膜联蛋白 A6 通过启动子甲基化在胃癌中下调。
Annexin A6 is down-regulated through promoter methylation in gastric cancer.
机构信息
Department of Medical Oncology, Laboratory of Cancer Biology, Institute of Clinical Science, Sir Runrun Shaw Hospital, Medical School of Zhejiang University Hangzhou, China.
出版信息
Am J Transl Res. 2013 Aug 15;5(5):555-62. eCollection 2013.
BACKGROUND
The aberrant activation of oncogenic signaling such as Ras/MAPK signaling is a frequent event in human cancers. In addition to genetic changes, epigenetic silencing of inhibitors in Ras/MAPK signaling contributes to the activation of Ras/MAPK signaling. Recently, ANXA6 has been shown to interact with Ras-GAP1 and inhibit Ras activation in human breast cancer. However, whether and how it is involved in human cancers remain unknown.
METHODS
Real-time PCR was used to determine ANXA6 expression in gastric cancer cells and primary gastric carcinomas. Next, we explored the methylation of ANXA6 promoter in cell lines and tumor tissues with methylation-specific PCR and bisulfite genomic sequencing. We also investigated the function of ANXA6 in gastric cancer cells with colony formation assay and western blotting analysis.
RESULTS
ANXA6 was down-regulated in gastric cancer cells and primary gastric carcinomas. Ectopic ANXA6 expression inhibited the growth of gastric cancer cells and the activity of Ras/MAPK signaling. Its expression was restored after pharmaceutical demethylation. ANXA6 promoter was methylated in gastric cancer cell lines (6/6) and primary gastric carcinoma tissues (29/156). Interestingly, the knockdown of oncoprotein Yin Yang 1 (YY1) also restored ANXA6 expression and promoted the demethylation of ANXA6 promoter. However, ANXA6 methylation was not associated with clinical parameters such as differentiation, and TNM staging. Neither Kaplan-Meier Curve nor Cox regression analysis revealed a significant role of ANXA methylation to predict the survival of gastric cancer patients.
CONCLUSIONS
We firstly reported that ANXA6 is epigenetically silenced through promoter methylation in human cancers and YY1 is important to initiate or maintain ANXA6 promoter methylation in gastric cancer cells. ANXA6 functions as a tumor suppressor in gastric cancer cells through the inhibition of Ras/MAPK signaling. ANXA6 methylation is not a prognostic factor for gastric cancer patients.
背景
致癌信号（如 Ras/MAPK 信号）的异常激活是人类癌症中的常见事件。除了遗传变化外，Ras/MAPK 信号通路中抑制剂的表观遗传沉默也有助于 Ras/MAPK 信号的激活。最近，已有研究表明 ANXA6 可与 Ras-GAP1 相互作用并抑制人乳腺癌中的 Ras 激活。然而，它是否以及如何参与人类癌症尚不清楚。
方法
实时 PCR 用于确定胃癌细胞和原发性胃癌中 ANXA6 的表达。接下来，我们通过甲基化特异性 PCR 和亚硫酸氢盐基因组测序研究了细胞系和肿瘤组织中 ANXA6 启动子的甲基化。我们还通过集落形成实验和 Western blot 分析研究了 ANXA6 在胃癌细胞中的功能。
结果
ANXA6 在胃癌细胞和原发性胃癌中下调。异位 ANXA6 表达抑制了胃癌细胞的生长和 Ras/MAPK 信号的活性。用药物去甲基化后其表达得到恢复。在胃癌细胞系（6/6）和原发性胃癌组织（29/156）中，ANXA6 启动子均发生甲基化。有趣的是，癌蛋白 Yin Yang 1 (YY1) 的敲低也恢复了 ANXA6 的表达，并促进了 ANXA6 启动子的去甲基化。然而，ANXA6 甲基化与分化和 TNM 分期等临床参数无关。Kaplan-Meier 曲线和 Cox 回归分析均未显示 ANXA 甲基化对预测胃癌患者生存的显著作用。
结论
我们首次报道 ANXA6 在人类癌症中通过启动子甲基化而被表观遗传沉默，YY1 对胃癌细胞中 ANXA6 启动子甲基化的起始或维持很重要。ANXA6 通过抑制 Ras/MAPK 信号在胃癌细胞中起肿瘤抑制作用。ANXA6 甲基化不是胃癌患者的预后因素。
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