Otani Koji, Dong Yujuan, Li Xiaoxing, Lu Jing, Zhang Ning, Xu Lixia, Go Minnie Y Y, Ng Enders K W, Arakawa Tetsuo, Chan Francis K L, Sung Joseph J Y, Yu Jun
Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong; Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
J Pathol. 2014 Nov;234(3):302-15. doi: 10.1002/path.4391. Epub 2014 Aug 28.
We report that the odd-skipped related 1 (OSR1) gene encoding a zinc-finger transcription factor was preferentially methylated in gastric cancer by genome-wide methylation screening. OSR1 expression was frequently silenced or down-regulated in gastric cancer cell lines. OSR1 expression was also significantly down-regulated at both mRNA and protein levels in primary gastric cancer tissues compared with adjacent normal tissues. The silencing or down-regulation of OSR1 was closely associated with promoter hypermethylation. Overexpression of OSR1 significantly inhibited cell growth, arrested the cell cycle, and induced apoptosis in the gastric cancer cell lines AGS, MKN28, and MGC803. Conversely, knockdown of OSR1 by OSR1-short hairpin RNA significantly enhanced cell growth, promoted the cell cycle, and inhibited apoptosis in the normal gastric epithelial cell line GES1. The dual-luciferase reporter assay revealed that OSR1 activated p53 transcription and repressed the T-cell factor (TCF)/lymphoid enhancer factor (LEF). Complementary DNA expression array and western blotting showed that OSR1 increased the expression of nuclear p53, p21, Fas, and death receptor-5, and suppressed the expression of cyclin D1 and cyclin-dependent kinase 4 in the p53 signalling pathway. In addition, OSR1 suppressed the expression of cytoplasmic β-catenin, TCF-1, and LEF1 in the Wnt/β-catenin signalling pathway. OSR1 methylation was detected in 51.8% of primary gastric cancer patients (85 of 164) by bisulphite genomic sequencing. Multivariate Cox regression analysis showed that OSR1 methylation was an independent predictor of poor survival. Kaplan-Meier survival curves revealed that OSR1 methylation was associated with shortened survival in TNM stage I-III patients. In conclusion, OSR1 acts as a functional tumour suppressor through the transcriptional activation of p53 and repression of TCF/LEF in gastric cancer. Detection of OSR1 methylation may serve as a potential biomarker of the early stage of gastric cancer.
我们报告称，通过全基因组甲基化筛查发现，编码锌指转录因子的odd-skipped相关1（OSR1）基因在胃癌中存在优先甲基化现象。在胃癌细胞系中，OSR1表达经常沉默或下调。与相邻正常组织相比，原发性胃癌组织中OSR1表达在mRNA和蛋白质水平均显著下调。OSR1的沉默或下调与启动子高甲基化密切相关。OSR1的过表达显著抑制了胃癌细胞系AGS、MKN28和MGC803的细胞生长，使细胞周期停滞并诱导细胞凋亡。相反，用OSR1短发夹RNA敲低OSR1可显著增强正常胃上皮细胞系GES1的细胞生长，促进细胞周期进程并抑制细胞凋亡。双荧光素酶报告基因检测显示，OSR1激活p53转录并抑制T细胞因子（TCF）/淋巴样增强因子（LEF）。互补DNA表达阵列和蛋白质印迹表明，OSR1增加了p53信号通路中核p53、p21、Fas和死亡受体5的表达，并抑制了细胞周期蛋白D1和细胞周期蛋白依赖性激酶4的表达。此外，OSR1抑制了Wnt/β-连环蛋白信号通路中细胞质β-连环蛋白、TCF-1和LEF1的表达。通过亚硫酸氢盐基因组测序在51.8%的原发性胃癌患者（164例中的85例）中检测到OSR1甲基化。多变量Cox回归分析表明，OSR1甲基化是生存不良的独立预测因素。Kaplan-Meier生存曲线显示，OSR1甲基化与TNM I-III期患者的生存缩短相关。总之，在胃癌中，OSR1通过转录激活p53和抑制TCF/LEF发挥功能性肿瘤抑制作用。检测OSR1甲基化可能作为胃癌早期阶段的潜在生物标志物。
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