scholarly journals Hepatitis B virus P protein initiates glycolytic bypass in HBV-related hepatocellular carcinoma via a FOXO3/miRNA-30b-5p/MINPP1 axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wenbiao Chen ◽  
Jingjing Jiang ◽  
Lan Gong ◽  
Zheyue Shu ◽  
Dairong Xiang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Tumor Cells ◽  
Bioinformatics Analysis ◽  
Hbv Infection ◽  
B Virus ◽  
And Migration ◽  
Hcc Cells ◽  
Proliferation And Migration

Abstract Background Hepatitis B virus (HBV) infection is a crucial risk factor for hepatocellular carcinoma (HCC). However, its underlying mechanism remains understudied. Methods Microarray analysis was conducted to compare the genes and miRNAs in liver tissue from HBV-positive and HBV-negative HCC patients. Biological functions of these biomarkers in HBV-related HCC were validated via in vitro and in vivo experiments. Furthermore, we investigated the effect of HBV on the proliferation and migration of tumor cells in HBV-positive HCC tissue. Bioinformatics analysis was then performed to validate the clinical value of the biomarkers in a large HCC cohort. Results We found that a gene, MINPP1 from the glycolytic bypass metabolic pathway, has an important biological function in the development of HBV-positive HCC. MINPP1 is down-regulated in HBV-positive HCC and could inhibit the proliferation and migration of the tumor cells. Meanwhile, miRNA-30b-5p was found to be a stimulator for the proliferation of tumor cell through glycolytic bypass in HBV-positive HCC. More importantly, miRNA-30b-5p could significantly downregulate MINPP1 expression. Metabolic experiments showed that the miRNA-30b-5p/MINPP1 axis is able to accelerate the conversion of glucose to lactate and 2,3-bisphosphoglycerate (2,3-BPG). In the HBV-negative HCC cells, miRNA-30b-5p/MINPP1 could not regulate the glycolytic bypass to promote the tumorigenesis. However, once HBV was introduced into these cells, miRNA-30b-5p/MINPP1 significantly enhanced the proliferation, migration of tumor cells, and promoted the glycolytic bypass. We further revealed that HBV infection promoted the expression of miRNA-30b-5p through the interaction of HBV protein P (HBp) with FOXO3. Bioinformatics analysis on a large cohort dataset showed that high expression of MINPP1 was associated with favorable survival of HBV-positive HCC patients, which could lead to a slower progress of this disease. Conclusion Our study found that the HBp/FOXO3/miRNA-30b-5p/MINPP1 axis contributes to the development of HBV-positive HCC cells through the glycolytic bypass. We also presented miRNA-30b-5p/MINPP1 as a novel biomarker for HBV-positive HCC early diagnosis and a potential pharmaceutical target for antitumor therapy.

Functional analysis of miR-101-3p and Rap1b involved in hepatitis B virus-related hepatocellular carcinoma pathogenesis

2014 ◽  
Vol 92 (2) ◽  
pp. 152-162 ◽  
Author(s):  
Yanrui Sheng ◽  
Shijia Ding ◽  
Ke Chen ◽  
Juan Chen ◽  
Sen Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Promoter Activity ◽  
Down Regulation ◽  
B Virus ◽  
And Migration ◽  
Hcc Cells ◽  
Proliferation And Migration

MicroRNA-101(miR-101) has been shown to be down-regulated in hepatocellular carcinoma (HCC). The hepatitis B virus (HBV) is a major risk factor in the development and progression of HCC. However, the correlation between HBV and miR-101 has not yet been fully elucidated. In this study, we reported that HBV could repress miR-101-3p by inhibiting its promoter activity and identified the potential effects of miR-101-3p on some important biological properties of HCC cells by targeting Rap1b. Dual-luciferase reporter assays showed that HBV down-regulated miR-101-3p by inhibiting its promoter activity. Down-regulation of miR-101-3p promoted cell proliferation, migration, and reduced apoptosis, and resulted in up-regulation of Rap1b, while overexpression of miR-101-3p inhibited these processes. Moreover, overexpression of Rap1b was able to reverse the suppressed cell proliferation and migration mediated by miR-101-3p. Our data showed that HBV down-regulated miR-101-3p expression by inhibiting its promoter activity, which resulted in up-regulation of Rap1b, and down-regulation of miR-101-3p or up-regulation of Rap1b promoted proliferation and migration of HCC cells. This provides a new understanding of the mechanism of HBV-related HCC pathogenesis and the potential application of miR-101-3p in cancer therapy.

scholarly journals LncRNA XIST upregulates TRIM25 via negatively regulating miR-192 in hepatitis B virus-related hepatocellular carcinoma

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jiancheng Wang ◽  
Gang Yin ◽  
Hu Bian ◽  
Jiangli Yang ◽  
Pengcheng Zhou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Expression Levels ◽  
Qrt Pcr ◽  
B Virus ◽  
Lncrna Xist ◽  
Direct Target ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background Long non-coding RNA (lncRNA) XIST has been implicated in the progression of a variety of tumor diseases. The purpose of this study was to explore the molecular role of lncRNA XIST in human hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods The expression levels of lncRNA XIST, miR-192 and TRIM25 in HBV-related HCC tissues and HepG2.2.15 cells were detected by qRT-PCR. Biological information and luciferin gene reporter assay were performed to detect the interaction among lncRNA XIST, miR-192 and TRIM25. CCk-8 assay, wound healing assay and colony formation assay were conducted to detect the proliferation and migration ability of HepG2.2.15 cells. Results qRT-PCR results showed that the expression levels of lncRNA XIST were remarkably increased in HBV-related HCC tissues and HepG2.2.15 cells. In addition, miR-192 was a direct target gene of lncRNA XIST, and the expression of miR-192 and lncRNA XIST were negatively correlated. Moreover, overexpression of miR-192 observably inhibited the proliferation and migration of HCC cells, while overexpression of lncRNA XIST showed an opposite effect. Furthermore, TRIM25 was a direct target of miR-192, and lncRNA XIST could up-regulate the expression of TRIM25 by targeting miR-192. Conclusion LncRNA XIST could up-regulate the expression of TRIM25 by targeting and binding to miR-192, thus accelerating the occurrence and development of HCC.

scholarly journals IL-17 Activates the IL-6/STAT3 Signal Pathway in the Proliferation of Hepatitis B Virus-Related Hepatocellular Carcinoma

2017 ◽  
Vol 43 (6) ◽  
pp. 2379-2390 ◽  
Author(s):  
Zongqiang Hu ◽  
Ding Luo ◽  
Dongdong Wang ◽  
Linjie Ma ◽  
Yingpeng Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Knockout Mice ◽  
Hepg2 Cells ◽  
Wild Type ◽  
B Virus ◽  
And Migration ◽  
Proliferation And Migration

Background/Aims: We performed this study to determine the role of IL-17 in the immune microenvironment of hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). Methods: HepG2 cells were treated with IL-17, STAT3 inhibitor S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb). Cell proliferation and migration were compared using the Cell Counting kit-8 (CCK-8) and Transwell assays, respectively. Real-time quantitative PCR (RT-qPCR), Western Blot, ELISA, immunofluorescence and histological staining were used for determining the expression levels of IL-17, IL-6, MCP-1, CCL5, VEGF, STAT3 and p-STAT3. HCC xenograft models were constructed in wild type and IL-17 knockout mice to clarify the effects of IL-17 on HCC in vivo. Results: Exogenous IL-17 enhanced the proliferation and migration of HepG2 cells, and it activated the phosphorylation of STAT3. RT-qPCR and ELISA showed that IL-17 promoted the expression of IL-6. The CCK-8 and Transwell assays showed that S31-201 or IL-6 mAb remarkably reversed the promotion effects of proliferation and migration by exogenous IL-17 in HepG2 cells. Additionally, IL-6 could promote the phosphorylation of STAT3, while IL-6 mAb acted as an inhibitor, and exogenous IL-17 could neutralize the inhibitory effects of IL-6 mAb. In vivo, compared to the wild type mice, the tumor volume, weight, density and size were decreased in IL-17 knockout mice. Additionally, the expression levels of p-STAT3, IL-6, MCP-1, CCL5 and VEGF decreased in IL-17 knockout mice. Conclusions: IL-17 can enhance the proliferation of HepG2 cells in vitro and in vivo via activating the IL-6/STAT3 pathway. Therefore, the IL-17/IL-6/STAT3 signaling pathway is a potential therapeutic target for HBV-related HCC.

scholarly journals Creation of a Six-fingered Artificial Transcription Factor That Represses the Hepatitis B Virus HBx Gene Integrated into a Human Hepatocellular Carcinoma Cell Line

2012 ◽  
Vol 18 (4) ◽  
pp. 378-387 ◽  
Author(s):  
Xinghui Zhao ◽  
Zhanzhong Zhao ◽  
Junwei Guo ◽  
Peitang Huang ◽  
Xudong Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Hbv Infection ◽  
Luciferase Reporter ◽  
Artificial Transcription Factor ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Chronic hepatitis B virus (HBV) infection is an independent risk factor for the development of hepatocellular carcinoma (HCC). The HBV HBx gene is frequently identified as an integrant in the chromosomal DNA of patients with HCC. HBx encodes the X protein (HBx), a putative viral oncoprotein that affects transcriptional regulation of several cellular genes. Therefore, HBx may be an ideal target to impede the progression of HBV infection–related HCC. In this study, integrated HBx was transcriptionally downregulated using an artificial transcription factor (ATF). Two three-fingered Cys2-His2 zinc finger (ZF) motifs that specifically recognized two 9-bp DNA sequences regulating HBx expression were identified from a phage-display library. The ZF domains were linked into a six-fingered protein that specified an 18-bp DNA target in the Enhancer I region upstream of HBx. This DNA-binding domain was fused with a Krüppel-associated box (KRAB) transcriptional repression domain to produce an ATF designed to downregulate HBx integrated into the Hep3B HCC cell line. The ATF significantly repressed HBx in a luciferase reporter assay. Stably expressing the ATF in Hep3B cells resulted in significant growth arrest, whereas stably expressing the ATF in an HCC cell line lacking integrated HBx (HepG2) had virtually no effect. The targeted downregulation of integrated HBx is a promising novel approach to inhibiting the progression of HBV infection–related HCC.

Discovery of novel hepatitis B virus (HBV) antivirals and analysis of mechanisms of action of HBV-targeting agents

2017 ◽  
Author(s):  
◽  
Andrew Douglas Huber
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Treatment Options ◽  
Mechanisms Of Action ◽  
Hbv Infection ◽  
Viral Inhibition ◽  
University Of Missouri ◽  
Chronic Hepatitis B Virus ◽  
B Virus

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Chronic hepatitis B virus (HBV) infection leads to liver disease, cirrhosis, and hepatocellular carcinoma. Globally, an estimated 50% of all hepatocellular carcinoma cases are linked to chronic HBV infection. More than 240 million people are chronically infected, and there are 0.5-1 million deaths per year due to HBVrelated liver conditions. HBV treatment options rarely cure infections and are associated with adverse side effects that often outweigh the potential benefits of treatment. New treatments, therefore, are highly desired for HBV therapy. Towards this goal, we have developed novel compounds targeting two viral targets and assessed the mechanisms of action by which these compounds act. We have developed systems for the discovery and evaluation of compounds that inhibit 2 distinct steps in the HBV life cycle. Using these systems, we have developed potent inhibitors of HBV replication that have potential to become clinically used HBV drugs. Furthermore, we have used our methods to evaluate which properties of these compounds are likely to result in better viral inhibition. The work described in this thesis has led to at least 2 new compound groups for potential use as HBV antivirals and provides insight into mechanisms by which potent antivirals can be achieved.

scholarly journals Epidemiology of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) Related Hepatocellular Carcinoma

2018 ◽  
Vol 12 (1) ◽  
pp. 26-32 ◽  
Author(s):  
Arnolfo Petruzziello
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Infection ◽  
Sub Saharan Africa ◽  
Liver Cancers ◽  
B Virus

Introduction:Hepatocellular carcinoma (HCC) is one of the most prevalent primary malignant tumors and accounts for about 90% of all primary liver cancers. Its distribution varies greatly according to geographic location and it is more common in middle and low- income countries than in developed ones especially in Eastern Asia and Sub Saharan Africa (70% of all new HCCs worldwide), with incidence rates of over 20 per 100,000 individuals.Explanation:The most important risk factors for HCC are Hepatitis B Virus (HBV) infection, Hepatitis C Virus (HCV) infection, excessive consumption of alcohol and exposition to aflatoxin B1. Its geographic variability and heterogeneity have been widely associated with the different distribution of HBV and HCV infections worldwide.Chronic HBV infection is one of the leading risk factors for HCC globally accounting for at least 50% cases of primary liver tumors worldwide. Generally, while HBV is the main causative agent in the high incidence HCC areas, HCV is the major etiological factor in low incidence HCC areas, like Western Europe and North America.Conclusion:HBV-induced HCC is a complex, stepwise process that includes integration of HBV DNA into host DNA at multiple or single sites. On the contrary, the cancerogenesis mechanism of HCV is not completely known and it still remains controversial as to whether HCV itself plays a direct role in the development of tumorigenic progression.

scholarly journals Serum miR-375 Levels Are Closely Related to Disease Progression from HBV Infection to HBV-Related Hepatocellular Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Weilu Zhang ◽  
Ting Fu ◽  
Zhenjun Guo ◽  
Ye Zhang ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B ◽  
Disease Progression ◽  
Cellular Proliferation ◽  
Hbv Infection ◽  
Cell Counting ◽  
Specificity And Sensitivity ◽  
And Migration ◽  
Proliferation And Migration

Background. There is an urgent need to identify ideal serological biomarkers that not only are closely related to disease progression from hepatitis B virus (HBV) infection to hepatocellular carcinoma (HCC) but also have high specificity and sensitivity. We conducted this study to analyze whether miR-375 has a potential value in the early prediction of the progression from HBV-related hepatitis or cirrhosis to HCC. Methods. A total of 177 participants were enrolled. Receiver operating characteristic (ROC) curve was used to evaluate the predictive capability of selected miR-375 for HBV-HCC. We upregulated the miR-375 expression in HepG2, HepG2.2.15, and HepAD38 cells to determine its effect on cellular proliferation and migration, in vitro using Cell Counting Kit-8 (CCK-8) assays. Results. Serum miR-375 levels decreased in order from healthy controls to chronic hepatitis B (CHB) without cirrhosis, followed by cirrhosis, and finally, HBV-HCC patients. miR-375 levels were significantly lower in HBeAg-positive and HBV DNA-positive patients than negative (P<0.05) and significantly lower in patients with elevated alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) than normal levels (P<0.05). miR-375 might be a biomarker for HBV-HCC, with a high area under the curve (AUC) of 0.838 (95% confidence interval (CI) 0.780 to 0.897; sensitivity: 73.9%; specificity: 93.0%). The AUC (0.768 vs. 0.584) and sensitivity (93.8% vs. 75.0%) for miR-375 were higher than those for AFP. The overexpression of miR-375 noticeably inhibited proliferation and migration in HepG2, HepG2.2.15, and HepAD38, especially in HepG2.2.15 and HepAD38, which are stably infected with HBV. Conclusions. Serum miR-375 levels are closely related to disease progression from HBV-related hepatitis or cirrhosis to HCC.

scholarly journals Association of STAT3 and STAT4 polymorphisms with susceptibility to chronic hepatitis B virus infection and risk of hepatocellular carcinoma: a meta-analysis

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Han Shi ◽  
Hongyan He ◽  
Suvash Chandra Ojha ◽  
Changfeng Sun ◽  
Juan Fu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Meta Analysis ◽  
Hbv Infection ◽  
Chronic Hbv Infection ◽  
B Virus ◽  
Chronic Hbv

Abstract Background: It has been reported that polymorphisms of signal transducer and activator of transcription (STAT) 3 and STAT4 might be associated with susceptibility to hepatitis B virus (HBV) infection and risk of chronic hepatocellular carcinoma (HCC). Owing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association. Methods: We identified relevant studies by a systematic search of Medline/PubMed, Embase, Web of Science and the Cochrane Library up to 20 February 2019. The strength of the association measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied. All the statistical analyses were conducted based on Review Manager 5.3 software. Results: A total of 5242 cases and 2717 controls from five studies were included for the STAT3 polymorphism, 5902 cases and 7867 controls from nine studies for the STAT4 polymorphism. Our results suggested that STAT3 rs1053004 polymorphism was a significant risk factor of chronic HBV infection (C vs. T: OR = 1.17, 95% CI: 1.07–1.29, PA=0.0007; CC + CT vs. TT: OR = 1.38, 95% CI: 1.09–1.76, PA=0.008). Validation with all the genetic models revealed that rs7574865 polymorphism of STAT4 gene was closely associated with chronic HBV infection (PA<0.01) and chronic hepatitis B (CHB)-related HCC (PA<0.05). Meanwhile, the authenticity of the above meta-analysis results was confirmed by trial sequential analysis (TSA). Conclusions: The meta-analysis showed that STAT3 rs1053004 polymorphism may be the risk for developing chronic HBV infection but not associated with HCC. The present study also indicates that STAT4 rs7574865 polymorphism increased the risk of chronic HBV infection and HCC.

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