乙肝病毒感染与原发性肝细胞癌

乙肝病毒感染与原发性肝细胞癌密切相关，综述了乙肝病毒感染如何启动肝细胞癌变，从分子生物学的角度着重介绍了乙肝病毒基因的整合，乙肝病毒感染对癌／抑癌基因的影响。     

HBV 相关性肝细胞癌抑癌基因高甲基化现象及其机制的研究进展

肝细胞癌是临床上最常见的恶性肿瘤之一,肝细胞癌的发生与许多因素有关,其中的一个重要因素就是乙肝病毒感染。乙肝病毒感染是一个重大的世界性问题,HBV导致肝癌发生的过程还不明确,但是长期乙肝病毒携带与肝细胞癌的发生有重大的关系。HBV极大的促进了慢性肝炎向肝细胞癌的发展过程,但其致癌作用具体机制现在仍然存在争议。乙肝病毒（HBV）相关性肝细胞癌中存在抑癌基因高甲基化现象,在HBV相关性肝细胞癌的发生、发展、转移过程中起到重要作用。抑癌基因高甲基化现象具有明显的特异性,与HBV感染密切相关,并且通过DNA甲基转移酶1 维持,该现象为HBV相关性肝细胞癌的诊断和治疗提供了新的方法。为了早期诊断、风险评估和预防治疗,需要进一步的找到和理解HBV导致肝细胞癌的分子机制。针对HBV相关性肝细胞癌,可以通过抑癌基因甲基化来早期诊断。药物沉默抑癌基因的高甲基化,重新表达抑癌基因,可能会成为未来的一个研究方向。      

乙肝病毒与原发性肝癌

业已证实,乙肝病毒(HBV)慢性感染和肝细胞癌在流行病学上密切相关。HBV DNA的克隆和应用分子生物学技术进一步明确了乙肝病毒与肝细胞癌之间的相互作用。一、HBV DNA顺序被整合在肿瘤细胞的DNA中。这种整合在肝癌发生中的作用机理为:(1)最近在某一肿瘤研究中表明,整合可发生于与类固醇激素爱体基因相同的基因中;(2)整合部位,尤其在第11对染色体短臂的13带     

乙肝病毒与原发性肝癌

业巳证实,乙肝病毒(HBV)慢性感染和肝细胞癌在流行病学上密切相关。HBV DNA的克隆和应用分子生物学技术进一步明确了乙肝病毒与肝细胞癌之间的相互作用。一、HBV DNA顺序被整合在肿瘤细胞的DNA中。这种整合在肝癌发生中的作用机理为:(1)最近在某一肿瘤研究中表明,整合可发生于与类固醇激素爱体基因相同的基因中;(2)整合部位,尤其在第11对染色体短臂的13带     

HBsAg阳性肝细胞癌患者用干扰素或阿霉素治疗后其血清乙肝病毒DNA的改变

乙肝病毒(HBV)感染与肝细胞癌(HCC)之间的因果关系已被确认.本文主要讨论 HBsAg 阳性的 HCC 患者在用重组干扰素(γIFN-A)或阿霉素     

乙肝病毒HBX抗原与p53相互作用及其对肝细胞癌发生的影响

HBX抗原是乙肝病毒最小编码框x基因区编码的蛋白，研究证明它与HBV相关性肝癌的发生有关；抑癌基因p53的变异或失活也与肝细胞癌(HCC)的发生密切相关。研究HBX抗原与p53的相互作用关系，有助于进一步揭示HBV相关性肝癌的发病机制。     

乙肝病毒HBX抗原与p53相互作用及其对肝细胞癌发生的影响

HBC抗原是乙肝病毒最小编码杠X基因区编码的蛋白，研究证明它与HBV相关性肝癌的发生有关；抑癌基因p53的变异或失活也与肝细胞癌（HCC）的发生密切相关。研究HBX抗原与p53的相互作用关系，有助于进一步揭示HBV相关性肝癌的发病机制。     

血吸虫病流行区的原发性肝细胞癌

原发性肝细胞癌(PHC)为我国常见恶性肿瘤。我院从1982～1988年共收治PHC 99例。通过血吸虫(血凝法或免疫反应法阳性者)和乙肝病毒(酶联免疫法阳性者)检测,均有血吸虫、乙肝病毒或血吸虫与乙肝病毒的感染,为探讨血吸虫流行区的PHC与其间的关系,现作如下分析:     

乙肝病毒与原发性肝癌

业已证实,乙肝病毒(HBV)慢性感染和肝细胞癌在流行病学上密切相关。应用克隆 HBV DNA和分子生物学技术进一步明确了乙肝病毒与肝细胞癌的关系。1.HBV DNA 顺序被整合在肿瘤细胞 DNA 中。这种整合在肝癌发生中的作用机理为:①在一种肿瘤     

慢病毒介导的RNAi沉默TLR4基因对人乙肝病毒相关肝细胞癌裸鼠移植瘤生长的影响北大核心CSCD

目的探讨TLR4基因RNA干扰(RNAi)的重组慢病毒载体对人乙肝病毒相关肝细胞癌裸鼠移植瘤TLR4基因表达和移植瘤生长的影响。方法构建4个miR-TLR4质粒和一个阴性对照质粒,选择干扰效果最明显的质粒进行慢病毒包装。建立人乙肝病毒相关肝细胞癌裸鼠移植瘤模型,随机分成实验组、阴性对照组和空白对照组。隔天1次向各组动物肿瘤内分别注射TLR4 miRNA慢病毒颗粒、携带无关序列的慢病毒颗粒或0.2 ml 0.9%氯化钠溶液,共5次,测量各组肿瘤体积的大小,绘制肿瘤生长曲线;11天后处死裸鼠,应用半定量反转录-聚合酶链反应(RT-PCR)和Western blot技术检测移植瘤中TLR4基因的表达。结果与空白对照组和阴性对照组相比,实验组的移植瘤生长速度明显减慢(P<0.05),并且实验组移植瘤细胞TLR4 mRNA和蛋白表达明显下降(P<0.05)。结论 TLR4 miRNA慢病毒载体瘤内注射可抑制人乙肝病毒相关肝细胞癌裸鼠移植瘤的生长。     

乙型肝炎病毒感染在肝细胞癌发生机制中的研究进展

肝细胞癌（HCC）是世界范围内常见的恶性肿瘤之一,乙型肝炎病毒（HBV）感染是引起HCC的最主要原因。HBV 通过DNA整合影响插入点附近宿主基因的功能,促使宿主基因组的不稳定,产生具有致癌作用的融合蛋白;HBV的x基因产物（HBx蛋白）具有广泛的反式激活功能,如调控细胞的凋亡,抑制细胞DNA的修复,干扰细胞内信号通路及改变表观遗传学等。本文结合近年相关报道对HBV相关HCC流行和发生、HBV DNA整合、HBx蛋白等相关研究作一综述。     

Genes and viruses in hepatobiliary neoplasia

Hepatobiliary neoplasms comprise a significant portion of the worldwide cancer burden. Advances in basic science research have led to rapid progress in our understanding of the molecular events responsible for these dreaded diseases. The genetic changes associated with hepatocellular carcinoma (HCC) have received the most attention. Aflatoxin B1 exposure leads to mutations in the p53 tumor suppressor gene, most commonly a transversion in codon 249 that leads to a substitution of serine for arginine in the p53 protein. Numerous other tumor suppressor genes, oncogenes, and tumor gene pathways are altered in HCC. Hepatitis B virus (HBV) infection is strongly associated with HCC. HBV may cause HCC either directly via the HBV X protein, or indirectly by causing liver inflammation and cirrhosis. Hepatitis C virus (HCV) infection is also associated with HCC. Recent evidence suggests that the HCV core protein may play a role in hepatocarcinogenesis. Several inherited metabolic diseases are associated with HCC. It is likely that these diseases cause HCC indirectly by causing cirrhosis. The molecular pathogenesis of cholangiocarcinoma and gallbladder cancer has not been well defined. However, multiple tumor suppressor genes and oncogenes, including p53 and K-ras, are altered in these tumors. Further molecular characterization of hepatobiliary tumors may lead to earlier diagnosis, better staging, improved treatment planning, and the development of more effective therapies.     

Hepatic expression of oncogenes Bmi1 and Dkk1 is up‐regulated in hepatitis B virus surface antigen–transgenic mice and can be induced by treatment with HBV particles or lipopolysaccharides in vitro

Previous studies have shown that hepatocellular carcinoma (HCC) develops more frequently in hepatitis B virus surface antigen (HBsAg)‐transgenic mice (Alb/HBs) than in wild‐type (WT) mice. However, the mechanism of this HCC model has not been well documented. Toll‐like receptor 4 (Tlr4) signaling probably links innate immunity and HCC progression. This study was designed to investigate the role of innate immunity in hepatocarcinogenesis in Alb/HBs mice. Immunohistochemical analysis of liver specimens from Alb/HBs mice (16 per group) showed that the oncogenes Bmi1 (16/16, 100%) and Dkk1 (13/16, 81.25%) were highly expressed in Alb/HBs mice, whereas the other oncogenes evaluated were expressed in smaller percentages of mice (Afp, 9/16, 56.2%; Ctnnb1, 5/16, 31.3%; Epcam, 0/16; 0%). Comparable results were obtained by quantitative PCR analysis. Hepatic gene expression of Tlr2, Tlr4, Il6 and Tnf was additionally elevated in Alb/HBs mice. Stimulation of primary murine hepatocytes with cell culture‐derived HBV particles or LPS increased the expression of oncogenes (Bmi1, Dkk1) and inflammatory factors (Tnf, Il6, Tlr4). Proliferation and colony formation of hepatoma cells were enhanced by treatment with HBV and LPS and were impaired by the suppression of Bmi1 and Dkk1 by small interfering RNAs. Substantial induction of BMI1 and DKK1 was found in liver biopsy samples from patients with HBV‐related HCC but not in HCC samples without HBV infection background. These findings suggest that innate immunity may link inflammation and tumor progression during chronic HBV infection, involving the oncogenes BMI1 and DKK1.     

Overexpression and significance of focal adhesion kinase in hepatocellular carcinoma and its relationship with HBV infection

The prognosis of the hepatocellular carcinoma is influenced by its invasion and metastasis. Interacting with a number of oncogenes, HBV infection is a high risk factor for HCC. Overexpression of Focal adhesion kinase (FAK), a novel oncogene, has been suggested to play an important role in tumorigenesis and progression of many cancers, including HCC. However, the relationship between HBV infection and FAK for HCC prognosis is still unclear. A retrospective study of 89 archival specimens of subjects with histologically confirmed HCC was carried out. Immunohistochemistry was utilized to examine the expression of FAK. Then the FAK expression was analyzed with index of HCC, especially with HBsAg and HBV DNA. FAK overexpression was detected in 38/89 of the tumors. FAK overexpression in HCC significantly correlated with HBsAg (P = 0.033), HBV DNA level (P = 0.005), vascular invasion of HCC (P = 0.000*), and TNM stage (P = 0.003). FAK-positive patients exhibited a lower survival rate compared with those with negative FAK expression. Overexpression of FAK might have a correlation with HBV infection and contribute to HCC progression, raising the possibility of FAK overexpression as a potential marker for a poor prognosis in HCC.     

Molecular aspects of hepatocarcinogenesis and their clinical implications - review

The formation and development of cancer is associated with various genetic abnormalities. Recent progress in the study of genetic changes in hepatocellular carcinoma (HCC) have clarified the aberrations of oncogenes and tumor suppressor genes, as well as the role of the hepatitis virus in hepatocarcinogenesis. Overexpression of the c-myc gene, inactivation of the p53 and RB genes, and the loss of heterozygosity (LOH) of some chromosomes where tumor suppressor genes may be located have been reported in association with the progression of HCC. However, genetic abnormalities of HCC at the early stages have yet to be elucidated. On the other hand, the association between HCC and chronic infection with the hepatitis virus also shows the relevance of the oncogenic potential of the hepatitis virus to HCC formation. Some regions of HBV genome, especially the HBV X gene, stimulate the various cellular activities related to tumor promotion and contribute to hepatocarcinogenesis. The knowledge of genetic abnormalities is helpful in the elucidation of pathogenesis and probably in the diagnosis, prognosis and therapy of HCC. Further studies of these genetic changes will apparently promote molecular diagnosis and gene therapy in HCC.     

Multiple oncogenes and tumor suppressor genes are structurally and functionally intact during hepatocarcinogenesis in hepatitis B virus transgenic mice.

In the current study we sought to elucidate the molecular mechanisms which might contribute to hepatocarcinogenesis in a hepatitis B virus (HBV) envelope transgenic mouse model in which chronic hepatocellular injury and inflammation lead to regenerative hyperplasia and eventually to the development of chromosomal abnormalities and hepatocellular carcinoma (HCC), thereby reiterating many of the pathophysiological events that occur prior to the development of HCC in chronic HBV infection in humans. We have previously demonstrated that HBV envelope gene expression is decreased in regenerating hepatocytes and preneoplastic nodules early in the disease process and that expression of alpha-fetoprotein and the multidrug transporter gene mdr-III is activated in the tumors that develop in this model, but not prior to tumor development. In the current study, we examined the structure and expression of a large panel of dominant acting oncogenes and tumor suppressor genes in the liver at all stages of the disease process in order to determine the extent to which they contribute to hepatocarcinogenesis in these transgenic mice. To our surprise, no changes were observed in the structure or function of any of these genes, many of which are commonly activated in other rodent models of hepatocarcinogenesis but rarely activated in human HCC. These findings suggest that the HBV transgenic mouse model is different from most other rodent models of hepatocarcinogenesis and that it may relate more closely to the events involved in HBV-induced human hepatocarcinogenesis, where generalized chromosomal abnormalities are common, while structural and functional changes in most of the commonly studied positive-acting oncogenes examined herein are not. Since p53 and RB mutations have recently been reported to be late events in human hepatocarcinogenesis, the structural integrity of the RB locus and the absence of p53 mutations in the HBV transgenic mouse model suggest that they may represent a relatively early stage of hepatocellular tumorigenesis and that further manipulation of this model is warranted in order to more fully reproduce the molecular-genetic events that characterize HBV-induced HCC in humans.     

VEGF、COX-2在HBV感染型和非HBV感染型肝细胞癌中的表达差异及意义

目的：探讨血管内皮生长因子（VEGF）、环氧合酶-2（COX-2）蛋白表达水平和肿瘤血管形成在肝细胞癌（HCC）中表达的临床病理意义。方法：利用血清学指标检测56例HCC的乙型肝炎病毒（HBV）感染情况，采用快速免疫组化法检测肝细胞癌中VEGF、COX-2的蛋白表达，抗CD105单克隆抗体显示血管内皮细胞，根据CD105阳性的血管内皮细胞计数测定肿瘤微血管密度（MVD）。结果：HBV感染组中VEGF、COX-2蛋白以及MVD的阳性表达率均高于非HBV感染组，有统计学差异（P〈0．05）。VEGF和COX-2表达呈正相关（r=0．429，P〈0．05）。结论：HBV可能通过上调VEGF、COX-2等血管形成因子上调表达，共同促进了肿瘤血管的生成，从而促进HCC的生长、浸润和转移。     

Etiology of hepatocellular carcinoma in Africa

The important factors in the causation of hepatocellular carcinoma (HCC) in Africa include hepatitis B virus (HBV), aflatoxin and possibly malnutrition. The evidence in support of an association of HBV with HCC is mainly epidemiological and includes: (a) the similarity between the geographical distribution of chronic carriers of hepatitis B surface antigen (HBsAg) and that of HCC; (b) the increased prevalence of HBV markers in the serum of patients with HCC when compared with the general population; and (c) the observation that HBV infection precedes the general development of the tumour and that HBV infection increases the risk of HCC over 200-fold. Laboratory evidence has shown that HBV DNA is integrated in the host tissue in patients with HCC. A vaccination programme in Senegal showed that hepatitis B vaccine reduced HBV infection and it is hoped that it will eventually lead to a reduction in HCC. Studies in East Africa have shown a correlation between aflatoxin contamination and the incidence of HCC. The possible roles of malnutrition and/or alcohol are discussed.