A functional variant of CD40 modulates clearance of hepatitis B virus in hepatocytes via regulation of the ANXA2/CD40/BST2 axis.

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 chronic hepatitis B (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, flanking restriction enhanced pulldown and chromatin immunoprecipitation. 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. Moreover, the mechanism of CD40 was investigated by mRNA sequencing, quantitative real-time polymerase chain reaction, 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.

Identification of pyroptosis subtypes and prognosis model of hepatocellular carcinoma based on pyroptosis-related genes.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Pyroptosis, a type of programmed cell death, regulates tumor cell development. However, the role of pyroptosis-related genes (PRGs) in HCC and their association with prognosis are unclear. METHODS: We conducted bioinformatics analysis to identify PRGs in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) patients. Consensus clustering classified patients into different subtypes. We used LASSO regression to established a pyroptosis subtype-related score (PSRS) related to prognosis. OncoPredict identified potential pharmaceuticals based on PSRS. RESULTS: We found 20 HCC-related PRGs in 335 TCGA-LIHC patients. Consensus clustering classified patients into two subtypes. Subtype I had better overall survival and higher response to anti-PD1 treatment. The prognostic model involving 20 genes predicted poorer prognosis for high-PSRS group. The model was validated in two external cohorts. OncoPredict identified 65 potential pharmaceuticals based on PSRS. CONCLUSION: Our investigation revealed a correlation between pyroptosis and HCC. We established PSRS as independent risk factors for predicting prognosis. The study paves the way for using PRGs as prognostic biomarkers and exploring personalized therapy for HCC.

Implications of Stemness Features in 1059 Hepatocellular Carcinoma Patients from Five Cohorts: Prognosis, Treatment Response, and Identification of Potential Compounds.

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.

TRIM26 inhibits hepatitis B virus replication by promoting HBx degradation and TRIM26 genetic polymorphism predicts PegIFNα treatment response of HBeAg-positive chronic hepatitis B Patients.

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.

A Genetic Variant of PPP1CB Influences Risk of Hepatitis B Virus-Related Hepatocellular Carcinoma in Han Chinese: A Pathway Based Analysis.

PURPOSE: Activation of actin cytoskeleton remodeling is an important stage preceding cancer cell metastasis. Previous genome-wide association studies (GWAS) have identified multiple hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)-associated risk loci. However, limited sample size or strict significance threshold of GWAS may cause HBV-related HCC risk-associated genetic loci to be undetected. We aimed to investigate the performance of the SNP rs13025377 in PPP1CB in HCC. PATIENTS AND METHODS: We performed a case-control study including 1161 cases and 1353 controls to evaluate associations between single nucleotide polymorphisms (SNPs) from 98 actin-cytoskeleton regulatory genes and risk of HBV-related HCC. The effects of SNPs on HBV-related HCC risk were assessed under logistic regression model and corrected by false discovery rate (FDR). RESULTS: We found that rs13025377 in PPP1CB was significantly associated with HBV-related HCC risk [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.72~0.91, P = 4.88×10-4]. The risk allele A of rs13025377 increased PPP1CB expression levels in normal liver tissue. SNP rs4665434 was tagged by rs13025377 (r2 = 0.9) and its protective allele disrupted CTCF and Cohesin motifs. According to public datasets, PPP1CB, CTCF and Cohesin expression levels are increased in tumor tissues. Kaplan-Meier plots demonstrated that higher PPP1CB expression was significantly associated with shorter overall survival (OS). Moreover, we observed strong correlation between CTCF, Cohesin, and PPP1CB in various liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that PPP1CB plays a role in HCC through actin-cytoskeleton regulation. CONCLUSION: Thus, these findings indicated that PPP1CB may be a key gene in actin-cytoskeleton regulation and rs13025377 contributes to the risk of HBV-related HCC by regulating PPP1CB expression.

Pan-Cancer Analysis Identified C1ORF112 as a Potential Biomarker for Multiple Tumor Types.

C1ORF112 is an evolutionarily conserved gene across vertebrates. Over the last decade, studies have suggested that C1ORF112 may play a role in tumorigenesis. Using The Cancer Genome Atlas datasets, we explored the role of C1ORF112 across various tumor types in this study. In most tumor types, C1ORF112 expression was increased in tumor tissues compared to corresponding non-tumor tissues. In patients with certain tumor types, higher C1ORF112 expression was correlated with shorter overall survival, disease-free survival, and progression-free survival. Further analyses of C1ORF112 genetic alteration data showed that C1ORF112 amplification and mutations may have an impact on liver hepatocellular carcinoma and uterine corpus endometrial carcinoma prognosis. In cancers including lower grade glioma and adrenocortical carcinoma, C1ORF112 expression was linked to cancer-associated fibroblast infiltration. Gene Ontology analysis showed that C1ORF112 was co-expressed with genes involved in biological processes such as cell cycle and mitotic regulation. The protein interaction network demonstrated that C1ORF112 physically interacted with RAD51, DMC1, and FIGNL1, which have well characterized functions in DNA repair and cell cycle regulation. This pan-cancer study revealed the prognostic value and oncogenic role of C1ORF112 across multiple tumor types.

Fine Mapping of the MHC Region Identifies Novel Variants Associated with HBV-Related Hepatocellular Carcinoma in Han Chinese.

INTRODUCTION: Genome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive. METHODS: With a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) <0.20). A total of 14,930 variants within the MHC region were genotyped or imputed. RESULTS: We identified two variants, rs114401688 (P = 1.05 × 10-6, PFDR = 2.43 × 10-3) and rs115126566 (P = 9.04 × 10-5, PFDR = 1.77 × 10-1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1*04 and HLA-DRB1*04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥50, P = 0.03). DISCUSSION: Our findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.

STAT4: an immunoregulator contributing to diverse human diseases.

Signal transducer and activator of transcription 4 (STAT4) is a member of the STAT family and localizes to the cytoplasm. STAT4 is phosphorylated after a variety of cytokines bind to the membrane, and then dimerized STAT4 translocates to the nucleus to regulate gene expression. We reviewed the essential role played by STAT4 in a wide variety of cells and the pathogenesis of diverse human diseases, especially many kinds of autoimmune and inflammatory diseases, via activation by different cytokines through the Janus kinase (JAK)-STAT signaling pathway.

Correction to: Molecular pattern of lncRNAs in hepatocellular carcinoma.

In the original publication of this article [1], the author' affiliations need to be revised, because the first and second affiliations should combine as the same affiliation.

Molecular pattern of lncRNAs in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most notable lethal malignancies worldwide. However, the molecular mechanisms involved in the initiation and progression of this disease remain poorly understood. Over the past decade, many studies have demonstrated the important regulatory roles of long non-coding RNAs (lncRNAs) in HCC. Here, we comprehensively review recent discoveries regarding HCC-associated lncRNA functions, which we have classified and described according to their mechanism models.