我国是胃癌的高发区，每年新发现约40万胃癌患者，占世界胃癌发病人数的40%左右。我国胃癌死亡率是欧美发达国家的4-8倍，是当前危害人民身体健康的重大疾病。幽门螺旋杆菌感染，生活中情绪压力，不良的饮食习惯，如喜好熏烤、高盐、辛辣食物及酗酒，都会破坏和损伤胃粘膜，造成胃炎、胃溃疡等疾病，导致胃癌发生的高风险。蛋白酶激活受体4（Protease-Activated Receptor 4, PAR4）广泛表达于胃粘膜中，其在胃粘膜保护和损伤修复、胃癌发生中的作用是待解决的科学问题。
中科院昆明动物研究所动物模型与人类疾病机理重点实验室生物毒素与人类疾病课题组在张云研究员带领下，该课题组张勇和余国宇博士等在揭示蛋白酶激活受体可作为胃粘膜损伤修复三叶因子的细胞膜受体基础上（Cell Mol Life Sci. 2011 Apr 3），进一步与昆明医学院第一附属医院合作，采用分子生物学、细胞生物学和临床病理学研究技术发现该粘膜损伤修复的“中介”（PAR4受体）在胃癌病人中显著性下降，其缺失与胃癌的淋巴结转移、低分化程度相关；PAR4受体基因启动区超甲基化是引起该受体表达缺失的主要原因，揭示不良生活习惯和环境因素等在胃癌发生中的重要作用。
文章已在线发表于《国际生物化学与细胞生物学期刊》（International Journal of Biochemistry and Cell biology） 。上述结果为深入解析人胃粘膜保护、损伤修复和胃癌发生的生理病理机制提供了新的视角和线索，也为临床胃癌病理进程及预后检测提供了新的可能性。
该研究受到国家973计划项目、国家基金委重点项目以及中国科学院重要方向项目的资助。（生物谷Bioon.com）
专题：MicroRNA 和 癌症
生物谷推荐原文出处：
Journal of Biochemistry and Cell biology DOI： 10.1016/j.biocel.2011.05.008
Decreased expression of protease-activated receptor 4 in human gastric cancer
Yong Zhang, Guoyu Yu, Ping Jiang, Yang Xiang, Wenliang Li, Wenhui Lee and Yun Zhang
Protease-activated receptors (PARs) are a unique family of G-protein coupled receptors. PAR4, the most recently identified PAR member, was reported to be overexpressed during the progression of colon and prostate cancers. Though PAR4 mRNA was detected in normal stomach, the role of PAR4 in gastric cancer has not been investigated. In this study, differential expression of PAR4 was measured by real-time PCR (n = 28) and tissue microarrays (n = 74). We showed that PAR4 was located from basal to middle portions of normal gastric mucosa. PAR4 expression was remarkably decreased in gastric cancer tissues as compared with matched noncancerous tissues, especially in positive lymph node or low differentiation cancers. Furthermore, methylation of the PAR4 promoter in cell lines was assessed by treatment with 5-aza-2′-deoxycytidine and genomic bisulfite sequencing. AGS and N87 human gastric cancer cell lines did not express PAR4, as compared to HT-29 human colon cancer cell line with significant PAR4 expression. Treatment with 5-aza-2′-deoxycytidine restored PAR4 expression in AGS and N87 cells, which exhibited significantly more 5-methylcytosines in the PAR4 promoter compared with HT-29 cells. Our results revealed that down-regulation of PAR4 expression occurs frequently in gastric cancers and exhibits association with more aggressive gastric cancer. Interestingly, the loss of PAR4 expression in gastric cancers may result from hypermethylation of the PAR4 promoter.
