Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds. In vitro studies demonstrated that AIM2 expression was modulated by hepatitis B virus X protein (HBx) at transcriptional and post‐translational levels. HBx overexpression markedly blocked the expression of AIM2 at mRNA and protein levels by enhancing the stability of Enhancer of zeste homolog 2 (EZH2). Furthermore, HBx interacted with AIM2, resulting in an increase of AIM2 degradation via ubiquitination induction. Functionally, knockdown of AIM2 enhanced cell migration, formation of cell pseudopodium, wound healing and tumor metastasis, whereas reintroduction of AIM2 attenuated these functions. The loss of AIM2 induced the activation of epithelial‐mesenchymal transition (EMT). Fibronectin 1 (FN1) was found to be a downstream effector of AIM2, with its expression reversely modulated by AIM2. Silencing of FN1 significantly halted cell migration induced by AIM2 depletion. These data demonstrate that HBx‐induced loss of AIM2 is associated with poor outcomes and facilitates HCC metastasis by triggering the EMT process. The results of the present study therefore suggest that AIM2 is a potential prognostic biomarker in hepatitis B virus‐related HCC, as well as a possible therapeutic target for tumor metastasis.

Background:Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear.Methods:A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan–Meier analysis was conducted to assess the prognostic value of P2-HNF4α.Results:The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression (p = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC (p = 0.002) and vascular invasion (p = 0.017). Kaplan–Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group (p = 0.01), validation group (p = 0.034), and overall group of patients with HCC (p < 0.001).Conclusions:Our data show that the role of HNF4α in cancer development needs to be further refined. P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

For chronic hepatitis B patients with coexisting components of metabolic syndrome, stratification by independent risk factors for nonalcoholic fatty liver disease and fibrosis can help with management of their disease.

This study compared virologic response to entecavir monotherapy and de novo lamivudine plus adefovir (LAM + ADV) combination therapy in patients with chronic hepatitis B (CHB) with high viral load (HVL). Hepatitis B e antigen (HBeAg)-positive patients [hepatitis B virus (HBV) DNA levels >1 × 10(7) copies/ml] were assigned to LAM + ADV or entecavir treatment. The primary efficacy endpoint measure of the multicenter prospective cohort study was proportion of patients with CHB with virologic response, defined as HBV DNA <300 copies/ml at week 48. During treatment, 39.1 % (18/46) of patients in the LAM + ADV group and 48.1 % (25/52) of those in the entecavir group achieved virologic response in week 48 (P = 0.37). A baseline alanine aminotransferase (ALT) level ≥5 × ULN (upper limit of normal) or baseline serum HBV DNA level <8 log10 IU/ml could predict virologic response at week 48 (P = 0.025). The mean reduction in HBV DNA was comparable (P = 0.45); no significant difference was found in the proportion of ALT normalization (P = 0.46) or HBeAg seroconversion (P = 0.88). Two cases of genotypic resistance were found (rtM204 V + rtL180 M and rtA181T/V) in the LAM + ADV group, with a resistance rate of 4.3 %; there was no genotypic resistance in the entecavir group (P = 0.13). De novo LAM + ADV combination therapy is as effective as entecavir monotherapy in HBeAg-positive patients with CHB with HVL. Moreover, genotypic resistance was only found in the LAM + ADV group at week 48. Baseline ALT levels ≥5 ULN or baseline serum HBV DNA levels <8 log10 IU/ml were favorable predictors of virologic response in CHB with HVL.