KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome
KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome
复制标题
KCNMA1与PTK2协同作用是胃癌的新型抑癌基因，与疾病结局相关
DOI：
10.1186/s12943-017-0613-z
复制
发表时间：
2017-02-23
期刊：
影响因子：
37.3
通讯作者：
Chu, Haiyan
中科院分区：
文献类型：
--
作者：
Ma, Gaoxiang;Liu, Hanting;Chu, Haiyan
背景抑癌基因启动子区甲基化失活在肿瘤的发生发展中起着重要作用。为了揭示胃癌发生发展过程中全基因组DNA异常甲基化的详细模式，我们对12对胃癌组织及其相应的正常组织进行了全基因组甲基化检测。采用甲基化特异性PCR（MSP）和亚硫酸氢盐测序（BSP）检测特异性CpG位点的甲基化状态。在生物信息学分析的基础上，构建了细胞表型和小鼠模型实验来检测目的基因的作用。结果KCNMA 1基因启动子区的CpG位点cg 24113782差异最显著，是导致胃癌细胞和原发性胃癌组织中KCNMA 1基因沉默的主要原因。KCNMA 1基因启动子区甲基化在肿瘤组织中的阳性率为68.7%（77/112），而在正常组织中的阳性率为16.2%（18/112），差异有显著性（P< 0.001）。生存曲线显示KCNMA 1甲基化与胃癌患者生存期缩短显著相关（P= 0.036）; KCNMA 1在体外可通过诱导细胞凋亡抑制胃癌细胞的生物学恶性行为，在小鼠皮下移植瘤模型中可抑制肿瘤生长（P均< 0.001）。结论KCNMA 1是胃癌发生过程中的重要抑癌基因，其甲基化是影响胃癌患者预后的独立因素。
BackgroundInactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. It is necessary to uncover the detailed pattern of whole genome-wide abnormal DNA methylation during the development of gastric cancer (GC).MethodWe performed a genome-wide methylation detection using 12 paired of GC tissues and their corresponding normal tissues. Methylation-specific PCR (MSP) and bisulphite sequencing (BSP) were used to measure methylation status of specific CpG site. Based on the bioinformatic analysis, the cell phenotypes and mouse model experiments were constructed to detect effect of the target gene. Using the Kaplan–Meier survival curve, the clinical value ofKCNMA1was assessed in GC patients.ResultsThe CpG site cg24113782 located at the promoter ofKCNMA1showed the most significant difference, contributing to the commonly silencedKCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation ofKCNMA1was detected in 68.7% (77/112) of tumor tissues, compared with 16.2% (18/112) of normal tissues (P< 0.001). The survival curve indicated thatKCNMA1hypermethylation was significantly associated with the shortened survival in GC patients (P= 0.036).KCNMA1significantly inhibited biological malignant behavior of gastric cancer cell by inducing cell apoptosis in vitro, and suppressed xenograft tumor growth in subcutaneous mouse models (bothP< 0.001). Furthermore, the anti-tumor effect ofKCNMA1was mediated through suppressing the expression ofPTK2.ConclusionKCNMA1is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer.