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Figure 1. Direct oncogenic mechanisms of HBV- and NAFLD- HCC. HBV-encoded proteins lead to cellular heterogeneity via multiple manners. HBx stabilizes oncoproteins by suppressing ubiquitination or regulates transcription of host genes through transactivation. Cytoplasmic accumulation of HBs induces ER stress and thereby initiates cellular hippo pathways. Besides ER response, NF-κB, Src/PI3K/Akt and TRAIL/Fas pathways are involved in HBc-induced abnormal proliferation and metabolism of hepatocytes. Furthermore, HBV DNA integration and viral protein result in DNA damage and genomic instability, which drive cellular heterogeneity. Excessive lipid accumulation stimulates ER stress and dysregulates apoptosis and fibrogenesis via STAT3 and hippo pathways. The STAT5 and Akt pathways are involved in upregulation of the lipogenetic genes and downstream targets. Moreover, gene polymorphism is significantly related with NAFLD progression. HBV: hepatitis B virus; NAFLD: nonalcoholic fatty liver disease; HCC: hepatocellular carcinoma; ER: endoplasmic reticulum