Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma
Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma
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DOI：
10.1172/jci200523183
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发表时间：
2005-02-01
影响因子：
15.9
通讯作者：
Mercurio, AM
中科院分区：
文献类型：
--
作者：
Bates, RC;Bellovin, DI;Mercurio, AM
我们使用结肠癌球体模型来分析整合素动态作为上皮-间充质转化（EMT）的函数，该过程为了解癌细胞如何获得更具侵袭性的表型提供了范例。这种EMT涉及β 6整联蛋白亚基的转录激活和随后的α v β 6表达诱导。这种整合素增强结肠癌的致瘤特性，包括自分泌TGF-β的激活。和间质纤连蛋白上的迁移。重要的是，这项研究验证了EMT的临床相关性。对488例结直肠癌中β 6表达的Kaplan-Meier分析显示，β 6高表达患者的中位生存时间显着缩短。升高的受体表达并不简单地反映肿瘤分期的增加，因为对数秩分析显示，与晚期疾病相比，早期疾病对患者的生存率有更显著的影响。考克斯回归分析证实这种整合素是这些肿瘤的独立变量。这些发现将α v β 6整合素定义为早期疾病的重要危险因素和结肠直肠癌的新治疗候选物。
We used a spheroid model of colon carcinoma to analyze integrin dynamics as a function of the epithelial-mesenchymal transition (EMT), a process that provides a paradigm for understanding how carcinoma cells acquire a more aggressive phenotype. This EMT involves transcriptional activation of the beta6 integrin subunit and a consequent induction of alphavbeta6 expression. This integrin enhances the tumorigenic properties of colon carcinoma, including activation of autocrine TGF-beta. and migration on interstitial fibronectin. Importantly, this study validates the clinical relevance of the EMT. Kaplan-Meier analysis of beta6 expression in 488 colorectal carcinomas revealed a striking reduction in median survival time of patients with high beta6 expression. Elevated receptor expression did not simply reflect increasing tumor stage, since log-rank analysis showed a more significant impact on the survival of patients with early-stage, as opposed to late-stage, disease. Cox regression analysis confirmed that this integrin is an independent variable for these tumors. These findings define the alphavbeta6 integrin as an important risk factor for early-stage disease and a novel therapeutic candidate for colorectal cancer.