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.

Background/Aims:The aim of this study was to identify the predictors for relapse after discontinuation of oral nucleos(t)ide analog treatment for chronic hepatitis B (CHB).Patients and Methods:We evaluated patients who were receiving long-term, regular antiviral therapy with nucleos(t)ide analogs, and subsequently achieved the discontinuation criteria from the Asia-Pacific guideline. After they voluntarily discontinued the drug therapy, data were prospectively collected to observe the potential virologic relapse, and the parameters that predicted recurrence were analyzed.Results:Sixty-five patients met the inclusion criteria, and were included in this study. Twenty-eight patients relapsed, and the accumulative recurrence rates at the 3-month, 6-month, and 1-year follow-ups were 13.85%, 32.31%, and 49.23%, respectively. There was no difference in the accumulative recurrence rate 12 months after discontinuation among patients who were positive or negative for the hepatitis B e antigen (HBeAg) before they received the medication. Logistic regression analysis revealed that the time to complete response, age at discontinuation, and HBsAg levels at discontinuation affected the rate of relapse.Conclusions:Among patients who received orally administrated nucleos(t)ide analogs, serum levels of HBsAg, age at discontinuation, and the time to complete response might be used as a guide to discontinue treatment. Among younger patients, those with low serum HBsAg levels, and those with an earlier complete response, the risk of relapse is lower and discontinuation is much safer.

BackgroundPatients with chronic hepatitis B virus (HBV) infection who are hepatitis B virus e antigen (HBeAg) positive are increasingly being treated with nucleos(t)ide analogs (NUCs). However, the predictive value of serum hepatitis B virus core antibody (HBcAb) levels for HBeAg seroconversion among patients with high viral load remains unclear.MethodsThis study consisted of 74 patients with high viral load (HBV DNA >1 × 107 copies/mL) enrolled in a multicenter, randomized, controlled trial, treated with lamivudine and adefovir (N = 32) or entecavir (N = 42) for up to 96 weeks. Serum HBV DNA, quantitative hepatitis B virus surface antigen (HBsAg), HBeAg, and HBeAb was tested at each visit. Quantitative HBcAb evaluation was conducted for all the available samples in the trial, by using a newly developed double-sandwich anti-HBc immunoassay.ResultsSerum HBcAb levels were significantly higher in patients with a serum alanine aminotransferase (ALT) level more than five times the upper limit of normal (ULN) compared with patients with ALT levels within 5 × ULN (4.25 ± 0.61 vs. 3.94 ± 0.47 log10 IU/mL, P = 0.0345). Patients with HBeAg seroconversion were associated with a higher level of HBcAb at baseline, compared with those without HBeAg seroconversion (4.38 ± 0.54 vs. 4.02 ± 0.58 log10 IU/mL, P = 0.029). The area under receiver operating characteristic curve of baseline HBcAb for HBeAg seroconversion was 0.71 (95% CI: 0.55–0.86, P = 0.013). When the baseline HBcAb level was >4.375 log10 IU/mL, the sensitivity and specificity to predict HBeAg seroconversion at week 96 were 62.5% and 74.2%, and the positive likelihood ratio (LR) and negative LR were 2.42 and 0.51, respectively. The multivariate analysis result indicated that baseline serum HBcAb level was the only independent predictor for HBeAg seroconversion at week 96, with an odds ratio of 4.78.ConclusionBaseline serum HBcAb level >4.375 log10 IU/mL could satisfactorily predict HBeAg seroconversion among patients with high viral load treated with NUC.

IntroductionHepatocellular carcinoma (HCC) has a close relationship with lipid metabolism. Peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the regulation of fatty acid oxidation in the liver. However, the role of PPARα in HCC remains unclear.MethodsA total of 804 HCC specimens were collected to construct a tissue microarray and for immunohistochemical analysis. The relationship between PPARα expression and clinical features of HCC patients was analyzed. Kaplan–Meier analysis was conducted to assess the prognostic value of PPARα expression levels.ResultsThe expression of PPARα in HCC was noticeably decreased in HCC tissues. HCC patients with high levels of PPARα expression in cytoplasm had smaller tumors (P=0.027), less vascular invasion (P=0.049), and a higher proportion of complete involucrum (P=0.038). Kaplan–Meier analysis showed that HCC patients with low PPARα expression in the cytoplasm had significantly worse outcomes in terms of overall survival (P<0.001), disease-free survival (P=0.024), and the probability of recurrence (P=0.037). Similarly, overall survival was significantly shorter in HCC patients with negative PPARα expression in the nucleus (P=0.034). Multivariate Cox analyses indicated that tumor size (P=0.001), TNM stage (P<0.001), vascular invasion (P<0.001), and PPARα expression in the cytoplasm (P<0.001) were found to be independent prognostic variables for overall survival.ConclusionOur data revealed that PPARα expression was decreased in HCC samples. High PPARα expression was correlated with longer survival times in HCC patients, and served as an independent factor for better outcomes. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

Objective:The objective of this study was to develop a noninvasive diagnostic test for nonalcoholic hepatic steatosis in patients with chronic hepatitis B (CHB) by using routinely available clinical markers.Methods:A retrospective study of patients with CHB, with or without hepatic steatosis (fatty change) who were diagnosed with controlled attenuation parameter (CAP) measured by transient elastography were included. Patient information was analyzed on lifestyle; laboratory tests, including serum lipid levels; blood pressure; blood uric acid; and medical history of type 2 diabetes mellitus (T2DM).Results:A total of 1312 patients were included in the study; 618 patients had confirmed hepatic steatosis. The CAP levels were significantly correlated with patient height (p < 0.001), weight (p < 0.001), waistline measurement (p < 0.001), hipline measurement (p < 0.001), and diastolic blood pressure (DBP) (p < 0.001). Multivariate logistic regression analysis resulted in the development of an equation for the diagnostic of simple steatosis: the fatty liver (FL) test. The area under the receiver operating characteristic (AUROC) curve of the FL test was 0.79 (p < 0.001) in the training group and 0.82 in the validation group. When the FL test was >−0.425, the sensitivity, specificity, positive likelihood ratio (LR) and negative LR were 74.72%, 72.12%, 2.68, and 0.35 respectively. The average FL test result was −0.54 ± 1.26 in patients with CHB without hypertension, and 0.42 ± 1.35, 1.12 ± 1.65, and 1.98 ± 1.22 in patients with hypertension grade 1, 2, and 3, respectively (p < 0.001).Conclusion:This study has demonstrated a noninvasive test for hepatic steatosis in patients with CHB.