The pre-S2 deletion mutants and type II GGHs therefore represent novel biomarkers of HBV-related HCCs. A versatile DNA array chip has been developed to detect pre-S2 mutants in serum. Overall, the presence of pre-S2 mutants in serum has implications for anti-viral treatment and can predict HCC development. Targeting at pre-S2 mutant protein-induced, ER stress-dependent, mTOR signal cascade and metabolic disorders may offer potential strategy for chemoprevention or therapy in high risk chronic HBV carriers.
Highlights
Hepatitis B virus ( hepatitis B virus (HBV) ) has been well established to cause hepatocellular carcinoma ( HCCs ) [1]
We demonstrated that pre-S2 mutant could activate two mTOR-induced metabolic pathways, one involving Yin Yang 1 (YY1), c-myc and, glucose transporter 1 (GLUT1) to upregulate aerobic glycolysis, and the other involving sterol regulatory element-binding protein-1 (SREBP-1) and acyl-CoA lyase (ACLY) to promote de novo lipid biosynthesis (Teng C.F. et al, unpublished data)
The HBV pre-S2 deletion mutant proteins are retained in the endoplasmic reticulum (ER) and induce ER stress response
Summary
Hepatitis B virus ( HBV ) has been well established to cause hepatocellular carcinoma ( HCCs ) [1]. Ectopic expression of pre-S mutant proteins in Huh-7 cells increased the levels of ER chaperones (Grp and 94) and activated PERK and C-jun N-terminal kinase (JNK) [11] These results indicate that both pre-S1 and pre-S2 mutant surface proteins induce ER stress signals in hepatocytes. In consistence with this assumption, elevated Grp expression was detected in both type I and type II GGHs in the liver [11]. The combined effects of cell cycle progression, genomic instabilities, and survival advantage exhibited by pre-S2 mutant proteins strongly suggest that type II GGHs are potential preneoplastic loci for HCC development and de novo recurrence after surgical resection. Further studies or clinical trials are needed to validate the effect of the natural products, with or without the combination of antivirals in chemoprevention or therapy of HBV-related HCCs
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