Establishment of epigenetic epidemiology

(1)DNA甲基化导致的表观基因沉默是包括胃在内的肿瘤发生机制中的重要步骤之一。癌症患者过去的生活方式因素，如蔬菜的摄入，对影响胃癌的发生是非常重要的。然而，DNA甲基化与癌症患者既往饮食习惯之间的关系在很大程度上仍不清楚。分析CDX2、BMP-2、p16的甲基化状态。采用甲基化特异性聚合酶链式反应技术，检测106例胃癌组织中CACNA2D3、GATA-5和雌激素受体基因的表达，并与既往生活方式进行比较。CDX2和BMP-2基因甲基化与绿茶摄入量减少相关。CACNA2D3基因甲基化与体力活动呈负相关。因此，过去的生活方式可能是决定基因甲基化状态和由此导致的致癌基因异常表达的重要因素。(2)SOX转录因子发挥着关键的ro…作用在决定细胞命运、分化和增殖方面有更多的LES。我们曾报道SOX2蛋白在正常胃粘膜中表达，但在某些人胃癌中表达下调。为了阐明SOX2在胃癌发生中的作用，我们在胃上皮细胞系中进行了SOX2的功能鉴定。外源性SOX2表达抑制胃上皮细胞增殖。流式细胞仪分析显示SOX2过表达细胞出现细胞周期停滞和细胞凋亡。在部分SOX2表达不表达或弱表达的胃癌组织中，观察到SOX2高甲基化信号。在52名进展期胃癌患者中，那些出现SOX2甲基化的患者比那些没有这种甲基化的患者的生存时间显著缩短。因此，SOX2通过细胞周期停滞和细胞凋亡在抑制胃上皮细胞生长中发挥重要作用，SOX2表达缺失可能与胃癌的发生和预后不良有关。较少

(1) Epigenetic gene silencing through DNA methylation is one of the important steps in the mechanism underlying tumorigenesis, including of the stomach. Past lifestyle factors of cancer patients, such as intake of vegetables, are very important to affect gastric carcinogenesis. However, the relationship between DNA methylation and past dietary habits in cancer patients remains largely unknown. We analyzed the methylation states of the CDX2, BMP-2, p16. CACNA2D3, GATA-5, and estrogen receptor genes in 106 primary gastric cancers by methylation-specific PCR, and compared them with the past lifestyle of the patients. Methylation of CDX2 and BMP-2 was correlated with the decreased intake of green tea. Methylation of CACNA2D3 was inversely correlated with the physical activity. Thus, the past lifestyle could be important factors determining the methylation states of genes and the resultant aberrant expression of genes involved in carcinogenesis.(2) SOX transcription factors play critical ro … More les in cell fate determination, differentiation and proliferation. We previously reported that the SOX2 protein is expressed in normal gastric mucosae but down-regulated in some human gastric carcinomas. To clarify the roles of SOX2 in gastric carcinogenesis, we carried out functional characterization of SOX2 in gastric epithelial cell lines. Exogenous expression of SOX2 suppressed cell proliferation in gastric epithelial cells. Flow cytometry analysis revealed that SOX2-overexpressing cells exhibited cell cycle arrest and apoptosis. SOX2 hypermethylation signals were observed in some cultured and primary gastric cancers with no or weak SOX2 expression. Among the 52 patients with advanced gastric cancers, those with cancers showing SOX2 methylation had a significantly shorter survival time than those without this methylation. Hence, SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis in gastric epithelial cells, and the loss of SOX2 expression may be related to gastric carcinogenesis and poor prognosis. Less