Glutamate receptor, ionotropic, kainate 2 silencing by DNA hypermethylation possesses tumor suppressor function in gastric cancer

• Published in: International journal of cancer 2010-06, Vol.126 (11), p.2542-2552
• Main Authors: Wu, Chi‐Sheng, Lu, Yen‐Jung, Li, Hsin‐Pai, Hsueh, Chuen, Lu, Chang‐Yi, Leu, Yu‐Wei, Liu, Hao‐Ping, Lin, Kwang‐Huei, Hui‐Ming Huang, Tim, Chang, Yu‐Sun
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Cell Division; Cell Line, Tumor; Cell Movement; Colony-Forming Units Assay; DNA Methylation; DNA Primers; DNA, Neoplasm - genetics; Female; gastric cancer; Gastroenterology. Liver. Pancreas. Abdomen; Gene Silencing - physiology; GluK2 Kainate Receptor; GRIK2; Humans; hypermethylation; Intestinal Neoplasms - genetics; Intestinal Neoplasms - pathology; Male; Medical sciences; Middle Aged; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Receptors, Kainic Acid - genetics; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Suppression, Genetic; Transfection; tumor suppressor gene; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24958

Aberrant DNA methylation is considered a major mechanism for silencing tumor suppressor genes in gastric cancer. We used CpG microarray and differential methylation hybridization strategies to identify potential tumor suppressor genes and recovered glutamate receptor, ionotropic, kainate 2 (GRIK2) as a novel epigenetic target in gastric cancer. Additional experiments showed that the promoter region of GRIK2 was hypermethylated in 3 of the 4 tested gastric cancer cell lines, and its expression was restored by treatment of cells with the DNA methylation inhibitor, 5′‐aza‐dC. In clinical samples, the GRIK2 promoter was differentially hypermethylated in tumor tissues compared with adjacent normal tissues (p < 0.001), and this methylation was inversely correlated with the expression level of GRIK2 mRNA (r = −0.44). Functional studies further showed that GRIK2‐expressing gastric cancer cell lines showed decreased colony formation and cell migration. Taken together, these results suggest that GRIK2 may play a tumor‐suppressor role in gastric cancer. Future studies are warranted to examine whether DNA hypermethylation of the GRIK2 promoter can be used as a potential tumor marker for gastric cancer.