DNA甲基化与癌

在哺乳动物DNA中,5-甲基胞嘧啶(5-methylcytosin,~mC)是唯一天然存在的修饰碱基,约占全部胞嘧啶的2～5％,这些甲基化部位的绝大部分存在于CG顺序中,按如下形式对称排列:5’-~mCG-3’ 3’-G^mC-5’,但是新复制的DNA是半甲基化(hemimethyla-tion)的,新合成链无~mG。核内DNA甲基化酶(DNA methylase)识别模板链上的甲基化部位,按照原则,在新链的相应部位进行甲基化修饰,完成~mC复制。因此,DNA甲基化类型(DNA methylation pattern)

The altered DNA methylation pattern and its implications in liver cancer

DNA methylation is the most intensively studied epigenetic phenomenon, disturbances of which result in changes ingene transcription, thus exerting drastic imparts onto biological behaviors of cancer. Both the global demethylation andthe local hypermethylation have been widely reported in all types of tumors, providing both challenges and opportunitiesfor a better understanding and eventually controlling of the malignance. However, we are still in the very early stage ofinformation accumulation concerning the tumor associated changes in DNA methylation pattern. A number of excellentrecent reviews have covered this issue in depth. Therefore, this review will summarize our recent data on DNA methy-lation profiling in cancers. Perspectives for the future direction in this dynamic and exciting field will also be given.

DNA methylation in hepatocellular carcinoma

As for many other tumors,development of hepatocellular carcinoma(HCC)must be understood as a multistep process with accumulation of genetic and epigenetic alterations in regulatory genes,leading to activation of oncogenes and inactivation or loss of tumor suppressor genes(TSG).In the last decades,in addition to genetic alterations,epigenetic inactivation of(tumor suppressor) genes by promoter hypermet hylation has been recognized as an important and alternative mechanism in tumorigenesis.In HCC,aberrant methylation of promoter sequences occurs not only in advanced tumors, it has been also observed in premalignant conditions just as chronic viral hepatitis B or C and cirrhotic liver. This review discusses the epigenetic alterations in hepatocellular carcinoma focusing DNA methylation.

Aberrantly Methylated MGMT,hMLH1 and hMSH2 in Tumor and Serum DNA of Gliomas Patients

OBJECTIVE This study is to investigate the prevalence ofpromoter CpG island methylation of O^6-methylguananine-DNAmethyltransferase (MGMT), mismatch repair genes (hMLH1 andhMSH2) in both tumor and serum samples of gliomas.METHODS Methylation-specific PCR (MSP) was employed todetect promoter CpG island methylation of the MGMT, hMLH1and hMSH2 genes in 39 samples taken from surgery and 32samples of pretreatment serum all from the patients with gliomas.RESULTS Promoter CpG island methylation of MGMT, hMLH1and hMSH2 was detected and the results were 46.2%, 10.3% and20.5%, respectively in tumor DNA of the cases with gliomas,and 40.6%, 9.4% and 18.8%, respectively in serum DNA of thecases. The methylation pattern in primary tumor and serum wasfound to be concordant in matched tissue and serum samplesof 21 patients. In the cases with positive result of methylationfor MGMT, hMLH1 and hMSH2 in tumor tissues, the results ofdetection for those in the paired serum sample were 77.8% (7/9),66.7% (2/3) and 75.0 % (3/4), respectively. False positive resultswere not obtained in any of the patients who did not exhibitmethylation. No association was found between the promotermethylation of MGMT, hMLH1, and hMSH2 genes in primarygliomas and gender, age, localization, grade of malignant or tumorstage.CONCLUSION Promoter CpG island methylation is a frequentevent in gliomagenesis. Methylation analysis appears to bea promising predictive factor of the prognosis for the gliomapatients treated with alkylating drugs and a noninvasive tumormarker in serum DNA.

Epigenetic changes in virus-associated human cancers

Epigenetics of human cancer becomes an area of emerging research direction due to a growing understanding ofspecific epigenetic pathways and rapid development of detection technologies. Aberrant promoter hypermethylation is aprevalent phenonmena in human cancers. Tumor suppressor genes are often hypermethylated due to the increasedactivity or deregulation of DNMTs. Increasing evidence also reveals that viral genes are one of the key players inregulating DNA methylation. In this review, we will focus on hypermethylation and tumor suppressor gene silencing andthe signal pathways that are involved, particularly in cancers closely associated with the hepatitis B virus, simian virus40 (SV40), and Epstein-Barr virus. In addition, we will discuss current technologies for genome-wide detection ofepigenetically regulated targets, which allow for systematic DNA hypermethylation analysis. The study of epigeneticchanges should provide a global view of gene profile in cancer, and epigenetic markers could be used for early detection,prognosis, and therapy of cancer.

DNA methylation in the tumor microenvironment

The tumor microenvironment （TME） plays an important role in supporting cancer progression. The TME is composed of tumor cells, the surrounding tumor-associated stromal cells, and the extracellular matrix （ECM）. Crosstalk between the TME components contributes to tumorigenesis. Recently, one of our studies showed that pancreatic ductal adenocarcinoma （PDAC） cells can induce DNA methylation in cancer-associated flbroblasts （CAFs）, thereby modifying tumor-stromal interactions in the TME, and subsequently creating a TME that supports tumor growth Here we summarize recent studies about how DNA methylation affects tumorigenesis through regulating tumor- associated stromal components including fibroblasts and immune cells. We also discuss the potential for targeting DNA methylation for the treatment of cancers.