Hepatitis B Virus-Associated Hepatocellular Carcinoma
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Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.Keywords:
Hepatitis D virus
Liver disease
Hepatitis B
HBx
Viral Hepatitis
Liver function
The role of the hepatitis B virus X protein (HBx) in the pathogenesis of hepatitis B virus (HBV) infection remains unclear. HBx exhibits pleiotropic biological effects, whose in vivo relevance is a matter for debate. In the present report, we have used a combination of HBx-expressing transgenic mice and liver cell transplantation to investigate the in vivo impact of HBx expression on liver cell proliferation and viability in a regenerative context. We show that moderate HBx expression inhibits liver regeneration after partial hepatectomy in HBx-expressing transgenic mice. We also demonstrate that the transplantation of HBx-expressing liver cells, isolated from HBx transgenic mice, is sufficient to inhibit overall recipient liver regeneration after partial hepatectomy. Moreover, the injection of serum samples drawn from HBx-expressing transgenic mice mimicked the inhibitory effect of HBx on liver regeneration. Finally, the incubation of primary rat hepatocytes with the supernatant of HBx-expressing liver cells inhibits cellular DNA synthesis. Taken together, our results demonstrate a paracrine inhibitory effect of HBx on liver cell proliferation and lead us to propose HBV as one of the few viruses implicated in human cancer which act, at least in part, through paracrine biological pathways.
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长期的肝炎 B 病毒(HBV ) 感染强烈与 hepatocellular 癌被联系了。HBV 编码 oncogenic 肝炎 B 病毒 X 蛋白质(HBx ) ，它是通过和主机因素的直接、间接的相互作用调制信号 transduction，抄写，房间周期进步，蛋白质降级， apoptosis，和基因稳定性的一个多功能的管理者。HBx 的 subcellular 本地化主要是细胞质的，与在原子核的小部分。另外， HBx 表示高级导致反常 mitochondrial 分布。HBx 的动态分发能对在 HBV 生命周期的不同阶段的 HBx 的多重功能重要。这短评论作为它的细胞内部的本地化的功能给出 HBx 的微分角色的概述。
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长期的肝炎 B 病毒( HBV )感染是主要原因 ofhepatocellular 癌( HCC )之一，并且 HBV X ( HBx )基因在HBV相关的 HCC.We 的分子的致病起一个关键作用调查了是否有特别 HBx 基因变化，从南部的中国在病人与 HCC 联系。HBx 基因被嵌套的聚合酶链反应(PCR ) 从 HBVcarrier 与 HCC 和 25 件浆液样品从病人在 51paraffin-embedded 肿瘤织物样品检验，搁浅单人赛的 conformational 多型性 andheteroduplex 分析。有从肿瘤织物样品的潜在地重要的变化的 HBx 基因被克隆，在肿瘤织物样品与出版 HBx 基因 sequence.HBV 遗传型定序并且排列被在肿瘤织物的31.3% HBx 基因碎片取样的基因多型性显示出的 HBx 的嵌套的 PCR.Analyses 分析有特殊 pattern.A 在 29 点突变伴随的 HBxgene 的 nt 382-400 的普通删除随机在四被检测有在 HBx 开的读物引起了框架移动的这个模式的选择肿瘤织物样品在 atnt 上与一条新站鳕鱼装裱 1818 ，导致 HBx 多肽链在这些情况中在 C 结束截断了。在四件随机选择的样品之中，三是 HBV 遗传型 B ，并且一个人没被我们的现在的 assay.Inanother 肿瘤织物样品检测，全身的 HBx 基因的扩大产出揭示的这碎片的 shorterfragment.Sequencing 在 1577 HBVgene.These 和 1840 结果建议的 nt 之间的 264 bp 删除那个 HBx 基因变化在 HCC 样品经常发生，并且在 HBx 基因的 nt 382-400 的删除可能在南部的中国在 HCC 的 carcinogenesis 起一个作用。
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Molecular Diagnostic Testing for Viral Hepatitis: Methods and Applications, Stephen J. Polyak and David R. Gretch Hepatitis A Virus, Manuel Battegay and Stephen M. Feinstone Hepatitis B Virus: Molecular Biology and Immunopathology-Experimental and Clinical Features, Barbara Rehermann and Frank V. Chisari Hepatitis B Virus: Clinical Disease-Prevention and Therapy, Steven A. Rogers, Jules Dienstag, and T. Jake Liang Hepatitis C, Juan I. Estaban, Jordi Gomez, Maria Martell, and Jaime Guardia Hepatitis D Virus, Adrian M. Di Bisceglie Overview of the Epidemiology and Virology of the Hepatitis E Virus, Gregory R. Reyes Other Hepatitis Viruses Including the Hepatitis G Virus, Raymond S. Koff The Role of Hepatitis Viruses in Acute Liver Failure, Christopher J. Tibbs and Roger Williams Hepatocellular Carcinoma and Viral Hepatitis, Brian J. McMahon Extrahepatic Manifestations of Chronic Viral Hepatitis, Richard A. Willson Overlap of Chronic Viral Hepatitis and Autoimmune Hepatitis, Albert J. Czaja Liver Transplantation and Viral Hepatitis B, C, and D, Didier Samuel, Cyrille Feray, and Henri Bismuth Viral Hepatitis in Marrow and Stem-Cell Transplant Patients, Darik Taniguchi and George B. McDonald Viral Hepatitis in the Immunocompromised Host, Gary L. Davis The Role of Iron in Chronic Viral Hepatitis: Implications for Therapy, Kris V. Kowdley
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Hepatitis C
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Hepatitis B virus X protein (HBx) is involved in the development of hepatocellular carcinoma (HCC). The HBx sequence is a preferential site of integration into the human genome, leading to the formation of C-terminal-truncated HBx proteins (Ct-HBx). We previously reported that Ct-HBx proteins were able to potentiate cell transformation in vitro. Our present goal was to compare the ability of Ct-HBx and full-length HBx (FL-HBx) proteins to develop or enhance HCC in transgenic mice. In the absence of treatment, neither Ct-HBx- nor FL-HBx-transgenic mice developed HCC. In young mice treated with diethylnitrosamine (DEN) at 8 months of age, a significantly higher incidence and number of liver lesions were observed in Ct-HBx mice than in FL-HBx and control mice. The earlier development of tumours in Ct-HBx-transgenic mice was associated with increased liver inflammation. At 10 months, macroscopic and microscopic analyses showed that, statistically, FL-HBx mice developed more liver lesions with a larger surface area than control mice. Furthermore, during DEN-induced initiation of HCC, Ct-HBx- and FL-HBx-transgenic mice showed higher expression of IL-6, TNF-α and IL-1β transcripts, activation of STAT3, ERK and JNK proteins and an increase in cell apoptosis. In conclusion, in DEN-treated transgenic mice, the expression of Ct-HBx protein causes a more rapid onset of HCC than does FL-HBx protein. HBV genome integration leading to the expression of a truncated form of HBx protein may therefore facilitate HCC development in chronically infected patients.
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BACKGROUND: The acute Hepatitis B virus (HBV) infection usually ceases before six months, but chronic infection that lasts for more than six months might develop into liver cirrhosis and hepatocellular carcinoma (HCC). Viral particle load, HBV genotypes and association to the HBV x (HBx) gene mutations are the probable factors related to HCC occurrence. The mutation which leads to HBx T118N was found as the second most common HBx mutation in Indonesia, as compared to the known cancer-related HBx K130M/V131I mutant. However, the effect of T118N mutation and its combination with K130M/V131I on human hepatoma cells has not been elucidated well. Hence, this study was conducted to dissect the role of HBx T118N and its mutant combination in colony formation, as compared to the wild type HBx and cancer-related HBx K130M/V131I.METHODS: In this study, the genes encoding wild type HBx, HBx T118N, and HBx K130M/V131I mutations were obtained as synthetic gene. Meanwhile, the gene encoding HBx T118N/K130M/V131I mutations was successfully generated using site-directed mutagenesis. The optimum condition for colony formation assays was determined through Zeocin sensitivity test of HepG2 cells.RESULTS: Selection of HepG2 cells using Zeocin was determined at 200 µg/mL. Colony formation assays performed upon expression of HBx T118N and HBx T118N/K130M/V131I mutant proteins showed reduced colony numbers as compared to the expression of wild type HBx, similar to the effect from HBx K130M/V131I mutant expression.CONCLUSION: The HBx T118N and HBx T118N/K130M/V131I mutation caused less colony formation of HepG2 cells, similar to the K130/M131I mutation. This indicates a possible role of the T118N mutation in liver cancer development.KEYWORDS: colony formation assay, hepatitis B virus, HBx, T118N, K130M/V131I
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The prevalence of viral hepatitis is high and remains a serious public health challenge throughout the world. New molecular biology techniques provided a better understanding of the viruses over the last decades. Novel therapeutic options seem to be promising but preventing measures including donor screening, immunization against hepatitis A virus (HAV) and hepatitis B virus (HBV), universal use of disposable syringes and implementation of better hygienic conditions play a major role in the control of viral hepatitis. The Mediterranean basin has special demographic and socioeconomic features. We reviewed in this article the seroepidemiological features of viral hepatitis in this particular region. Improving general conditions led to a tendency to be infected in older ages with HAV. Hepatitis B and C virus still remain to be the major causes of chronic hepatitis. The seroprevalence of hepatitis D virus, which was once endemic in the Mediterranean region seem to decrease nowadays whereas hepatitis E virus is still prevalent in some areas. Other viruses such as hepatitis G virus (HGV), TT virus (TTV) and SEN virus do not seem to be a major problem and their clinical importance remains to be determined in further studies.
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Hepatitis C virus (HCV) is one of the leading causes of chronic liver disease.Hepatocellular carcinoma (HCC) is a major complication associated with HCV virus infection, with significant mortality and morbidity rates.This study aimed to measure biochemical liver parameters and HCV RNA levels for detection the severity of hepatitis C virus-associated hepatocellular carcinoma.The study was conducted on 100 patients, with ages ranging from 36 to 68 years and patients grouped into four groups.The 1 st group served as control group (n= 25),the second group (n=25): Hepatitis C Virus, the third group (n=25): HCV-associated HCC and the fourth group (n=25): After HCC removal and tumor resection.Serum samples were collected from the studied patients.Liver function enzymes (ALT, AST, Alkaline phosphatase) and another function parameters (Albumin and Total bilirubin) were tested to all patients of the studied groups.The results showed that hepatitis C Virus, HCV-associated HCC, and after HCC removal groups had an increase in liver function enzymes, decrease in albumin levels, and an increase in total bilirubin levels which indicate damage in the liver.Viral loads indicated in males infected higher than in females and significantlyincreased in HCV patients, and a highly significant increase in HCV associated HCC patients.Conclusively, Hepatitis C Virus, HCV-associated HCC, and After HCC removal groups had an increase in liver function enzymes, decrease in albumin levels, and an increase in total bilirubin levels which indicate damage in the liver.Viral loads indicated in males infected higher than females are significantly increased in HCV patients, and a highly significant increase in HCV associated HCC patients.
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