We aimed to elucidate the effects and underlying mechanisms of hepatitis B virus (HBV) preS mutations on hepatocarcinogenesis. The association between preS mutations and hepatocellular carcinoma (HCC) occurrence was evaluated using a cohort of 2114 HBV-infected patients. Combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased HCC risk in patients without antiviral treatment, whereas preS2 deletion significantly increased the HCC risk in patients who received

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... treatment. The preS1/preS2/S mutants and their wild-type counterpart were delivered into Sleeping Beauty (SB) mouse models. preS1/preS2/S mutants induced a higher tumor rate and higher serum levels of inflammatory cytokines than did wild type-preS1/preS2/S in SB mice. The preS1/preS2/S mutants induced dramatic alteration of gene expression profiles partially through inducing pro-oncogenic inflammatory cytokine. Through enhancing the retention of HBV S protein in endoplasmic reticulum (ER), the preS1/preS2/S mutants enhanced ER stress, induced the alteration in metabolism, affected the response to hypoxia, and upregulated the protein level of signal transducer and activator of transcription 3 (STAT3). Inhibiting the STAT3 pathway attenuated the positive effects of preS1/preS2/S mutants on cell proliferation. Thus, G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promote hepatocarcinogenesis via inducing ER stress, metabolism, and pro-oncogenic STAT3 inflammatory pathways, which can be transformed into specific prophylaxis of HCC.