Androgen receptor-induced molecules and androgen contribute synergistically to male-predominance of hepatocellular carcinoma.

We aimed to clarify the mechanisms of male predominance of hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC). Androgen receptor (AR) facilitates HCC cell growth, which was augmented by androgen (dihydrotestosterone [DHT]) and attenuated by anti-androgen (flutamide). AR upregulated the expressions of BIRC7, IGFBP3, and NTSR1 via increasing their promoter activities, which were enhanced by DHT. Wild-type HBV X (WT-HBx) upregulated AR transcription, which depended on DHT; whereas the effect of C-terminal carboxy-truncated HBx on AR transcription was independent of DHT. BIRC7, IGFBP3, and NTSR1 increased the growth of HCC. High expression of BIRC7 and NTSR1 contributes to poor HCC outcomes in male patients, but not in female patients. Downregulation of NTSR1 inhibits tumor growth in male mice rather than in female mice. Conclusively, AR promotes HCC at least partially via upregulating BIRC7, IGFBP3, and NTSR1, which is enhanced by androgen and HBx. BIRC7 and NTSR1 facilitate HCC progression in a male-predominant manner.

HBV preS Mutations Promote Hepatocarcinogenesis by Inducing Endoplasmic Reticulum Stress and Upregulating Inflammatory Signaling.

This study aimed to elucidate the effects and underlying mechanisms of hepatitis B virus (HBV) preS mutations on hepatocarcinogenesis. The effect of the preS mutations on hepatocellular carcinoma (HCC) occurrence was evaluated using a prospective cohort study with 2114 HBV-infected patients, of whom 612 received antiviral treatments. The oncogenic functions of HBV preS mutations were investigated using cancer cell lines and Sleeping Beauty (SB) mouse models. RNA-sequencing and microarray were applied to identify key molecules involved in the mutant-induced carcinogenesis. Combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased HCC risk in patients without antiviral treatment, whereas the preS2 deletion significantly increased HCC risk in patients with antiviral treatment. In SB mice, the preS1/preS2/S mutants induced a higher rate of tumor and higher serum levels of inflammatory cytokines than did wild-type counterpart. The preS1/preS2/S mutants induced altered gene expression profiles in the inflammation- and metabolism-related pathways, activated pathways of endoplasmic reticulum (ER) stress, affected the response to hypoxia, and upregulated the protein level of STAT3. Inhibiting the STAT3 pathway attenuated the effects of the preS1/preS2/S mutants on cell proliferation. G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promote hepatocarcinogenesis via inducing ER stress, metabolism alteration, and STAT3 pathways, which might be translated into HCC prophylaxis.

The Effects and Underlying Mechanisms of Hepatitis B Virus X Gene Mutants on the Development of Hepatocellular Carcinoma.

We aimed to elucidate the mechanism by which hepatitis B virus X (HBx) mutations increase the occurrence of hepatocellular carcinoma (HCC) and identify novel putative therapeutic targets. Wild-type HBx (WT-HBx) and four HBx mutants (M1, A1762T/G1764A; M2, T1674G+T1753C+A1762T/G1764A; M3, C1653T+T1674G+A1762T/G1764A; and Ct-HBx, carboxylic acid-terminal truncated HBx) were delivered into Sleeping Beauty (SB) mouse models. The HCC incidence was higher in the M3-HBx- and Ct-HBx-injected SB mice. M3-HBx had a stronger capacity of upregulating inflammatory cytokines than other HBx variants. Ectopic expression of M3-HBx and Ct-HBx significantly increased proliferation and S phase proportion of HepG2 and HeLa cells, compared to WT-HBx. Plasminogen activator inhibitor-1 (PAI1) and cell division cycle 20 (CDC20) were identified as novel effectors by cDNA microarray analysis. M3-HBx and Ct-HBx significantly upregulated the expression of PAI1 and CDC20 in HepG2 and HeLa cells as well as the livers of SB mice. Silencing PAI1 attenuated the effects of M3-HBx and Ct-HBx on the growth of HepG2 and HeLa cells. PAI1, an important player bridging the HBx mutants and HCC, should be a promising candidate as a prognostic biomarker and therapeutic target in HBV-related HCC.

Direct-acting antivirals and interferon-based therapy on hepatocellular carcinoma risk in chronic hepatitis-C patients.

Aim: It was controversial whether direct-acting antiviral (DAA) is better than interferon-based therapy (IBT) in preventing HCV-related hepatocellular carcinoma (HCC). Therefore, we accomplished this large, stepwise meta-analysis. Materials & methods: The PubMed, Cochrane and ScienceDirect were searched for studies published during January 2009-March 2019. Antiviral type, number of chronic hepatitis C (CHC) patients, number of HCC cases from CHC patients, sustained virological response (SVR) status and important covariate data were extracted from each study. Results & conclusion: It is demonstrated that antiviral treatment reduces the occurrence of HCC in patients with CHC; achieving SVR to antiviral treatment reduces HCC; DAA treatment is not better than IBT in the prophylaxis of HCC; DAA treatment and cirrhosis are independently associated with a higher incidence of HCC than IBT in middle-aged CHC patients who achieve SVR.