Promoter hypermethylation of the RUNX3 gene in esophageal squamous cell carcinoma
Promoter hypermethylation of the RUNX3 gene in esophageal squamous cell carcinoma
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DOI：
10.1080/07357900701561131
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发表时间：
2007-12-01
影响因子：
2.4
通讯作者：
Yuan, Yunchang
中科院分区：
文献类型：
--
作者：
Long, Chaozhong;Yin, Bangliang;Yuan, Yunchang
转化生长因子-β（TGF-β）信号通路的改变是食管鳞状细胞癌（ESCC）的主要原因之一。人类runt相关转录因子3（RUNX3）是TGF-β途径的重要组成部分，位于1p36，在包括食管鳞癌在内的多种人类癌症中通常被删除。 RUNX3启动子的高甲基化常见于胃肠道癌症，包括胃癌、肝癌、结肠癌和胰腺癌。然而，ESCC 中 RUNX3 启动子甲基化状态尚未研究。本研究的目的是确定RUNX3基因的启动子甲基化是否与ESCC肿瘤进展相关。因此，我们首先测定了42个ESCC原发性肿瘤和ESCC细胞系Eca-109中RUNX3 mRNA的表达及其启动子区域的甲基化状态。通过 RT-PCR 在 42 个 ESCC 样本和 Eca-109 细胞中的 23 个 (54.8%) 中检测到 RUNX3 mRNA 表达缺失。通过甲基化特异性聚合酶链反应 (MS-PCR) 在 42 个 ESCC 样本和 Eca-109 细胞中的 27 个 (64.3%) 中检测到启动子高甲基化。重要的是，我们发现不仅启动子高甲基化与肿瘤临床病理分期之间存在正相关性（P=0.003），而且RUNX3 mRNA表达缺失与肿瘤进展之间也存在正相关性（P=0.016）。最后，我们观察到 RUNX3 mRNA 表达的丧失与这些肿瘤中启动子的高甲基化具有统计相关性（P < 0.001）。我们的结果表明，通过启动子高甲基化对RUNX3基因表达的表观遗传沉默可能在食管鳞癌的发展中发挥重要作用。
Alteration in transforming growth factor-beta (TGF-beta) signaling pathway is one of the main causes of esophageal squamous cell carcinoma (ESCC). The human runt-related transcription factor 3 (RUNX3), an important component of TGF-beta pathway which is located at 1p36, is commonly deleted in a variety of human cancers, including ESCC. Hypermethylation of RUNX3 promoter was frequently found in gastrointestinal cancers, including those of stomach, liver, colon and pancreas. However, RUNX3 promoter methylation status in ESCC has not been studied. The aim of this study was to determine whether promoter methylation of the RUNX3 gene correlates with ESCC tumor progression.Accordingly, we first determined RUNX3 mRNA expression and methylation status of its promoter region in 42 primary tumors with ESCC and Eca-109, an ESCC cell line. Loss of RUNX3 mRNA expression was detected by RT-PCR in 23 out of 42 (54.8%) ESCC specimens and Eca-109 cells. The Promoter hypermethylation was detected by Methylation Specific Polymerase Chain Reaction (MS-PCR) in 27 out of 42 (64.3%) ESCC specimen and Eca-109 cells. Importantly, we found positive correlations, not only between the promoter hypermethylation and tumor clinical pathologic stages (P = 0.003), but also between the loss of RUNX3 mRNA expression and the tumor progression (P= 0.016). Finally, we observed that the loss of RUNX3 mRNA expression is statistically correlated with the promoter hypermethylation in these tumors (P < 0.001). Our results suggest that epigenetic silencing of RUNX3 gene expression by promoter hypermethylation may play an important role in ESCC development.