CHFR基因与胃癌关系研究新进展

CHFR(checkpoint with FHA and ringfinger),是Scolnick和Halazonetis于2000年新发现的一种能够检测分裂期正常细胞的分裂情况及控制分裂进行的基因,是一个新的有丝分裂前期检查点基因,同时也是一种新发现的抑癌基因.CHFR编码一种具有FHA和RING区的蛋白,当微管抑制剂诱发有丝分裂应激时,这种蛋白具有延迟染色体的浓集、阻止细胞进入有丝分裂中前期的作用,在正常人组织中普遍表达,而在多种肿瘤组织中发现其表达缺失,而CpG岛的甲基化是导致CHFR表达缺失或沉默的重要机制.胃癌是世界上发病率最高的肿瘤之一,在肿瘤引起的死亡原因中占第二位.胃癌的发生过程涉及到许多基因和复杂的步骤,相关基因包括癌基因,抑癌基因,DNA修复基因,抑癌基因的功能由于基因突变、启动子的甲基化而丢失.甲基化发生于基因的启动子区时会导致基因的沉默,由此而引发肿瘤的发生.启动子区异常甲基化已经作为细胞恶变的一个独立的途径而被许多文献所报道,有研究显示胃癌的发生发展过程中也涉及许多抑癌基因的甲基化现象,其中包括CHFR基因.本文对CHFR基因的结构、编码蛋白的功能及其与胃癌关系的研究进展作一综述.     

DNA甲基化及其在肾癌诊治中的应用

研究表明,肿瘤相关基因启动子区域的异常甲基化是引发肾癌的重要原因之一,并与肿瘤的分化、侵袭、转移、分期和预后等密切相关.检测相关抑癌基因甲基化有助于肾癌的早期诊断.甲基转移酶抑制剂可逆转肿瘤细胞的异常甲基化,并可增加其他化疗药物的疗效,在肾癌的治疗中起重要作用.     

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.     

微小RNA与DNA甲基化相互调控在胃癌中的作用

表观遗传修饰在胃癌发生发展及预后中起重要作用.微小RNA( miRNA)和DNA甲基化是表观遗传学的两个重要调控机制.miRNA抑制靶基因信使RNA的翻译,参与基因转录后水平调控.基因启动子区CpG岛的异常甲基化与肿瘤的发生关系密切,可导致癌基因、抑癌基因或其他肿瘤相关基因的表达异常.胃癌中存在miRNA和DNA甲基化...     

急性白血病PTEN的表达及甲基化状态

0引言急性白血病(Acute leukemia,AL)的发生涉及多种抑癌基因和癌基因的异常表达.PTEN基因是一种广泛的抑癌基因,在多种肿瘤中存在失活现象,其失活原因除突变、缺失外,DNA异常甲基化可能是其失活的第三条途径.本研究采用反转录聚合酶链反应(RT-PCR)及甲基化特异性聚合酶链反应( MSP)技术检测AL患者骨髓单个核细胞中PTEN基因mRNA的表达及其启动子甲基化状态,探讨其与AL的关系,为AL的发生、发展机制提供分子生物学依据.     

DNA甲基化与食管癌的关系

肿瘤细胞普遍存在DNA甲基化模式的改变,DNA甲基化异常包括原癌基因低甲基化和抑癌基因高甲基化。近年来研究结果表明,在食管癌发生过程中同样存在相关抑癌基因启动子区甲基化导致的基因表达的紊乱。其中由DNA甲基转移酶（DNA methyltransferase,DNMT）和去甲基化酶的活性改变导致的抑癌基因CpG岛超甲基化的研究,已成为食管癌发病机制研究中的热点之一。综述DNA甲基化的特点及其抑制基因转录和表达的分子生物学机制;DNA异常甲基化与食管癌发生发展的关系;食管癌相关肿瘤抑制基因的甲基化谱构成了食管癌独特的表遗传学标志;目前常用的甲基化检测手段及各方法的优缺点;DNA甲基化和去甲基化研究的展望及所需要解决的的问题等。     

DNA甲基化与肿瘤发生及治疗

DNA甲基化对肿瘤相关基因表达的调控起重要的作用,肿瘤细胞中的基因甲基化异常主要表现为基因组整体水平的低甲基化、癌基因的低甲基化以及抑癌基因、错配修复基因等高甲基化等。近期,关于DNA甲基化在肿瘤的诊断、治疗及预后等方面的作用及意义的研究正深入展开。现综述肿瘤基因的异常甲基化及DNA甲基化在肿瘤临床中应用的研究进展。     

DNA甲基化与肿瘤发生及治疗

DNA甲基化对肿瘤相关基因表达的调控起重要的作用,肿瘤细胞中的基因甲基化异常主要表现为基因组整体水平的低甲基化、癌基因的低甲基化以及抑癌基因、错配修复基因等高甲基化等。近期,关于DNA甲基化在肿瘤的诊断、治疗及预后等方面的作用及意义的研究正深入展开。现综述肿瘤基因的异常甲基化及DNA甲基化在肿瘤临床中应用的研究进展。     

抑癌基因甲基化与胃癌研究进展

DNA甲基化是基因表达调控的一种方式，抑癌基因启动子高甲基化可以使其表达受抑，这与肿瘤的发生关系密切。胃癌的发生是由多因素多基因多阶段异常累计的结果，其中抑癌基因甲基化与胃癌的发生具有重要的关系。     

DNA甲基转移酶在肿瘤发生预后治疗中的作用

DNA甲基转移酶(DNMT)在多种肿瘤细胞中呈表达上调,异常表达的DNMT通过催化肿瘤抑制基因启动子区域CpG岛甲基化,引起抑癌基因甲基化失活,从而促进正常细胞向肿瘤细胞转化.研究表明,DNMT在消化道肿瘤、乳腺癌、肺癌等肿瘤细胞中呈表达丰度异常,且与肿瘤的发生呈明显相关性,并影响肿瘤预后.药物及靶向干扰可抑制DNMT的活性,可使甲基化的基因去甲基化复活,进而抑制肿瘤细胞生长,促进细胞凋亡.     

Aberrant promoter CpG methylation and its translational applications in breast cancer

Breast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations.Recent studies revealed that abnormal gene expression induced by epigenetic changes,including aberrant promoter methylation and histone modification,plays a critical role in human breast carcinogenesis.Silencing of tumor suppressor genes(TSGs) by promoter CpG methylation facilitates cells growth and survival advantages and further results in tumor initiation and progression,thus directly contributing to breast tumorigenesis.Usually,aberrant promoter methylation of TSGs,which can be reversed by pharmacological reagents,occurs at the early stage of tumorigenesis and therefore may serve as a potential tumor marker for early diagnosis and therapeutic targeting of breast cancer.In this review,we summarize the epigenetic changes of multiple TSGs involved in breast pathogenesis and their potential clinical applications as tumor markers for early detection and treatment of breast cancer.     

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.     

DNA甲基化与胶质瘤

表遗传学修饰的DNA甲基化在胶质瘤的发生发展中起重要作用。大量肿瘤抑制基因、细胞周期调控基因、DNA损伤修复基因、肿瘤侵袭相关基因等启动子区域CpG岛甲基化,与胶质瘤的发生发展密切相关。不同基因的甲基化发生频率与胶质瘤的组织类型和病理分级有关。某些基因的DNA甲基化可以为胶质瘤的早期诊断和预后评价提供分子生物学标记物,同时由于DNA甲基化具有可逆转性,也可为胶质瘤的基因治疗提供新的治疗靶点。     

Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma

Renal cell carcinoma (RCC), the most common adult kidney neoplasm, is histopathologically heterogeneous, with most sporadic RCCs ( approximately 80%) classified as clear cell (CC) tumors. Chromosome 3p allele loss is the most frequent genetic alteration in RCC but is associated specifically with sporadic and hereditary forms of clear cell RCC (CC-RCC) and is not a feature of non-CC-RCC, such as papillary (chromophilic) RCC. The VHL tumor suppressor gene (TSG) maps to chromosome 3p25, and somatic inactivation of the VHL gene occurs in up to 70% of CC-RCC tumors and cell lines. However, VHL inactivation is not sufficient for CC-RCC tumorigenesis, and inactivation of 3p12-p21 TSG(s) appears to be necessary in CC-RCC irrespective of VHL gene inactivation status. Recently, we demonstrated that the candidate 3p21 TSG, RASSF1A, is hypermethylated in most small cell lung cancers. We have now investigated the role of RASSF1A inactivation in primary RCC tumors. RASSF1A promoter methylation was detected in 23% (32 of 138) of primary CC-RCC tumors. In CC-RCC cell lines, RASSF1A methylation was associated with silencing of RASSF1A expression and restoration of expression after treatment with 5'-azacytidine. The frequency of RASSF1A methylation was similar in CC-RCC with and without VHL gene inactivation (24% versus 21%), and there was no association between epigenetic silencing of the RASSF1A and VHL TSGs, because 0 of 6 tumors with VHL hypermethylation had RASSF1A methylation, and VHL was not methylated in 26 CC-RCCs with RASSF1A methylation. Although 3p allele loss has been reported rarely in papillary RCC, we identified RASSF1A methylation in 44% (12 of 27) of papillary RCCs analyzed. Thus: (a) inactivation of RASSF1A is a frequent event in both CC-RCC and papillary RCC tumors; (b) there is no relationship between epigenetic silencing of RASSF1A and VHL inactivation status in CC-RCC. Fifty-four CC-RCCs analyzed for RASSF1A methylation were informative for 3p21 allele loss, and 20% (7 of 35) with 3p21 allele loss demonstrated RASSF1A methylation. All informative CC-RCCs with 3p21 allele loss and no RASSF1A methylation also demonstrated allele losses at other regions of 3p so that tumorigenesis in these cases may result from: (a) haploinsufficiency of RASSF1A; (b) inactivation of other 3p21 TSGs; or (c) inactivation of 3p TSGs from outside of 3p21. RASSF1A is the first TSG to be inactivated frequently in both papillary and CC-RCCs. The finding of frequent epigenetic inactivation of RASSF1A in papillary RCCs despite previous studies reporting infrequent 3p21 allele loss in this tumor type illustrates how the systematic identification of all major human cancer genes will require detailed analysis of the cancer genome and epigenome.     

Epigenetic signatures of familial cancer are characteristic of tumor type and family category

Tumor suppressor genes (TSG) may be inactivated by methylation of critical CpG sites in their promoter regions, providing targets for early detection and prevention. Although sporadic cancers, especially colorectal carcinoma (CRC), have been characterized for epigenetic changes extensively, such information in familial/hereditary cancer is limited. We studied 108 CRCs and 63 endometrial carcinomas (EC) occurring as part of hereditary nonpolyposis CRC, as separate familial site-specific entities or sporadically, for promoter methylation of 24 TSGs. Eleven genes in CRC and 6 in EC were methylated in at least 15% of tumors and together accounted for 89% and 82% of promoter methylation events in CRC and EC, respectively. Some genes (e.g., CDH13, APC, GSTP1, and TIMP3) showed frequent methylation in both cancers, whereas promoter methylation of ESR1, CHFR, and RARB was typical of CRC and that of RASSF1(A) characterized EC. Among CRCs, sets of genes with methylation characteristic of familial versus sporadic tumors appeared. A TSG methylator phenotype (methylation of at least 5 of 24 genes) occurred in 37% of CRC and 18% of EC (P = 0.013), and the presence versus absence of MLH1 methylation divided the tumors into high versus low methylation groups. In conclusion, inactivation of TSGs by promoter methylation followed patterns characteristic of tumor type (CRC versus EC) and family category and was strongly influenced by MLH1 promoter methylation status in all categories. Paired normal tissues or blood displayed negligible methylation arguing against a constitutional methylation abnormality in familial cases.     

CpG island methylator phenotypes in aging and cancer.

CpG islands are short stretches of CpG rich regions that are frequently associated with the promoter region of genes. Aberrant methylation of CpG islands is one mechanism of inactivating tumor suppressor genes (TSGs) in neoplasia, and there is growing evidence that altered cytosine methylation play important roles in cancer development. However, the differences in global CpG island methylation patterns between normal and cancer cells remain poorly understood. By examining a large number of loci in a series of cancers, global methylation profiles can be constructed. Such studies revealed that in colorectal cancer, there appears to be two types of methylation that are associated with cancer progression: type A (for age-related) methylation, and type C (for cancer-specific) methylation. Initially, type A methylation arises as a function of age in normal colorectal epithelial cells. By affecting genes that regulate the growth and/or differentiation of these cells, such methylation may result in a predisposition state that precedes tumor formation in the colon. Type C methylation, by contrast, was found exclusively in a subset of cancers, which display a CpG island methylator phenotype (CIMP). CIMP is a novel molecular instability pathway that appears to be responsible for most cases of aberrant TSG methylation in colorectal cancer, and which has important interactions with genetic pathways as well. In fact, CIMP+ tumors account for the majority of sporadic colorectal cancers with microsatellite instability, through methylation of the mismatch repair gene hMLH1. This model whereby age-related methylation increases cell-susceptibility to transformation and cancer-specific methylation results in neoplastic progression in a subset of cases may be applicable to many human neoplasms.     

肿瘤抑制基因DNA甲基化与肝癌

DNA甲基化是最早发现的基因表观修饰方式之一.肿瘤抑制基因(tumor suppressor genes,TSGs)DNA甲基化是肝癌的常发事件,该文从转录调节因子、负调控转录因子、细胞周期调控因子、信号通路的调节因子、DNA损伤修复因子等方面综述了TSGs DNA甲基化状态在肝癌发生、发展中的作用,对肝癌早期诊断、分期、预后、个体化治疗具有重要意义.