Summary
Background
Hepatitis B virus (HBV) infection is a serious global health burden. TRIM26 has been reported to affect hepatitis C virus replication.
Aims
To manifest the role of TRIM26 on HBV replication and explore if there are single‐nucleotide polymorphisms (SNPs) in TRIM26 associated with response to pegylated interferon‐alpha (PegIFNα) treatment in patients with chronic hepatitis B (CHB).
Methods
We investigated the effect and mechanism of TRIM26 on HBV replication in vitro. The association between SNPs in TRIM26 and PegIFNα treatment response was evaluated in two independent cohorts including 238 and 707 patients with HBeAg‐positive CHB.
Results
Knockdown of TRIM26 increased, while overexpression of TRIM26 inhibited, HBV replication. Co‐immunoprecipitation assays and immunofluorescence showed that TRIM26 interacted and co‐localised with HBx. Co‐transfection of HBx‐HIS and TRIM26‐FLAG plasmids in Huh7 cells showed that TRIM26 inhibited the expression of HBx. Furthermore, TRIM26 inhibited HBV replication by mediating HBx ubiquitination degradation, and TRIM26 SPRY domain was responsible for the interaction and degradation of HBx. Besides, IFN increased TRIM26 expression. TRIM26 rs116806878 was associated with response to PegIFNα in two CHB cohorts. Moreover, a polygenic score integrating TRIM26 rs116806878, STAT4 rs7574865 and CFB rs12614 (previously reported to be associated with response to PegIFNα) was related to response to PegIFNα in CHB.
Conclusions
TRIM26 inhibits HBV replication; IFN promotes TRIM26 expression. TRIM26 exerts an inhibitory effect on HBx by promoting ubiquitin‐mediated degradation of HBx. Furthermore, TRIM26 rs116806878 is a potential predictive biomarker of response to PegIFNα in patients with CHB.
Cancer stemness has been reported to drive hepatocellular carcinoma (HCC) tumorigenesis and treatment resistance. In this study, five HCC cohorts with 1059 patients were collected to calculate transcriptional stemness indexes (mRNAsi) by the one-class logistic regression machine learning algorithm. In the TCGA-LIHC cohort, we found mRNAsi was an independent prognostic factor, and 626 mRNAsi-related genes were identified by Spearman correlation analysis. The HCC stemness risk model (HSRM) was trained in the TCGA-LIHC cohort and significantly discriminated overall survival in four independent cohorts. HSRM was also significantly associated with transarterial chemoembolization treatment response and rapid tumor growth in HCC patients. Consensus clustering was conducted based on mRNAsi-related genes to divide 1059 patients into two stemness subtypes. On gene set variation analysis, samples of subtype I were found enriched with pathways such as DNA replication and cell cycle, while several liver-specific metabolic pathways were inhibited in these samples. Somatic mutation analysis revealed more frequent mutations of TP53 and RB1 in the subtype I samples. In silico analysis suggested topoisomerase, cyclin-dependent kinase, and histone deacetylase as potential targets to inhibit HCC stemness. In vitro assay showed two predicted compounds, Aminopurvalanol-a and NCH-51, effectively suppressed oncosphere formation and impaired viability of HCC cell lines, which may shed new light on HCC treatment.
More than 250 million people in the world are chronically infected with hepatitis B virus (HBV), which causes serious complications. Host genetic susceptibility is essential for CHB, and our previous genome-wide association study identified a single-nucleotide polymorphism (SNP), rs1883832, in the 5′ untranslated region of CD40 predisposing to chronic HBV infection, but the underlying mechanism remains undefined. This study aimed to investigate whether rs1883832 was the real functional SNP (fSNP) of CD40 and how it modulated HBV clearance in hepatocytes. We determined the fSNP of CD40 and its regulatory protein(s) using luciferase reporter assays, electrophoretic mobility shift assay (EMSA), flanking restriction enhanced pulldown (FREP) and chromatin immunoprecipitation (ChIP). The potential anti-HBV activity of CD40 and its downstream molecule BST2 was assessed in HBV-transfected and HBV-infected hepatoma cells and HBV-infected primary human hepatocytes (PHHs). Moreover, the mechanism of CD40 was investigated by mRNA sequencing, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence and western blot. We revealed rs1883832 as the true fSNP of CD40 and identified ANXA2 as a negative regulatory protein that preferentially bound to the risk allele T of rs1883832 and hence reduced CD40 expression. Furthermore, CD40 suppressed HBV replication and transcription in hepatocytes via activating the JAK–STAT pathway. BST2 was identified to be the key IFN-stimulated gene regulated by CD40 after activating JAK–STAT pathway. Inhibition of JAK/STAT/BST2 axis attenuated CD40-induced antiviral effect. In conclusion, a functional variant of CD40 modulates HBV clearance via regulation of the ANXA2/CD40/BST2 axis, which may shed new light on HBV personalized therapy.
Aim: To summarize HBV-related biomarkers predicting nucleos(t)ide analogs (NAs) discontinuation and hepatitis B virus (HBV) recurrence after drug withdrawal in chronic hepatitis B (CHB) patients, providing references for clinical medication, so as to manage CHB patients more scientifically.Methods: Related pieces of literature were retrieved in PubMed and the results were sorted out. We then analyzed and summarized these articles.
Results:We found that HBV related biomarkers maybe could predict NAs withdrawal safely and the possibility of relapse after treatment cessation, including hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV DNA, HBV RNA, pregenomic-RNA (pgRNA), hepatitis B core-related antigen (HBcrAg), hepatitis B core antibody (anti-HBc), and models containing several indicators for predicting the effectiveness of treatment.Conclusions: HBV DNA, HBV RNA, pgRNA, HBcrAg, anti-HBc, as well as the prediction models formed by several biomarkers could predict the safe discontinuation of NAs before HBsAg loss and recurrence.
As a key immune cytokine, C-X-C motif chemokine ligand 13 (CXCL13) has been reported to play critical roles in immune control of hepatitis B virus (HBV) infection.We aimed to screen single-nucleotide polymorphisms (SNPs) of CXCL13 for predicting response to pegylated interferon-alpha (PegIFNα) therapy of chronic hepatitis B (CHB) patients. Two independent cohorts with a total of 945 (Cohort 1, n = 238; Cohort 2, n = 707) hepatitis B e antigen (HBeAg)-positive CHB patients treated with PegIFNα were enrolled in this retrospective cohort study. Eight candidate SNPs were selected through gene-wide SNP mining within or flanking CXCL13. A polygenic score (PGS) was utilized to assess the cumulative effects of multiple SNPs. The associations of candidate SNPs and PGS with combined response (CR, defined as the combination of HBeAg seroconversion and HBV DNA level <3.3log 10 IU/mL) and hepatitis B surface antigen (HBsAg) level were evaluated. Among the eight candidate SNPs, rs76084459 which is located at upstream of CXCL13 was significantly associated with both CR (p = 0.002) and HBsAg level (p = 0.015). A PGS integrating CXCL13_rs76084459 and five other SNPs, which were previously identified as predictors of PegIFNα treatment response, was further strongly correlated with CR (p = 1.759 × 10 −10 ) and HBsAg level (p = 0.004). This study demonstrated that CXCL13_rs76084459 can predict response to PegIFNα treatment of HBeAg-positive CHB patients. A PGS composed of six SNPs including CXCL13_rs76084459 predicts PegIFNα treatment response better. K E Y W O R D S chronic hepatitis B (CHB), C-X-C motif chemokine ligand 13 (CXCL13), hepatitis B virus (HBV), pegylated interferon-alpha (PegIFNα), single-nucleotide polymorphism (SNP)
LINKED CONTENT
This article is linked to Luo et al papers. To view these articles, visit https://doi.org/10.1111/apt.17124 and https://doi.org/10.1111/apt.17159
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