抑癌基因高甲基化与鼻咽癌

抑癌基因启动子高度甲基化被认为是除突变和缺失以外的抑癌基因功能失活的关键机制.某些抑癌基因高甲基化与鼻咽癌(NPC)发生密切相关.抑癌基因的甲基化状态检测具有重要的临床意义,有望为肿瘤的早期诊断提供新的思路,而逆转抑癌基因的甲基化则可能成为肿瘤治疗的新方向.     

抑癌基因高甲基化与鼻咽癌

抑癌基因启动子高度甲基化被认为是除突变和缺失以外的抑癌基因功能失活的关键机制.某些抑癌基因高甲基化与鼻咽癌(NPC)发生密切相关.抑癌基因的甲基化状态检测具有重要的临床意义,有望为肿瘤的早期诊断提供新的思路,而逆转抑癌基因的甲基化则可能成为肿瘤治疗的新方向.     

抑癌基因高甲基化与鼻咽癌

抑癌基因启动子高度甲基化被认为是除突变和缺失以外的抑癌基因功能失活的关键机制.某些抑癌基因高甲基化与鼻咽癌(NPC)发生密切相关.抑癌基因的甲基化状态检测具有重要的临床意义,有望为肿瘤的早期诊断提供新的思路,而逆转抑癌基因的甲基化则可能成为肿瘤治疗的新方向.     

Tip30基因甲基化与肝细胞癌临床预后的关系

肿瘤细胞DNA甲基化紊乱常表现为癌基因去甲基化和抑癌基因高甲基化,即抑癌基因功能失活是通过表观遗传调控抑制,而不是通过基因缺失或突变。既往研究在肝细胞癌中p16、SOCS-1、TFPI-2、E—cadherin、RASSF1A和NORE1B等抑癌基因常常表现为高甲基化状态,这些基因的高甲基化状态与肝细胞癌的发生、发展关系密切。     

DNA甲基化在肿瘤诊断和治疗中的研究进展

DNA甲基化在基因表达调控、基因突变、细胞增殖、分化以及基因印迹等方面与肿瘤的发生发展有着密切的联系.抑癌基因的高甲基化和特异癌基因的低甲基化是目前肿瘤中DNA甲基化异常的主要形式.通过诱导癌基因和抑癌基因的DNA甲基化可抑制肿瘤的生长及癌基因的表达,是目前抗肿瘤治疗和诊断的新思路.本文就癌基因及抑癌基因的甲基化治疗和诊断在临床前的研究进展做一综述.     

食管鳞癌DNA甲基化的研究进展

近年来研究结果表明,相关抑癌基因启动子区超甲基化导致的基因表达紊乱已成为食管癌发病机制研究的热点之一.众多研究表明DNA甲基化在食管癌的发生、侵袭和转移过程中发挥了积极的作用,外周血DNA甲基化谱可作为食管癌早期诊断、预后判断及随访的检测指标,有望将抑癌基因去甲基化作为食管癌的治疗靶点.     

抑癌基因甲基化与宫颈上皮内瘤变

DNA甲基化是抑癌基因失活的第三种机制,在肿瘤形成过程中有着重要作用。本文综述了一些抑癌基因甲基化与CIN的相关性。提出这些抑癌基因甲基化在CIN诊断、治疗以及预测病情发展方向中可能发挥的作用。     

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。     

抑癌基因甲基化在肾细胞癌研究中的新进展

抑癌基因启动子高度甲基化被认为是除突变和缺失以外的抑癌基因功能失活的关键机制,在肿瘤的发生和发展中起重要作用,已成为目前肿瘤病因学基础研究的热点.肾细胞癌是泌尿系统最常见的恶性肿瘤之一,近年来也有许多文献报道了肾细胞癌中抑癌基因的异常甲基化情况.肾细胞癌临床发病隐匿,出现症状时多为晚期,肾细胞癌相关基因异常甲基化检测有望为肾癌的早期无创诊断提供新的途径.针对肾癌对放、化疗效果均不敏感的特点,改变DNA甲基转移酶活性和抑癌基因甲基化状况可作为肾细胞癌辅助治疗的一种新思路.本文对抑癌基因甲基化与肾细胞癌关系的研究进展作一综述,介绍DNA甲基化在肿瘤发生过程中的作用及机理;总结近7年来肾细胞癌中抑癌基因甲基化的研究情况和肾细胞癌独特的甲基化谱,并着重介绍了新近报道的HOXB13,HAI2/SPINT2,CDH1,CTNNG/JUP四个基因启动子异常甲基化与肾细胞癌的关系;阐述DNA甲基化研究对肾细胞癌的临床意义.     

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。     

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.     

The association of hepatocellular carcinoma in childhood with hepatitis B virus infection

Eleven cases of hepatocellular carcinoma (HCC) in childhood were investigated by immunohistochemistry for association with hepatitis B virus (HBV) infection. Seven of 11 cases (64%) demonstrated positivity for hepatitis B surface antigen (HBsAG), whereas all 11 were negative for hepatitis B core antigen (HBcAG). Cirrhosis was absent in all cases, and other causes for HCC in childhood were not found. All children with HBV-associated HCC died within 6 months of diagnosis. The median survival time of these children was 2 months. Only one child with HCC of trabecular subtype without HBV association is still living after 18 months. However, this child has metastases and a local recurrence. Three other children with HCC of fibrolamellar subtype are free of disease after 2, 5, and 6 years, respectively. The high number of cases of HBV-associated HCC shows the important role of HBV infection as an etiologic factor for the development of childhood HCC in middle Europe.     

慢性乙型肝炎病毒感染与p16INK4A基因启动子甲基化关系的研究

目的探讨慢性乙型肝炎病毒(HBV)感染对p16INK4A基因启动子甲基化的影响及其在HBV相关肝细胞癌(HCC)形成中的作用。方法选取23例HBV相关HCC癌及癌旁组织、25例慢性乙型肝炎肝穿刺组织,采用甲基化特异性PCR(MSP)检测p16INK4A基因启动子的甲基化状态;免疫组化EnVision二步法测定肝组织内HBsAg、HBcAg、HBeAg和HBx蛋白的表达;荧光实时定量PCR检测肝组织HBV DNA含量;PCR扩增和直接测序检测HBV x基因变异。结果癌组织p16INK4A基因启动子甲基化阳性率(47.83%)明显高于癌旁组织(17.39%),慢性乙型肝炎患者p16INK4A基因启动子甲基化阳性率(36.00%)与癌组织、癌旁组织差异无统计学意义。在癌旁组织和慢性乙型肝炎, p16INK4A基因启动子甲基化者HBx蛋白表达中位数分别为3.000和0.250,明显高于非甲基化者(0.500和0.000),但在癌组织中,HBx蛋白的表达与p16INK4A基因启动子甲基化状态无关。HBsAg、HBcAg、组织HBV DNA含量和x基因突变均与p16INK4A基因启动子甲基化状态无关。结论在癌前病变中,p16INK4A基因启动子甲基化与HBx蛋白高表达有关,HBx蛋白可能通过诱导p16INK4A基因启动子甲基化而使该抑癌基因失活,在HBV相关HCC形成中起重要作用。     

Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis

Growing evidence demonstrates that hepatitis B virus (HBV) integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in hepatocellular carcinomas (HCCs). To determine if HBV integration occurs and affects cellular genes at such a stage of infection, we analysed viral-host junctions in chronic hepatitis tissues without HCC using PCR amplification with primers specific to human Alu-repeat and HBV. We obtained 42 independent viral-host junctions from six patients examined and identified chromosomal locations for 20 of the 42 junctions. In six clones, each integration apparently affected a single gene. These six candidate genes included one known tumor suppressor gene, three human homologs of drosophila genes that are critical for organ development, one putative oncogene and one recently found chemokine. Our data, together with previously reported HBV integrants in HCCs, suggested preferential HBV integration into chromosome 3 (P = 0.022). Our virus-tagging approach provided (a) firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and (b) revealed cellular genes possibly affected by HBV integration and potentially involved in early steps of the process leading to carcinogenesis.     

FGA、HSP90α、SPP1联合对HBV相关性肝细胞癌的早期诊断价值

目的探讨FGA、HSP90α、SPP1联合对HBV相关性肝细胞癌的早期诊断价值。方法纳入早期HBV相关性肝细胞癌患者70例为肿瘤组、肝硬化患者70例为肝硬化组、健康体检者70例为对照组;检测肿瘤组、肝硬化组和对照组血清中FGA、HSP90α、SPP1的表达量;用受试者工作特征曲线(receiver operating characteristic curve,ROC)的AUC分析FGA、HSP90α、SPP1检测在HBV相关性肝细胞癌中的诊断意义。结果HBV相关性肝细胞癌患者血清中FGA、HSP90α、SPP1的表达量均显著高于肝硬化患者(P<0.05)和健康体检者(P<0.05);肝硬化患者血清中FGA的表达量高于健康体检者(P<0.05)。区分早期HBV相关性肝细胞癌患者与健康体检者的FGA、HSP90α、SPP1的灵敏度分别为87%,80%,83%,特异度分别为83%,87%,83%。血清中FGA、HSP90α、SPP1联合对HBV相关性肝细胞癌的诊断的的灵敏度为88%,特异度为90%,准确度为89%。结论血清中FGA、HSP90α、SPP1的表达量可作为诊断早期HBV相关性肝细胞癌的潜在标志。     

Difference in histological activity of non-tumorous liver tissue between hepatitis B virus- and hepatitis C virus-associated hepatocellular carcinoma without cirrhosis

To elucidate the difference in the liver carcinogenetic process during hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, non-tumorous liver tissues obtained from 10 patients who developed HBV-associated hepatocellular carcinoma (HCC) without cirrhosis were compared with those obtained from 26 patients who developed HCV-associated HCC without cirrhosis. The extent of fibrosis was similar in both groups. In contrast, necroinflammatory activities were significantly higher in patients with HCV than in patients with HBV. These results indicate that ongoing liver inflammation mediates the hepatocarcinogenesis more pronouncedly in HCV infection than in HBV infection.     

Genetic analysis of the liver putative tumor suppressor (LPTS) gene in hepatocellular carcinomas

Recently, a novel liver-related putative tumor suppressor (LPTS), which has a growth inhibitory function in the hepatocellular carcinoma (HCC) cell line, has been identified at chromosome 8p23. To determine the relationship of the LPTS with the development or progression of HCC, we analyzed the genetic alterations and the expression pattern of the LPTS gene in a series of 80 HCCs, six dysplastic nodules, and eight large regenerating nodules, determining the genomic structures. We identified a total of seven exons, of which two were alternative, and three LPTS isoforms, short (LPTS-S), medium (LPTS-M), and long-sizes (LPTS-L). In the genetic alteration study of the LPTS gene, no mutation was detected in the large regenerating nodules, dysplastic nodules, and HCC, whereas ten (34.5%) of 29 informative cases at one or more intragenic polymorphic sites showed loss of heterozygosity (LOH). Interestingly, LOH was identified only in HCC samples with hepatitis B virus (HBV) infection and the frequency of LOH was not statistically related with histologic grade and clinical stage, suggesting that allelic loss of the LPTS gene may occur as an early event in the development of HCC, especially in the cases with HBV infection.     

Hepatitis B virus large surface antigen promotes liver carcinogenesis by activating the Src/PI3K/Akt pathway

Of the three envelope glycoproteins encoded by hepatitis B virus (HBV) that are collectively referred to as HBV surface antigen (HBsAg), the large HBsAg (LHBs) glycoprotein is expressed preferentially in HBV-associated hepatocellular carcinoma. LHBs can act as an oncogene in transgenic mice, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of LHBs during HBV-associated hepatocarcinogenesis. LHBs increased tumor formation of hepatoma cells. Moreover, expression of LHBs but not other HBV envelope glycoproteins specifically promoted proliferation of hepatoma and hepatic cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal stimulation of PKCα/Raf1 signaling by LHBs. Proliferation induced by stable LHBs expression was associated with increased G(1)-S cell-cycle progression and apoptosis resistance mediated by Src kinase activation, as established in hepatocellular carcinoma clinical specimens. Importantly, LHBs-induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that LHBs promotes tumorigenesis of hepatoma cells by triggering a PKCα/Raf1 to Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV-associated hepatocarcinogenesis.     

Management of hepatocellular carcinoma: advances in diagnosis,treatment and prevention

Since the major causes of hepatocellular carcinoma are hepatitis viruses, the difference and similarity of clinical features in relation to the causative virus may indicate that persistent inflammation of the liver is a major role in hepatocellular carcinoma development in both HBV and HCV infection. However, there is a variety of molecular products of virus-inducing mutagenesis, especially in HBV. An advance in the diagnosis of hepatocellular carcinoma is imaging modality to detect hemodynamics of hepatocellular carcinoma with noninvasive methods of ultrasonography and tumor markers. Chemoprevention using synthetic retinoid is another important issue for the prevention of hepatocellular carcinoma development, as well as viral eradication and suppression of inflammation in the liver using interferon and other drugs.