Abstract
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 of KCNMA1 was assessed in GC patients.ResultsThe 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.ConclusionKCNMA1 is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer.
Highlights
Inactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis
The CpG site cg24113782 located at the promoter of Potassium channel (KCNMA1) showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues
By bioinformatics analysis based on The Cancer Genome Atlas (TCGA), we found the KCNMA1could regulate the expression of focal adhesion kinase (FAK), named PTK2, which is a non-receptor tyrosine kinase and moderate cancer proliferation, migration and survival [12]
Summary
Inactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. We found that the gene, potassium channel, calcium activated large conductance subfamily M alpha, member 1(KCNMA1), the function of which remains largely unexplored, was moderated by promoter methylation in gastric cancer. By bioinformatics analysis based on The Cancer Genome Atlas (TCGA), we found the KCNMA1could regulate the expression of FAK (focal adhesion kinase), named PTK2, which is a non-receptor tyrosine kinase and moderate cancer proliferation, migration and survival [12]. It may regulate the cell apoptosis by PI3K-AKT pathway [13]. It is possible that the Ca2+ is involved in apoptosis by cooperating with PTK2
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