Ma Gaoxiang, Liu Hanting, Hua Qiuhan, Wang Meilin, Du Mulong, Lin Yadi, Ge Yuqiu, Gong Weida, Zhao Qinghong, Qiang Fulin, Tao Guoquan, Zhang Zhengdong, Chu Haiyan
Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.
Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
Mol Cancer. 2017 Feb 23;16(1):46. doi: 10.1186/s12943-017-0613-z.
Inactivation 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).
We 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 of KCNMA1 was assessed in GC patients.
The CpG site cg24113782 located at the promoter of KCNMA1 showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation of KCNMA1 was 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 that KCNMA1 hypermethylation was significantly associated with the shortened survival in GC patients (P = 0.036). KCNMA1 significantly inhibited biological malignant behavior of gastric cancer cell by inducing cell apoptosis in vitro, and suppressed xenograft tumor growth in subcutaneous mouse models (both P < 0.001). Furthermore, the anti-tumor effect of KCNMA1was mediated through suppressing the expression of PTK2.
KCNMA1 is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer.
启动子高甲基化导致肿瘤抑制基因失活在肿瘤发生过程中起关键作用。有必要揭示胃癌（GC）发生发展过程中全基因组异常DNA甲基化的详细模式。
我们使用12对GC组织及其相应的正常组织进行了全基因组甲基化检测。甲基化特异性PCR（MSP）和亚硫酸氢盐测序（BSP）用于测量特定CpG位点的甲基化状态。基于生物信息学分析，构建细胞表型和小鼠模型实验以检测靶基因的作用。使用Kaplan-Meier生存曲线评估KCNMA1在GC患者中的临床价值。
位于KCNMA1启动子的CpG位点cg24113782显示出最显著差异，导致KCNMA1在胃癌细胞和原发性GC组织中普遍沉默。在68.7%（77/112）的肿瘤组织中检测到KCNMA1的启动子甲基化，而正常组织中为16.2%（18/112）（P < 0.001）。生存曲线表明，KCNMA1高甲基化与GC患者生存期缩短显著相关（P = 0.036）。KCNMA1在体外通过诱导细胞凋亡显著抑制胃癌细胞的生物学恶性行为，并在皮下小鼠模型中抑制异种移植肿瘤生长（均P < 0.001）。此外，KCNMA1的抗肿瘤作用是通过抑制PTK2的表达介导的。
KCNMA1是胃癌发生中的关键肿瘤抑制因子，其高甲基化是胃癌患者的独立预后因素。
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