无肝硬化的肝癌与丙型肝炎病毒相关

丙型肝炎病毒(HCV)的慢性感染是肝细胞癌的危险因素,尤其多见于肝硬化病人。作者选择19例乙型肝炎表面抗原阴性的白人,在无肝硬化史的肝细胞癌,分析其肝脏的HCV基因组,探讨HCV是否具有直接的致癌作用。     

乙型肝炎病毒X蛋白与原发性肝细胞癌

近年来,乙型肝炎病毒X基因及表达产物HBxAg的研究取得了令人瞩目的成就。X基因克隆化及体外表达已在许多实验室获得成功。X基因与肝细胞DNA的整合及表达后的反式激活作用是肝细胞转化的重要因素。对X基因及HBxAg广泛、深入的研究对从分子生物学水平阐述乙型肝炎病毒的致癌机理意义重大。     

肝细胞癌中抑癌基因CDKN2A甲基化的研究进展

肝细胞癌（HCC）的发生是一个涉及多基因、多步骤的复杂过程，相关癌基因激活和抑癌基因失活的致癌模式逐渐为人们所认识。DNA甲基化是转录水平的DNA修饰方式之一，在调节基因表达及维持细胞正常分化中起着重要作用。其状态的改变是肝癌相关基因调控的一种方式，属于肝癌发生的早期事件。本文就抑癌基因CDKN2A（cyclin—dependent kinase inhibitor，CDKN2A）的结构与功能及其与肝癌的关系等方面的研究进展进行综述。     

RIT1基因在肝细胞癌中的扩增及其临床意义

背景与目的:已有的研究显示肝细胞癌的染色体1q有高频扩增,1q21-22是最小的高频扩增区带之一,可能存在肝细胞癌相关的候选癌基因。RIT1基因位于1q21.3区带,是Ras的亚家族成员,RIT1蛋白在分子结构和功能方面与Ras蛋白非常相似,推测RIT1基因可能是肝细胞癌的候选癌基因之一。因此,本研究通过检测肝细胞癌RIT1基因的扩增情况,并与临床指标相联系,探讨该基因对肝细胞癌发生和发展的可能作用。方法:建立荧光定量PCR的方法,在PEABI7000型荧光定量PCR仪上检测43例肝细胞癌患者手术切除的癌组织及远癌肝组织RIT1基因的拷贝数,并用癌组织与癌旁肝组织基因拷贝数的比值作为RIT1基因的扩增倍数。结果:在43例肝细胞癌患者中,11例有RIT1基因的扩增,扩增率为25.6%;将基因扩增组与非扩增组比较,基因扩增组的生存期(平均15个月)明显短于非扩增组(平均34个月),P=0.0009,且在病理分级和肝硬化程度方面也具有明显的差异,P<0.01。结论:基因扩增可能是癌基因RIT1在肝细胞癌的激活方式之一,该基因的扩增可能对肝细胞癌的发生发展起一定的作用。     

广西原发性肝细胞癌病因探讨——118例配对病例—对照的条件Logistic回归分析

本文应用单因素和多元条件Logistic回归模型配合相结合的统计分析技术,进一步对广西原发性肝细胞癌的病因进行综合研究。结果表明,乙肝病毒血清学标志抗—HBc、10年前吃玉米占口粮比例和微量元素Se/Cu比值是广西原发性肝细胞癌的三大重要致病因素,而10年前饮用塘沟水、肝癌或肝病家族史、5年前肝病史是次要或辅助的致癌因子。综合本研究结果提示:广西原发性肝细胞癌是多因素综合作用的可能性大。     

肝细胞癌患者的谷胱甘肽转移酶M1基因型分析

目的 研究广西黄曲霉毒素（AFB1）高危区肝细胞癌（HCC）患者谷胱甘肽转移酶（GST）M1的基因型。方法 用GSTM1特异引物和PCR方法检测末稍血白细胞中的GSTM1基因,研究对象为：病理确诊为HCC患者162例（HCC组）、当地无癌成年人177例（对照I组）和HCC低发区北京、河北青年40例（对照Ⅱ组）。结果 GSTM1基因缺失（GSTM1－null)型在HCC组为102例,占63％;对照I组为92例,占52％;对照Ⅱ组为13例,占33％。各组相比,差异有显著性。结论 GSTM1为AFB1Ⅱ期代谢解毒酶,遗传性缺失这种酶的个体对HCC的遗传易感性增高。广西HCC高发的因素,既有遗传易感性,又有AFB1高污染的环境因素,还有致癌病毒HBV和HCV等的协同致癌作用。     

日本今后十年肿瘤综合战略研究课题

厚生省的十年研究课题一、人的致癌基因(癌原)的研究* 人的新致癌基因的检测和鉴定* 人和动物模型的致癌过程中致癌基因的鉴定及其机能的解释人肺癌的致癌基因及特异基因的研究二、病毒引致人癌的研究     

抑癌基因PTEN在人肝癌组织中的表达及其与HCV核心蛋白的关系

目的：研究抑癌基因PTEN在人肝细胞肝癌中的表达及其与HCV核心蛋白间的关系.方法：采用SP法检测人肝细胞肝癌组织中PTEN和HCV核心蛋白的表达.结果：42例肝癌组织中PTEN阳性表达14例（33.3%）,而在癌旁肝组织中全部为阳性表达（28例）,PTEN蛋白在癌旁组织中的阳性表达率明显高于肝癌组织（P＜0.01）,PTEN的表达在HCC组织病理分级间亦有显著差别（P＜0.01）;肝癌组织中HCV核心蛋白阳性表达17例（40.5%）,HCV核心蛋白的表达在HCC组织病理分级间无显著差别（P＞0.05）;spearman相关分析显示,在肝癌组织中HCV核心蛋白与PTEN表达之间呈负相关（r=-0.424,P＜0.01）,即HCV核心蛋白阳性表达的肝癌组织中PTEN低表达.结论：在人丙型肝炎相关性肝细胞肝癌中存在着PTEN的表达缺失或下降;在HCV导致的肝癌的发生中,丙肝核心蛋白可能通过抑制PTEN的表达最终导致癌变的发生.     

黄曲霉毒素B1诱导性大鼠肝癌超微结构观察及DNA甲基化转移酶3表达变化

由DNA甲基化转移酶(DNA methyltransferase,DNMT)活性改变诱导的DNA甲基化模式改变是肿瘤异常表观遗传修饰的重要机制,主要表现为基因组整体的低甲基化和区域性高甲基化,通过改变癌基因、抑癌基因的表达和基因组的稳定性,诱导正常细胞癌性转变[1-2].DNMT3基因是DNMT家系重要成员,在建立组织特异性甲基化模式方面发挥关键作用.黄曲霉毒素B1(aflatoxin B1,AFB1)为公认的原发性肝癌(hepatocellular carcinoma,HCC)致癌因素之一,其致癌过程中同样涉及DNA甲基化模式异常改变[3-6].DNMT3在肝细胞癌变过程中动态变化的研究少见报道,本研究旨在分析AFB1诱导性大鼠肝细胞癌变不同阶段DNMT3a mRNA和DNMT3b mRNA变化特征,初步研究AFB1诱导性大鼠HCC发生的表观遗传学机制.     

HCV核心基因转染胆管癌细胞中NF-κB的表达

目的 探讨丙型肝炎病毒（HCV）感染在胆管癌中的致癌机理。方法 通过分子克隆技术构建HCV－C基因重组质粒,经酶切鉴定后,经染胆管癌细胞（QBC939）,经G418选择培养,以免疫细胞学测定、Western blotting鉴定其表达;以透射电镜观察细胞形态学改变,并用免疫细胞学检测NF－κB的表达。结果 限制性内切酶反应证明HCV－C基因质粒构建成功,构建的PBK－HCVc质粒经免疫细胞学、Western blotting鉴定在QBC939细胞中有稳定表达。透射电镜可见胞质空泡内球型病毒颗粒,直径约50－80nm,有外膜结构。HCV核心蛋白可激活NF－κB表达。结论 进一步探讨HCV感染在胆管癌中的致癌机理提供了理想的实验细胞株,NF－κB可能与HCV感染的胆管癌细胞免疫逃逸及致癌有关。     

Molecular mechanism of viral hepatocarcinogenesis

Overwhelming lines of epidemiological evidence have indicated that chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). In the pathogenesis of HCC associated with HBV or HCV, it remains controversial whether these hepatitis viruses play a direct role or merely an indirect role. By virtue of transgenic mice established by us, it has become evident that the product of the HBV X gene (HBx protein) and the core protein of HCV have an oncogenic potential, although the pathways through which these two viral proteins operate may differ. The findings in our studies indicate that HBV and HCV are directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with chronic hepatitis may play a role as well. Combined, our results suggest that there might be a mechanism in the development of HCC in persistent infection with hepatitis viruses that is distinct from that in other cancers. Similarly to the pathogenesis of other malignancies represented by colorectal cancer, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HBx protein and HCV core protein, to which an oncogenic potential is attributed, may allow some of the multiple stages skipped in hepatocarcinogenesis. Unlike for the other cancers, therefore, infection with HBV or HCV may be capable of inducing HCC in the absence of a complete set of genetic aberrations. Such a scenario would explain an unusually high incidence and multicentric nature of HCC developing in chronic hepatitis B or C.     

HCV感染对肝癌一些癌相关基因产物表达的影响

目的 研究丙型肝炎病毒（ＨＣＶ）的致癌机理。方法 以免疫组化ＡＢＣ法对４６例肝细胞癌（ＨＣＣ）及其癌旁肝组织的ＨＣＶＣＰ１０、ＮＳ３及ＮＳ５抗原和rasp２１、c-myc、c-erbB-2、突变型p５３及p１６蛋白进行染色,并将ＨＣＣ分为ＨＣＶ抗原阳性组和ＨＣＶ抗原阴性组,对比分析ＨＣＶ感染对上述癌相关基因蛋白产物表达的影响。结果 ４６例ＨＣＣ患者中,１～３种ＨＣＶ抗原性２０例（４３．５％）,２～３种ＨＣＶ抗原阳性     

IL-4, IL-17 and CD163 Immunoexpression and IL-6 Gene Polymorphism in Chronic Hepatitis C Patients and Associated Hepatocellular Carcinoma

Objective: To assess the expression of IL-4, IL-17 and CD-163 as well as study of IL6-572 C/G gene polymorphism in chronic HCV and HCC on top of HCV. Methods: Sixty HCC specimens and 60 adjacent hepatic tissue with HCV of different grades of necro-inflammation and different stages of fibrosis. In addition to 55 HCV, 60 HCC and 50 healthy venous blood samples for evaluation of IL6-572 C/G gene polymorphism. Results: high expression of IL-4, IL-17 and CD163 in higher grades of activity, late stages of fibrosis and higher degrees of steatosis of HCV. IL-4 and CD163 showed higher expression in advanced grades of HCC, while IL-17 more expressed in lower grades. No significant difference in IL6-572 C/G gene polymorphism among studied groups regarding G/C, G/G, C/C frequencies or G and C allele’s frequencies. Conclusion: IL-4, IL-17 and CD163 were associated with HCV severity. Their expression in HCC suggests their important role in HCC development. Blocking of these proteins may be a good target to control inflammation in HCV and can hinder progression to cirrhosis then to HCC. On the other hand, IL6-572 promoter gene polymorphism is neither associated with HCV infection nor with HCC development and its progression.     

XRCC1 Gene Polymorphism Increases the Risk of Hepatocellular Carcinoma in Egyptian Population

Several major risk factors for hepatocellular carcinoma (HCC) have been identified, including chronic infection of hepatitis B virus (HBV) and hepatitis C virus (HCV). Nevertheless, only a fraction of infected patients develops HCC during their lifetime suggesting that genetic factors might modulate HCC development. X-ray repair cross complementing group1 (XRCC1) participates in the repair pathways of DNA. Aim: to investigate the association between XRCC1 gene polymorphism and HCC in Egyptian chronic hepatitis C patients. Methods: This study was assessed on 40 patients with HCC secondary to chronic HCV infection who were compared to 20 cirrhotic HCV patients and 40- age and gender- matched healthy control group. After collection of relevant clinical data and basic laboratory tests, c.1517G>C SNP of XRCC1 gene polymorphism was performed by (PCR-RFLP) technique. Results: A statistically higher frequency of XRCC1 (CC, GC) genotypes and increased (C) allele frequency in patients with HCC was found in comparison to cirrhotic HCV patients as well as control group. In addition, patients with the XRCC1 (CC, GC) genotypes had significantly higher number and larger size of tumor foci and significantly higher Child Pugh grades. Multivariate analysis showed that the presence of c.1517G>C SNP of XRCC1 gene is an independent risk for the development of HCC in chronic HCV patients with 3.7 fold increased risk of HCC development. In conclusion: XRCC1 gene polymorphism could be associated with increased risk of HCC development in chronic HCV Egyptian patients.     

Characteristic mutations in hepatitis C virus core gene related to the occurrence of hepatocellular carcinoma

Chronic hepatitis C virus (HCV) infection often results in hepatocellular carcinoma (HCC). Previous studies have shown that there might be some characteristic mutations in the core region of HCV related to HCC. Thus, we downloaded and analyzed HCV genotype 1b core gene sequences from HCV databases online to identify them. Based on the information of the sequences, 63 from patients with HCC and 188 from non-HCC were enrolled into our analysis. Then, the nucleotides at each position were compared by χ²-test between the two groups, and 24 polymorphisms were found to be associated with HCC. Further analysis of these 24 polymorphisms by logistic regression indicated that eight were significantly related to the increased HCC risk: A028C, G209A, C219U/A, U264C, A271C/U, C378U/A, G435A/C, and G481A. Moreover, U303C/A was associated with the decreased HCC risk. These mutations could bring about four amino acid substitutions: K10Q, R70Q, M91L, and G161S. In conclusion, eight characteristic mutations in the HCV-1b core gene related to the occurrence of HCC were identified. The structural and functional alterations of core protein due to these mutations and the relationship with the occurrence of HCC need to be further studied. ( Cancer Sci 2009; 100: 2465–2468)     

肝硬变和肝癌组织内HCV RNA及HBV X基因的存在及意义

采用原位分子杂交对７９例肝硬变及６４例肝细胞癌组织进行ＨＣＶ ＲＮＡ和ＨＢＶ Ｘ基因定位检测，ＨＣＶ ＲＮＡ，ＨＶＢ Ｘ基因在两种组织的阳性率分别是４８％及７２％；３９％，及８１％；二者同时阳性在两种组织分别为３８％及３３％。ＨＣＶ ＲＮＡ主要定位于肝细胞和癌细胞胞浆内，阳性细胞呈散在、灶状及弥漫分布三种形式。ＨＢＶ Ｘ基因在肝细胞及肝癌细胞中的分布呈胞浆型、核型及核浆型，阳性细胞也呈上述三种分布     

Unique situation of hepatocellular carcinoma in Egypt: A review of epidemiology and control measures

Hepatocellular carcinoma (HCC) is the sixth most common primary malignancy worldwide, and the third most common cause of death among cancers worldwide. HCC occurs in several pre-existing conditions, including hepatitis C, hepatitis B virus, and non-alcoholic cirrhosis. Egypt used to be the country with the heaviest hepatitis C virus (HCV) burden. The relationship between HCV and HCC is an important research area. In Egypt, HCC is a significant public health problem. A possible cause for the increasing rates of detection of HCC in Egypt is the mass screening program that was carried by the government for detecting and treating HCV. A multidisciplinary approach is now widely applied to HCC management in health centers all over Egypt. Different treatment modalities are available in Egypt, with success rates comparable to global rates. The Egyptian health authorities have made the elimination of HCV from Egypt a special priority, and this approach should lead to a decrease in number of HCC cases in the near future. In this article we review the current situation of HCC in Egypt, including epidemiological aspects, relevant risk factors for HCC development, strategies, and efforts established by health authorities for the screening and prevention of both HCV and HCC in Egypt. We highlight the different modalities for HCC treatment.