REC8 functions as a tumor suppressor and is epigenetically downregulated in gastric cancer, especially in EBV-positive subtype
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摘要REC8 meiotic recombination protein (REC8) was found to be preferentially methylated in gastric cancer (GC) using promoter methylation array. We aimed to elucidate the epigenetic alteration and biological function of REC8 in GC. REC8 was downregulated in 100% (3/3) of Epstein-Barr virus (EBV)-positive and 80% (8/10) of EBV-negative GC cell lines by promoter methylation, but the expression could be restored through demethylation treatment. Protein expression of REC8 was significantly lower in human primary gastric tumors than in adjacent non-tumor tissues. A negative correlation between methylation and mRNA expression of REC8 was observed in 223 gastric samples of The Cancer Genome Atlas study (r=-0.7018, P<0.001). The methylation level (%) of the REC8 promoter was significantly higher in EBV-positive gastric tumors than in EBV-negative gastric tumors, as shown by bisulfite genomic sequencing (77.6 (69.3-80.5) vs 51.4 (39.5-62.3), median (interquartile range); P<0.001); methylation levels in both subtypes of tumors were significantly higher than in normal stomach tissues (14.8 (4.2-24.0)) (both P<0.001). Multivariate analysis revealed that REC8 methylation was an independent factor for poor survival in GC patients (hazard ratio=1.68, P<0.05). REC8 expression significantly suppressed cell viability, clonogenicity and cell cycle progression; it induced apoptosis and inhibited migration of AGS-EBV (EBV-positive) and BGC823 (EBV-negative) GC cells, and it suppressed tumorigenicity in nude mice. In contrast, knockdown of REC8 in gastric epithelial immortalized GES-1 cells significantly increased cell viability, clonogenicity and migration ability. The tumor-suppressive effect of REC8 is mediated at least in part by the downregulation of genes involved in cell growth (G6PD, SLC2A1, NOL3, MCM2, SNAI1 and SNAI2), and the upregulation of apoptosis/migration inhibitors (GADD45G and LDHA) and tumor suppressors (PinX1, IGFBP3 and ETS2). In conclusion, REC8 is a novel tumor suppressor that is commonly downregulated by promoter methylation in GC, especially in the EBV-associated subtype. Promoter methylation of REC8 is an independent risk factor for the shortened survival of GC patients.
著者Yu J., Liang Q., Wang J., Wang K., Gao J., Zhang J., Zeng Y., Chiu P.W.Y., Ng E.K.W., Sung J.J.Y.
期刊名稱Oncogene
出版年份2017
月份1
日期12
卷號36
期次2
出版社Nature Publishing Group
出版地United Kingdom
頁次182 - 193
國際標準期刊號0950-9232
電子國際標準期刊號1476-5594
語言英式英語

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