The Emerging Role of Ground Glass Hepatocytes and Hepatitis B Virus Pre-S Mutants in Anti-Viral Therapy and HBV Tumor Genesis - Abstract
Although chronic hepatitis B virus (HBV) infection has been well-established to cause hepatocellular carcinoma (HCC), the preneoplastic lesions in liver and the exact molecular mechanism of HBV tumor genesis remains to be elucidated. Current views of HBV tumor genesis include inflammation and liver regeneration associated with cytotoxic immune injuries at the early stage, the random dysregulation of cellular growth control genes by genetic abnormalities, and the transcriptional activators of mutant HBV gene products at the advanced stage of chronic HBV infection. Besides HBx, the pre-S2 (deletion) mutant protein represents a newly recognized viral oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGH) due to ER proliferation. The retention of pre-S2 mutant protein in GGHs can induce ER stress-dependent and –independent pathway to initiate VEGF/Akt/mTOR, NFkB/COX-2 and JAB-1/p27/RB/cyclin A, D pathway, leading to growth advantage of type II GGH. The pre-S2 mutant protein-induced ER stress response can also cause DNA damage, centrosome overduplication, and genomic instability. Type II GGHs can co-express pre-S2 mutant protein and HBx antigen which together exhibit an enhanced oncogenic effect in transgenic mice. Distinct from type II GGHs, type I GGHs usually distribute sporadically and express stronger ER stress which will lead to apoptosis. Clinically, the presence of pre-S2 deletion mutants in sera frequently develops resistance to nucleoside analogues anti-virals and closely associate with HCC development. Whether type II GGHs represent a lesion of focal adenomatous hyperplasia and directly contribute to HCC development remains to be clarified. A versatile DNA array chip and ELISA kit have been developed to detect pre-S2 mutants in serum. Overall, the current evidence suggest that the presence of GGHs, particularly type II, and the detection of pre-S2 mutants in serum has implications for anti-viral treatment and can predict HCC development in patients with chronic HBV infection. A well-designed cohort study and clinical trial should be conducted to confirm that type II GGHs represent precursor lesions of HBV-related HCCs.