Downregulation of the Novel Tumor Suppressor DIRAS1 Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma
Downregulation of the Novel Tumor Suppressor DIRAS1 Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma
复制标题
DOI：
10.1158/0008-5472.can-12-2663
复制
发表时间：
2013-04-01
期刊：
影响因子：
11.2
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Zhu, Ying-Hui;Fu, Li;Guan, Xin-Yuan
染色体19 p缺失是食管鳞状细胞癌（ESCC）中最常见的等位基因失衡之一，提示该区域存在一个或多个肿瘤抑制基因。在这项研究中，我们研究了位于19p13.3的候选肿瘤抑制基因Ras样小GTdiras 1在ESCC中的作用。DIRAS 1的下调发生在约50%的原发性ESCC中，其中DIRAS 1与晚期临床分期、淋巴结转移和总生存率差显著相关。洛缺失和启动子甲基化分析提示DIRAS 1表达缺失是由表观遗传机制介导的。功能研究证实，ESCC细胞中DIRAS 1的异位再表达抑制细胞增殖、克隆形成、细胞运动和肿瘤形成。机制研究表明，DIRAS 1通过细胞外信号调节激酶（ERK 1/2; MAPK 3/1）和p38丝裂原活化蛋白激酶（MAPK; MAPK 14）信号传导，分别触发BAD Ser 112去磷酸化和基质金属蛋白酶（MMP）2/9转录失活，从而促进细胞凋亡和抑制转移。总之，我们的研究结果表明，DIRAS 1在ESCC发病机制中具有关键作用，可能用作新治疗策略的生物标志物和干预点。Cancer Res; 73（7）; 2298-309. (C)2013年AACR。
Loss of chromosome 19p is one of the most frequent allelic imbalances in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes within this region. In this study, we investigated a role in ESCCs for a candidate tumor suppressor gene located at 19p13.3, the Ras-like small GTPase DIRAS1. Downregulation of DIRAS1 occurred in approximately 50% of primary ESCCs where it was associated significantly with advanced clinical stage, lymph node metastasis, and poor overall survival. LOH and promoter methylation analyses suggested that loss of DIRAS1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of DIRAS1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation. Mechanistic investigations suggested that DIRAS1 acted through extracellular signal-regulated kinase (ERK1/2; MAPK3/1) and p38 mitogen-activated protein kinase (MAPK; MAPK14) signaling to trigger BAD Ser112 dephosphorylation and matrix metalloproteinase (MMP)2/9 transcriptional inactivation to promote apoptosis and inhibit metastasis, respectively. Taken together, our results revealed that DIRAS1 has a pivotal function in ESCC pathogenesis, with possible use as a biomarker and intervention point for new therapeutic strategies. Cancer Res; 73(7); 2298-309. (C) 2013 AACR.