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。     

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.     

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-     

表观遗传学与哺乳动物配子和胚胎发生发育的研究进展

<正>表观遗传学是指在细胞有丝分裂或减数分裂中未经DNA序列变化所引起的基因功能发生遗传学改变的学说。它的研究现已跨越了生物学和医学的许多不同领域。近年来,表观遗传学在生殖医学的研究中发展迅速,如在配子和胚胎形成过程中包括DNA甲基化、组蛋白修饰和RNA调控等修饰。其中,DNA的甲基化调控包括高甲基化、低甲基化、从头甲基化和去甲基化,在此过程中需要甲基化酶如DNMT或去甲基化酶的调控;组蛋白修饰则是在组蛋白的氨基酸残基上所进行的诸如甲基化、乙酰化、泛素化以及巴     

DNA甲基化和组蛋白修饰在肿瘤中的作用

在肿瘤的形成过程中包含两大类机制,基因机制(genetic mechanism)和表观基因机制(epigenetic mechanism).基因机制包括基因突变、染色体丢失和重排,产生结构异常的基因产物;表观基因机制主要指DNA5胞嘧啶甲基化,引起基因表达异常而DNA序列及基因产物不变.近几年来许多学者发现,组蛋白甲基化、乙酰化、磷酸化和泛素化等修饰导致染色质重构而抑制抑癌基因表达也是表观基因改变的一个重要机制.1999年,Alan Wolffe[1]将表观基因改变定义为"未发生DNA序列改变的可遗传的基因表达改变."     

肥胖导致男性不育的表观遗传机制研究进展

肥胖引发表观遗传改变可导致男性出现不育表型。关于肥胖与男性不育的关系问题,早期研究多集中于内分泌方面。近年研究发现肥胖还可以引发机体表观遗传改变,如DNA甲基化,残余组蛋白修饰,小RNA等,影响精子成熟发育。DNA甲基化是胞嘧啶-磷酸-鸟嘌呤二核苷酸的胞嘧啶残基上的调节标记,肥胖导致DNA甲基化异常,并改变mRNA表达丰度,还可以影响印记基因表达出现印记基因病。残余组蛋白修饰方式包括甲基化、乙酰化等,它们可以相互作用或协同作用,以保证精子正常生长发育。肥胖可以改变甲基化酶及乙酰化酶活性,直接影响残余组蛋白的甲基化和乙酰化;还可以影响精子小RNA的表达,导致精子缺陷。本文就肥胖引起的表观遗传学改变及导致男性不育的作用机制做逐一综述。     

表观遗传学与乳腺癌

表观遗传学是基于非DNA序列改变而产生的基因表达的变化,与肿瘤的发生密切相关,具有可逆性和遗传性,主要包括DNA甲基化、组蛋白修饰和染色体重组,它们相互作用,影响基因表达.乳腺癌中,表观遗传调节改变了一些重要基因的表达,导致了肿瘤的产生和发展.表观遗传学的研究对乳腺癌的发生、发展、早期诊断、预后评估、治疗和复发监测产生了深远的影响.     

DNA甲基化与肝细胞癌

肝细胞癌是原发性肝癌的主要类型,也是常见的恶性肿瘤之一,具有较高的发病率和病死率。然而在分子和细胞水平,肝癌的发病机制仍然不清楚。一般来说,肿瘤形成通常被认为是抑癌基因失活或原癌基因激活致DNA突变而诱导人类正常细胞向恶性细胞转化的过程。近年来随着对肿瘤研究的不断深入,人们发现表观遗传学改变与肝癌发生发展密切相关。其中DNA甲基化是人类基因组发生最为常见的一种表观遗传学事件,也是表观遗传学研究最为深入的一种机制。本文将就DNA甲基化在肝癌中的研究进展作一综述。     

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.     

胃癌DNA甲基化和组蛋白H3K27三甲基化基因修饰的相关性

目的 探讨DNA甲基化和组蛋白H3K27三甲基化在胃癌肿瘤细胞对多基因修饰的相关性.方法 收集我科2007年10月至2008年01月间8例胃癌患者肿瘤组织和正常胃黏膜组织,采用染色质免疫共沉淀联合芯片技术(ChIP-chip)对两种组织细胞在全基因组范围内的组蛋白H3K27三甲基化检测后挑选出4个阳性基因.随后采用染色质免疫共沉淀-实时定量聚合酶联反应(ChIP-qPCR)验证芯片结果,采用MeDIP-qPCR方法检测阳性基因的DNA甲基化水平.结果 ChIP-qPCR验证4个阳性基因结果与CpG岛芯片检测结果一致,胃癌肿瘤细胞4个基因DNA甲基化水平与正常胃壁细胞比较差异有统计学意义(P值均<0.05).结论 和正常胃黏膜组织细胞比较,胃癌肿瘤细胞多个基因DNA甲基化和组蛋白H3K27三甲基化存在显著改变,DNA甲基化和组蛋白H3K27三甲基化基因修饰存在相互作用.     

胃癌DNA甲基化和组蛋白H3K27三甲基化基因修饰的相关性

目的 探讨DNA甲基化和组蛋白H3K27三甲基化在胃癌肿瘤细胞对多基因修饰的相关性.方法 收集我科2007年10月至2008年01月间8例胃癌患者肿瘤组织和正常胃黏膜组织,采用染色质免疫共沉淀联合芯片技术(ChIP-chip)对两种组织细胞在全基因组范围内的组蛋白H3K27三甲基化检测后挑选出4个阳性基因.随后采用染色质免疫共沉淀-实时定量聚合酶联反应(ChIP-qPCR)验证芯片结果,采用MeDIP-qPCR方法检测阳性基因的DNA甲基化水平.结果 ChIP-qPCR验证4个阳性基因结果与CpG岛芯片检测结果一致,胃癌肿瘤细胞4个基因DNA甲基化水平与正常胃壁细胞比较差异有统计学意义(P值均<0.05).结论 和正常胃黏膜组织细胞比较,胃癌肿瘤细胞多个基因DNA甲基化和组蛋白H3K27三甲基化存在显著改变,DNA甲基化和组蛋白H3K27三甲基化基因修饰存在相互作用.     

胃癌DNA甲基化和组蛋白H3K27三甲基化基因修饰的相关性

目的 探讨DNA甲基化和组蛋白H3K27三甲基化在胃癌肿瘤细胞对多基因修饰的相关性.方法 收集我科2007年10月至2008年01月间8例胃癌患者肿瘤组织和正常胃黏膜组织,采用染色质免疫共沉淀联合芯片技术(ChIP-chip)对两种组织细胞在全基因组范围内的组蛋白H3K27三甲基化检测后挑选出4个阳性基因.随后采用染色质免疫共沉淀-实时定量聚合酶联反应(ChIP-qPCR)验证芯片结果,采用MeDIP-qPCR方法检测阳性基因的DNA甲基化水平.结果 ChIP-qPCR验证4个阳性基因结果与CpG岛芯片检测结果一致,胃癌肿瘤细胞4个基因DNA甲基化水平与正常胃壁细胞比较差异有统计学意义(P值均<0.05).结论 和正常胃黏膜组织细胞比较,胃癌肿瘤细胞多个基因DNA甲基化和组蛋白H3K27三甲基化存在显著改变,DNA甲基化和组蛋白H3K27三甲基化基因修饰存在相互作用.     

The expanding role of epigenetics in the development, diagnosis and treatment of prostate cancer and benign prostatic hyperplasia

PURPOSE: Prostate cancer research has focused significant attention on the mutation, deletion or amplification of the DNA base sequence that encodes critical growth or suppressor genes. However, these changes have left significant gaps in our understanding of the development and progression of disease. It has become clear that epigenetic changes or modifications that influence phenotype without altering the genotype present a new and entirely different mechanism for gene regulation. Several interrelated epigenetic modifications that are altered in abnormal growth states are DNA methylation changes, histone modifications and genomic imprinting. We discuss the status of epigenetic alterations in prostate cancer and benign prostatic hyperplasia progression. In addition, the rationale and status of ongoing clinical trials altering epigenetic processes in urological diseases are reviewed. MATERIALS AND METHODS: An online search of current and past peer reviewed literature on DNA methylation, histone acetylation and methylation, imprinting and epigenetics in prostate cancer and benign prostatic hyperplasia was performed. Relevant articles and reviews were examined and a synopsis of reproducible data was generated with the goal of informing the practicing urologist of these advances and their implications. RESULTS: Only 20 years ago the first study was published demonstrating global changes in DNA methylation patterns in tumors. Accumulating data have now identified specific genes that are commonly hypermethylated and inactivated during prostate cancer progression, including GSTpi, APC, MDR1, GPX3 and 14-3-3sigma. Altered histone modifications, including acetylation and methylation, were also recently described that may modify gene function, including androgen receptor function. These epigenetic changes are now being used to assist in prostate cancer diagnosis and cancer outcome prediction. Epigenetic changes appear to have a role in benign prostatic hyperplasia development as well as in the susceptibility of the prostate to developing cancer. Treatments involving 5-aza-deoxycytosine and other, more selective DNA methyltransferase inhibitors remove methyl residues from silenced genes, generating re-expression, and are currently being used in therapeutic trials. Histone deacetylase inhibitors have shown promise, not only by directly reactivating silenced genes, but also as regulators of apoptosis and sensitizers to radiation therapy. CONCLUSIONS: Evolving data support a significant role for epigenetic processes in the development of prostate cancer and benign prostatic hyperplasia. Epigenetic changes can predict tumor behavior and often distinguish between genetically identical tumors. Targeted drugs that alter epigenetic modifications hold promise as a tool for curing and preventing these diseases.     

赖氨酸特异性去甲基化酶1介导的经典Wnt信号通路在肿瘤领域的研究进展

作为全球性公共卫生问题,肿瘤是当今世界危害人类健康的主要疾病之一。根据2019年国家癌症中心发布的全国最新癌症数据统计,2015年我国共新发恶性肿瘤392.9万例,死亡约为233.8万例,发病率约为285.83/10万,病死率约为170.05/10万。肿瘤的发生、发展是一个多因素、多基因、多阶段渐进性累积的演变过程,涉及肿瘤的转化、生存、增殖、侵袭、血管生成和转移。在这个过程中伴随着遗传基因和表观遗传的变化:致癌基因、抑癌基因、错配修复基因、细胞黏附分子等在DNA、RNA和蛋白质水平发生改变。虽然近年来肿瘤诊断与治疗技术不断取得进步,但大多数患者就诊时已处于晚期状态,总体预后较差。因此探索肿瘤的发病机制,寻找更为有效的预防治疗手段具有重要意义。现有研究表明,表观遗传学改变在肿瘤发生、发展及侵袭转移中意义重大。目前已知的表观遗传修饰主要包括组蛋白修饰、DNA甲基化、核小体重塑、非编码RNA等。在真核生物中,组蛋白修饰包括了乙酰化、甲基化、磷酸化、核糖化及泛素化等。同其它组蛋白修饰一样,组蛋白甲基化是一个动态可逆的过程。赖氨酸特异性去甲基化酶1(LSD1)能够特异性催化组蛋白H3第4位赖氨酸(H3K4)和第9位赖氨酸(H3K9)的脱一甲基、二甲基反应,并与组蛋白去乙酰化酶相互作用,起到转录阻遏物的作用。该酶对哺乳动物生长发育至关重要并参与多种生物学过程,包括细胞分化、异染色质的形成、细胞内DNA甲基化状态的合理维持以及诱导多能干细胞形成等。目前证实LSD1在多种恶性肿瘤组织中高度表达,在肿瘤的发生、发展及耐药性产生中起到重要作用。Wnt信号通路是一条在进化上高度保守的信号通路,对细胞增殖、分化、迁移及凋亡起着重要作用,Wnt信号通路关键分子的基因突变在肿瘤的发生、发展过程中具有重要作用。虽然LSD1和Wnt信号通路都与肿瘤发生、发展有关,但两者之间是否存在联系尚未阐明。近年来越来越多的研究表明,LSD1可通过调节经典Wnt信号通路的活性影响肿瘤的发生、发展。笔者就LSD1介导的经典Wnt信号通路在肿瘤领域的研究进展作一综述。     

肿瘤抑制基因甲基化与胃癌

目的 探讨肿瘤抑制基因甲基化与胃癌的关系。方法 对近年来关于肿瘤抑制基因甲基化与胃癌关系的文献进行综述分析。结果 胃癌中，细胞周期调控基因、有丝分裂检测点基因、凋亡相关基因、错配修复基因、转移相关基因等多种肿瘤抑制基因发生甲基化而失活。结论 肿瘤抑制基因甲基化在胃癌的发生、发展过程中起重要作用，肿瘤抑制基因的甲基化有可能成为胃癌诊断、判断转移和评价预后的分子标记物，去甲基化干预有望成为胃癌治疗的新方法。     

DNA Methylation: An Alternative Pathway to Cancer

OBJECTIVE: To provide an introduction to the concept of DNA methylation and its function in normal cells, and to explain the possible mechanisms as to how abnormalities in this phenomenon can relate to carcinogenesis. The clinical implications with reference to common malignancies encountered in surgical practice are discussed. SUMMARY BACKGROUND DATA: Methylation of DNA is a heritable, enzyme-induced modification to DNA structure without alteration of the specific sequence of the base pairs responsible for encoding the genome. DNA methylation can both directly inhibit the expression of genes and also increase the probability that affected genes undergo a mutational event. Although DNA methylation plays an essential role in normal biologic processes, distinct and abnormal patterns of methylation are observed in cancers. In particular, there has been increased documentation that methylation of the promoter regions of several genes, including known tumor suppressor genes, results in the subsequent failure to express their functional proteins. Consequently, DNA methylation may represent an early and fundamental step in the pathway by which normal tissue undergoes neoplastic transformation. Further, an assessment of the methylation profiles within neoplastic tissues may provide key information in enhancing the diagnosis, predicting the clinical behavior, and designing specific treatment plans for individual patients. METHODS: Published literature from 1925 to 2000 contributing to an understanding of the purpose of DNA methylation and how pathology of this phenomenon could contribute to cancer are reviewed. Theories on these issues and the evidence that led to them are described. The present status of the subject in a clinical context is discussed. RESULTS: Gene expression can be significantly modulated by alterations in DNA methylation patterns. Methylation within the promoter regions of tumor suppressor genes causes their silencing, and methylation within the gene itself can induce mutational events. These mechanisms may play a fundamental role in precipitating the development of a large and diverse number of human cancers. CONCLUSIONS: DNA methylation is an important factor in the development of cancer. A greater understanding of the relationship between DNA methylation events at the molecular level and its interaction in the clinical context may provide the basis for future advances in the surgical and pharmacologic management of malignant diseases.