肝细胞癌表观遗传学改变和重编程

肝细胞癌是世界范围内常见的恶性肿瘤.研究表明,由遗传学和表观遗传学改变引起的细胞恶性改变是肿瘤发生的重要原因.近年来,人们发现表观遗传学异常在肿瘤的发生、发展过程中也起到非常重要的作用.表观遗传修饰主要包括组蛋白乙酰化和DNA甲基化,组蛋白乙酰化和DNA低甲基化可促进基因表达,反之,则可抑制基因表达.在肝细胞癌的发生发展过程中,抑癌基因的甲基化特别是高甲基化起着重要作用,与肝细胞癌的形成有密切关系.肝癌的表观遗传学研究对肝癌的早期诊断和病情预后的监测及其防治具有重要意义.     

DNA甲基化与肝癌

表观遗传学是指非遗传改变(DNA甲基化、组蛋白修饰以及miRNA等非编码RNA)对基因表达调控,这种调节不依赖基因序列的改变且可遗传,其中DNA甲基化是最常见的表观遗传现象。研究表明,在肝癌的发展过程中,表观遗传学改变起到了重要的作用,探讨DNA甲基化的致癌机制可为肿瘤诊治提供理论依据,同时也可作为生物标志物用于肿瘤早期诊断和预后评估。为此,将对肝癌中DNA甲基化改变的特征及其临床应用价值进行阐述。     

SFRP1基因甲基化在恶性肿瘤中的研究进展

DNA甲基化是真核细胞基因组最常见的一种表观遗传学修饰,与肿瘤的发生和发展密切相关。SFRP1基因是分泌型糖蛋白家族之一,是目前公认的表观遗传学标志物,其表观遗传学涉及多种肿瘤,本文对SFRP1基因在结直肠癌,胃癌,膀胱癌,前列腺癌,子宫内膜癌等肿瘤中的研究作一综述。     

DNA甲基化修饰与肾脏疾病

表观遗传学(epigenetics)是研究不涉及DNA序列改变的基因表达和调控的可遗传修饰,即探索从基因演绎为表型的过程和机制的一门新兴学科.DNA的甲基化是调节基因表达的一种表观遗传方式[1].DNA甲基化因其与人类发育和肿瘤的密切关系,已经成为表观遗传学的重要研究内容.所谓DNA甲基化是指在DNA甲基转移酶(DNMT)作用下,将s-腺苷甲硫氨酸(s-adenosylmethionine,SAM)的甲基基团共价结合到CpG二核苷酸的胞嘧啶5'碳位上的过程.     

表观遗传修饰与肝癌的关系

表观遗传学是指基因的核苷酸序列在不发生改变的情况下,基因表达了可遗传的表型变化.表观遗传机制的失调在人类恶性肿瘤包括肝癌发生、发展过程中发挥了重要作用.目前研究结果发现:大量表观遗传可调节有关基因靶点和信号转导通路,如DNA甲基化、组蛋白修饰、RNA调节基因沉默等与肝癌的发生和发展密切相关.探究这些异常的表观遗传机制对诊断和治疗肝癌有着重要的意义.     

乳腺癌基因甲基化的研究进展

乳腺癌的发生的分子机制仍然不明确。研究显示表观遗传学改变（Epigenetics）所导致的基因表达异常也是乳腺癌发生、发展的重要原因。表观遗传学改变是基因的核苷酸序列不发生改变的情况下基因表达的可遗传的变化,包括DNA甲基化、组蛋白乙酰化、染色质重塑、基因组印记以及非编码RNA等。乳腺腺的DNA甲基化是常见的分子事件,具有独特的DNA甲基化特征,既往的研究发现DNA甲基化可以作为乳腺癌早期诊断、分型、监测药物治疗效果和预后的分子标志物。本文将对DNA甲基化在乳腺癌的研究进展进行综述。     

肝细胞癌的表观遗传学研究进展

肝细胞癌简称肝癌(hepatocellular carcinoma)的发病率、病死率呈逐年上升趋势,尽管几种主要危险致病因素已经比较明确,但是肝癌发生的确切的分子生物学机制尚不完全清楚.近年来越来越多的证据表明,表观遗传修饰(epigenetics)在肝癌的发生发展中具有非常重要的作用.本文将就DNA的异常甲基化、组蛋白异常修饰与肝癌的关系,肝癌的表观遗传学检测及表观遗传学治疗现状做一综述.     

前列腺癌的表观遗传学研究进展

前列腺癌是男性最常见的恶性肿瘤之一,其病因和发病机制尚不清楚。表观遗传参与了前列腺癌病程的各个阶段,与前列腺癌的发生、发展及转移密切相关,其中DNA甲基化和组蛋白修饰是前列腺癌中最为重要的两种表观遗传表现形式。DNA异常甲基化对肿瘤发生影响机制主要有:基因组广泛性低甲基化、局部过度甲基化、基因突变热点,与前列腺癌DNA损伤修复、激素应答、肿瘤细胞浸润/转移、细胞周期调控等过程密切相关。而组蛋白修饰的异常则将引起相应染色体结构和基因转录水平改变,影响细胞周期、分化和凋亡,导致前列腺癌的发生。目前已有一些针对前列腺癌表观遗传改变的治疗,主要有DNA甲基化转移酶和组蛋白去乙酰化酶抑制剂,并取得了一定的效果。相信随着对表观遗传学研究的深入,必将为前列腺癌的治疗开辟一条新思路。     

DNA甲基化修饰在胰腺癌中的研究进展

胰腺癌的发病机制、早期诊断及治疗一直是医学界关注的热点与重点。近年来多项研究表明表观遗传学对肿瘤的发生发展发挥着重要的作用，其中DNA甲基化最常见。胰腺癌的发生发展与其相关癌基因或抑癌基因由于DNA甲基化水平变化引起的异常激活或抑制有关。DNA甲基化可能在体细胞突变前发生，且贯穿肿瘤的全过程，因此在肿瘤的诊断、治疗和预防中被广泛研究。笔者对DNA甲基化的概念、作用方式、在胰腺癌发生发展中所起的作用以及胰腺癌诊断和治疗上的前景作一综述，以期对胰腺癌未来的研究提供一定的参考。     

组蛋白去乙酰化酶在认知功能障碍中的作用

<正>表观遗传学是指在不改变DNA序列的情况下发生的可遗传变异的学科,主要包括DNA甲基化,组蛋白乙酰化、甲基化、磷酸化、泛素化等,其中组蛋白乙酰化是表观遗传学最为常见类型之一[1,2]。组蛋白乙酰化主要发生组蛋白H3和H4N-端尾部的赖氨酸残基上,受组蛋白乙酰转移酶(his-     

A review of the alterations in DNA methylation in esophageal squamous cell carcinoma

Epigenetic changes such as DNA methylation, histone modification, and loss of genome imprinting play a crucial role in esophageal squamous cell carcinogenesis, along with genomic and genetic alterations. DNA methylation is a fundamental epigenetic process that modulates gene expression. Cancer cells exhibit two types of alterations of DNA methylation: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. In several types of human cancers, the methods of detecting an aberrant methylation status have been applied to clinical fields to stratify high-risk groups, detect early cancer, and predict clinical outcomes. Importantly, epigenetic changes, including alterations in DNA methylation, are reversible and can thus be targets for cancer therapy or chemoprevention. Therefore, a better understanding of the DNA methylation in esophageal squamous cell carcinoma (ESCC) is important for optimizing cancer therapy and chemoprevention. We herein summarize the current knowledge regarding alterations in DNA methylation and the clinical implications in ESCC.     

The role of epigenetic alterations in pancreatic cancer

The past several years have witnessed an explosive increase in our knowledge about epigenetic features in human cancers. It has become apparent that pancreatic cancer is an epigenetic disease, as it is a genetic disease, characterized by widespread and profound alterations in DNA methylation. The introduction of genome-wide screening techniques has accelerated the discovery of a growing list of genes with abnormal methylation patterns in pancreatic cancer, and some of these epigenetic events play a role in the neoplastic process. The detection and quantification of DNA methylation alterations in pancreatic juice is likely a promising tool for the diagnosis of pancreatic cancer. The potential reversibility of epigenetic changes in genes involved in tumor progression makes them attractive therapeutic targets, but the efficacy of epigenetic therapies in pancreatic cancer, such as the use of DNA methylation inhibitors, remains undetermined. In this review, we briefly summarize recent research findings in the field of pancreatic cancer epigenetics and discuss their biological and clinical implications.     

DNA甲基化与胃癌发生发展的关系研究进展

胃癌作为临床上最常见的恶性肿瘤之一,严重危害着人类的生命健康。研究表明,胃癌的发生与细菌感染、病毒感染等有关,表观遗传学改变特别是DNA甲基化在胃癌发生、发展中扮演着重要角色,且DNA甲基化检测在胃癌的早期诊断、评估预后、治疗等临床应用方面,有着广阔前景。笔者主要就DNA甲基化和胃癌之间的关系及临床应用方面进行综述。     

Epigenetic alterations and their clinical implications in esophageal squamous cell carcinoma

Alterations in the regulation of gene expression that do not involve a change in the DNA sequence have been increasingly recognized as an important key event of carcinogenesis, referred to as “epigenetic” changes. Major epigenetic mechanisms include the methylation of cytosines in DNA, changes of histone and chromatin structure by covalent posttranslational modifications of histone proteins and alterations in the expression of microRNAs. These epigenetic alterations have also been identified in esophageal squamous cell carcinoma (ESCC). In this brief review, we will discuss DNA hypermethylation of the tumor suppressor gene promoters, histone modifications including histone acetylation/deacetylation and histone methylation and microRNAs in ESCC. Clinical implications of these epigenetic alterations in ESCC will be also discussed.     

Molecular pathobiology of gastric cancer.

Gastric carcinogenesis is a multistep process, during which numerous genetic and epigenetic alterations accumulate: there are abnormalities of growth factors/receptors, angiogenic factors, cell cycle regulators, DNA mismatch repair genes etc. These abnormalities define, at the same time, the biological character of the cancer cell and may thus serve as therapeutic targets. Genetic instability may cause accumulation of genetic abnormalities. The most important epigenetic alterations are DNA methylation, histone modification and chromatin remodeling. Some of these changes are common in gastric cancer, regardless of subtype, and some differ by histological type or (gastric or intestinal) mucin phenotype. Genetic polymorphism is a crucial endogenous cause and fundamental aspect of cancer risk. Importantly, genetic polymorphisms are also associated with the therapeutic efficacy and toxicity of anti-cancer drugs. Genomic science and technology such as Serial Analysis of Gene Expression (SAGE) allows the identification of novel genes and molecules specifically up-regulated or down-regulated in gastric cancer, e.g., RegIV and claudin-18 can be identified. Advances in our understanding of the genetic and molecular bases lead to improved diagnosis, personalised medicine and prevention of gastric cancer.     

Epigenetic profile of testicular germ cell tumours

DNA methylation is the best known and most thoroughly studied epigenetic mechanism. Hypermethylation of CpG islands associated with silencing of tumour suppressor genes or tumour-related genes is a common hallmark of human cancer. The list of tumour-related genes with aberrant hypermethylation in their CpG islands has been increasing. There is also the potential for using DNA methylation profile data as markers for various types of human cancer. In this paper, we review the methylation profile of testicular germ cell tumours (TGCTs). We show that TGCTs have distinctive DNA methylation profiles that differ from those of somatic tissue-derived cancers or somatic tissues. We also discuss the methylation profile of TGCTs in terms of the DNA reprogramming that occurs in primordial germ cells or pre-implantation embryos. Finally, we describe the potential clinical utility of this unique methylation phenotype in TGCTs with regard to developing a novel tumour marker. These data suggest that unmethylated DNA fragments in TGCTs may have diagnostic implications. Further elucidation of epigenetic profiles in TGCTs is expected to provide a new insight into the biology of this disease.     

差异甲基化位点对肝细胞癌预后的相关性分析

目的 通过TCGA和GEO数据库关于肝细胞癌病例的数据挖掘,扫描全基因组范围内的肝细胞癌预后相关的甲基化位点。方法 本研究采用TCGA、GSE54503、GSE57956和GSE37988肝细胞癌病例的数据集分析共同的甲基化位点,比较肝细胞癌和癌旁组织甲基化水平差异,得出共同的差异甲基化位点。采用Cox比例风险模型分析各差异位点甲基化水平对肝细胞癌总生存率影响,评估其与对应基因mRNA 表达的相关性,进一步评估mRNA表达对肝细胞癌预后的影响。结果 肝细胞癌预后相关最显著的甲基化位点为位于基因TFCP2区域的cg20927059（P=0.003）,对应的HR值及95%CI为10.53（2.26～49.03）。筛选的与肝细胞癌预后有关联性的15个甲基化位点中,13个甲基化位点的甲基化水平与对应基因的mRNA表达相关,其中cg13984181对应的EPHX4基因和cg14541950对应的HIST3H2BB基因的mRNA表达与肝细胞癌的预后有关（HR：1.17,95%CI：1.06～1.29,P=0.002;HR：1.06,95%CI：1.00～1.13P=0.043）。结论?本研究首次发现EPHX4和HIST3H2BB基因甲基化位点的甲基化水平对肝细胞癌的预后有影响。