丙型肝炎病毒诱发肝细胞癌的分子机制

丙型肝炎是由丙型肝炎病毒(hepatitis C virus,HCV)引起的一种肝脏疾病。肝细胞癌(hepatocellular carcinoma,HCC)是人类最常见的恶性肿瘤之一。大量实验和临床研究表明,HCV的感染是导致肝细胞癌的主要因素之一。尽管目前可以通过直接抗病毒药物治疗HCV感染,但是患肝细胞癌的风险仍然存在。HCV诱发肝细胞癌是一个多步骤过程,其可能是通过病毒因子直接作用和/或通过引起慢性炎症诱发肝癌。因此,需要更好地了解HCV诱发肝细胞癌的分子机制,为肝细胞癌的防治提供研究基础。本文就近年来国内外对丙型肝炎病毒直接作用诱发肝细胞癌的分子机制进行综述,具体从血管生成、细胞凋亡、细胞增殖、上皮 间质转化、脂肪变性和氧化应激6个方面进行阐述,以期更好地了解HCV诱发肝细胞癌的分子机制,为肝细胞癌的防治提供研究基础。     

丙型肝炎病毒诱发肝细胞癌的分子机制

丙型肝炎是由丙型肝炎病毒(hepatitis C virus,HCV)引起的一种肝脏疾病。肝细胞癌(hepatocellular carcinoma,HCC)是人类最常见的恶性肿瘤之一。大量实验和临床研究表明,HCV的感染是导致肝细胞癌的主要因素之一。尽管目前可以通过直接抗病毒药物治疗HCV感染,但是患肝细胞癌的风险仍然存在。HCV诱发肝细胞癌是一个多步骤过程,其可能是通过病毒因子直接作用和/或通过引起慢性炎症诱发肝癌。因此,需要更好地了解HCV诱发肝细胞癌的分子机制,为肝细胞癌的防治提供研究基础。本文就近年来国内外对丙型肝炎病毒直接作用诱发肝细胞癌的分子机制进行综述,具体从血管生成、细胞凋亡、细胞增殖、上皮 间质转化、脂肪变性和氧化应激6个方面进行阐述,以期更好地了解HCV诱发肝细胞癌的分子机制,为肝细胞癌的防治提供研究基础。     

丙型肝炎病毒受体及其感染机制

病毒与宿主细胞的吸附是病毒感染的第一步,其相互作用决定了病毒的宿主范围和组织、细胞的易感性。丙型肝炎病毒(HCV)受体的研究,对于阐明HCV的感染机制及感染模型具有重要意义。     

Cyclin D1, Bcl-2, P53和Survivin在丙型肝炎病毒相关肝细胞肝癌中 临床病理意义

目的:研究cyclin D1,bcl-2,p53和survivin在丙型肝炎病毒(hepatitis C virus,HCV)相关性肝细胞性肝癌(hepatocellular carcinoma,HCC)癌组织及癌旁组织中的表达,探讨其表达与丙型肝炎病毒相关性肝细胞性肝癌患者临床病理特征及生存预后之间的关系。方法:采用免疫组化检测方法检测cyclin D1,bcl-2,p53和survivin在丙型肝炎病毒相关性肝癌组织、癌旁组织和基本正常的肝组织中的表达,统计分析各因子的表达情况以及与患者临床病理特征的关系,并利用Kaplan-Meier分析法进一步分析各因子与患者生存预后之间的关系。结果:cyclin D1,bcl-2,p53和survivin在基本正常肝脏组织、癌旁组织和癌组织中的表达呈现递增的趋势,且cyclin D1,bcl-2,p53和survivin在癌组织的表达显著高于癌旁组织和基本正常的肝脏组织(P0.05);经统计学分析,cyclin D1,bcl-2和p53与肿瘤的分化程度相关(P0.05),而survivin与血管的浸润情况相关(P0.05);Kaplan-Meier分析显示,cyclin D1,p53和survivin与患者的不良预后有关(P0.05),而bcl-2与患者的不良预后无关(P0.05)。结论:cyclin D1,bcl-2,p53和survivin可能与丙型肝炎病毒相关性肝细胞性肝癌的发生存在一定的联系,除此之外,cyclin D1,p53和survivin与丙型肝炎病毒相关性肝细胞性肝癌患者的不良预后相关,而bcl-2与预后不存在显著相关性。     

microRNA-122与丙型肝炎病毒复制和肝细胞癌的相关研究进展

microRNA-122(miR-122)是一种肝脏特异性微小RNA,与丙型肝炎病毒(HCV)的复制和感染及肝细胞癌(HCC)的发生密切相关。近年来,科研人员关于miR-122的研究已取得了较大进展。在此,我们就miR-122与HCV复制和HCC的相关关系等方面的研究进展做简要综述。     

丙型肝炎病毒

<正>1989年,美国Chiron公司在世界上率先克隆了引起非甲非乙型肝炎的丙型肝炎病毒(HCV)的基因片段,并由此开发了C100-3抗体检测系统。1990年,冈本等人发现HCV结构基因中含有5＇非编码区(5＇noncoding region),从而使HCV的基因组成、分子生物学活性及免疫化学方面的抗原决定基等研究迅速进展,从临床及基础研究两方面逐渐搞清楚了其全貌。本文仅简述用PCR法诊断HCV基因组的过程。     

丙型肝炎病毒

本文综述了丙型肝炎病毒的分类学地位,基因组结构,病毒蛋白质,实验室诊断,及传播方式和致病性等内容。强调了丙型肝炎病毒是第一个通过分子生物学发现和鉴定的病毒。     

丙型肝炎病毒感染与肝细胞癌相关关系的研究进展

世界上有数亿的人口患有丙型肝炎,而丙型肝炎病毒(HCV)的感染易转为慢性,引起肝细胞炎性坏死及再生,导致肝纤维化、硬化甚至肝细胞癌(HCC),是危害人类健康的一个重要卫生问题。HCV的感染可导致HCC的发生,但HCV相关性HCC的发生机制尚不清楚。免疫逃避机制是感染慢性化的一个重要原因,病毒通过其基因组编码的蛋白使肝细胞发生转化,可能是肝细胞癌变的重要机制。     

丙型肝炎病毒感染与肝细胞癌相关关系的研究进展

世界上有数亿的人口患有丙型肝炎,而丙型肝炎病毒（HCV）的感染易转为慢性,引起肝细胞炎性坏死及再生,导致肝纤维化、硬化甚至肝细胞癌（HCC）,是危害人类健康的一个重要卫生问题。HCV的感染可导致HCC的发生,但HCV相关性HCC的发生机制尚不清楚。免疫逃避机制是感染慢性化的一个重要原因,病毒通过其基因组编码的蛋白使肝细胞发生转化,可能是肝细胞癌变的重要机制。     

Prevalence and characteristics of hepatitis C virus-related hepatocellular carcinoma in a Spanish university hospital

BackgroundHepatocellular Carcinoma (HCC) arises in chronic liver diseases, particularly caused by hepatitis C virus (HCV) and alcohol in Europe. We aimed at evaluating the characteristics and mortality of patients with HCV-related HCC as compared to other HCC etiologies.MethodsWe retrospectively evaluated data from 887 patients with HCC identified through the Hospital del Mar Cancer Registry (Barcelona, Spain), during the 2001–2020 period. We estimated crude and adjusted hazard ratios (aHR) of dying and its 95% confidence interval (95%CI).ResultsAmong 887 patients with HCC, 617 (69.6%) were HCV-infected. Underlying cirrhosis was more frequent in HCV-related HCC compared to other etiologies (97% vs. 89%, p < 0.001). The prevalence of HCV-related HCC decreased from 79% in 2001–2005 to 55% in 2015–2020 (p < 0.001). HCV infection did not increase the hazard of death [aHR 0.95 (CI95% 0.81–1.13)]. Mortality was independently related to age > 75 years, advanced BCLC stage at diagnosis, and diagnosis before 2010.ConclusionIn our cohort, HCV-related HCC frequently occurred in a cirrhotic background, but showed similar clinical characteristics and mortality as compared to other HCC etiologies.     

Overexpression of alpha enolase in hepatitis C virus-related hepatocellular carcinoma: association with tumor progression as determined by proteomic analysis

To identify proteins that could be molecular targets for diagnosis and treatment of hepatitis C virus-related hepatocellular carcinoma (HCV-related HCC), we used a proteomic approach to analyze protein expression in samples of human liver. Twenty-six pairs of tumorous and corresponding nontumorous liver samples from patients with HCV-related HCC and six normal liver samples were analyzed by two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry. One of the numerous spots that showed stronger intensity in tumorous than in nontumorous samples was identified as alpha enolase, a key enzyme in the glycolytic pathway. Expression of this protein increased with tumor dedifferentiation and was significantly higher in poorly differentiated HCC than in well-differentiated HCC. This pattern was reproduced by immunoblot analysis and immunohistochemistry. Expression of alpha enolase also correlated positively with tumor size and venous invasion. These results suggest that alpha enolase is one of the candidates for biomarkers for tumor progression that deserves further investigation in HCV-related HCC.     

Serum heat shock protein 27 levels in patients with hepatocellular carcinoma

Levels of serum heat shock protein 27 (sHsp27) have been studied in numerous cancer types, but their potential relevance in patients with hepatocellular carcinoma (HCC) is undetermined. Our aim was to compare sHsp27 levels in patients with HCC and HCC-free controls. Specifically, we recruited 71 patients with HCC (80 % with early tumour), 80 patients with chronic liver disease (59 with liver cirrhosis and 21 with chronic active hepatitis) and 42 healthy subjects. sHsp27 was measured by immunoenzymatic assay. Results showed that sHsp27 levels were significantly (p < 0.001) higher in patients with HCC than in the other groups, particularly in those with hepatitis C virus (HCV)-related disease. In HCC patients, sHsp27 levels were not associated with prognostic risk factors, such as size/multiplicity of nodules and stage. In logistic regression analysis, performed in patients with liver disease, log-sHsp27 was associated with a significant age-adjusted 2.5-fold increased odds ratio of HCC and with a significant 4.4-fold higher odds ratio of HCC in the subgroup with HCV-related liver disease. In receiver operating characteristic curve analysis, sensitivity and specificity of the best sHsp27 cut-off value (456.5 pg/ml) for differentiating patients with HCC from those with HCC-free chronic liver disease were 70 and 73 %, respectively. In conclusion, sHsp27 levels are enhanced in patients with HCC and may represent a candidate biomarker of HCC.     

肝癌病人血清中丙型肝炎病毒E2／NS1基因区cDNA的克隆及序列分析

从一个抗丙型肝炎病毒（ＨＣＶ）阳性的肝细胞癌（ＨＣＣ）病人血清中提取ＲＮＡ,随机引物逆转录为ｃＤＮＡ后,用ＨＣＶ特异引物进行聚合酶链反应。将扩增产的７８０ｂｐ插入ｐＵＣ１８和ｐＵＣ１９质粒载体,双脱氧链末端终止法测定其序列。与慢性丙型肝炎病人或携带者血清中的ＨＣＶ序列比较,核苷酸同源性介乎６９．２３％－８９．１０％,氨基酸同源性介乎７４．５９％－９０．５７％,分析表明,此序列属于１组Ⅱ型。本文结果     

Hepatitis viruses and hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is among the most frequent malignancies worldwide. Hepatitis viruses, such as the hepatitis B virus (HBV) and hepatitis C virus (HCV) are undoubtedly listed in the etiology of HCC. Studies show that, in the near future, viral hepatitis will carry increasing weight in the etiology of HCC. This review briefly discusses the known carcinogenic effects of HBV and HCV in the light of experimental and human studies. The data show that viral proteins may directly interfere with gene products responsible for cell proliferation and cell growth. Many other signal transduction cascades may be affected as well. Direct integration of HBV viral sequences into the host genome increases the genomic instability. The genomic imbalance allows the development and survival of malignant clones bearing defected genomic information. HBV and HCV infection induces indirect and direct mechanisms through cellular damage, increased regeneration and cell proliferation, therefore enhancing the development of HCC.     

Advances in research on hepatitis B virus DNA integration

Since HBV DNA integration was discovered for the first time in 1980, various methods have been used to detect and study it, such as Southern Blot, in situ hybridization, polymerase chain reaction and so on. HBV DNA integration is thought to be random on the whole although some hot spots of integration were described by some researchers, one of which might be the repetitive sequences of the genomic DNA. Besides, DNA damage, especially double-strand breaks could promote HBV DNA integration into host genome. HBV DNA integration into cells may damage the stability of the genome, cause DNA rearrangement, promote DNA deletion and induce the formation of HCC.     

miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma

Recent studies have revealed that microRNA-29c (miR-29c) is involved in a variety of biological processes including carcinogenesis. Here, we report that miR-29c was significantly downregulated in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) cell lines as well as in clinical tissues compared with their corresponding controls. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), a key regulator in inflammation and immunity, was found to be inversely correlated with miR-29c levels and was identified as a target of miR-29c. Overexpression of miR-29c in HepG2.2.15 cells effectively suppressed TNFAIP3 expression and HBV DNA replication as well as inhibited cell proliferation and induced apoptosis. We conclude that miR-29c may play an important role as a tumor suppressive microRNA in the development and progression of HBV-related HCC by targeting TNFAIP3. Thus miR-29c and TNFAIP3 represent key diagnostic markers and potential therapeutic targets for the prevention and treatment of HBV infection.