SLIT2 Attenuation during Lung Cancer Progression Deregulates β-Catenin and E-Cadherin and Associates with Poor Prognosis
SLIT2 Attenuation during Lung Cancer Progression Deregulates β-Catenin and E-Cadherin and Associates with Poor Prognosis
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DOI：
10.1158/0008-5472.can-09-2084
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发表时间：
2010-01-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Yi-Ching
中科院分区：
文献类型：
--
作者：
Tseng, Ruo-Chia;Lee, Shih-Hua;Wang, Yi-Ching
晚期肺癌中染色体 4p15.3 经常被缺失。我们研究了位于该区域的 SLIT2 基因对肺癌进展的重要性。 SLIT2 编码一种细胞外糖蛋白，可以通过调节 β-连环蛋白来抑制乳腺癌。在这项研究中，我们检查了肺癌细胞系和患者中 SLIT2、其受体 ROBO1 和 β-catenin 的结构或表达的变化，以及 AKT/糖原合酶激酶 3 beta (GSK3 beta)/β-转导蛋白重复序列蛋白 (beta TrCP) 通路的变化。 SLIT2低表达与肺癌患者病理分期的上升趋势和较差的生存率相关。重要的是，SLIT2、β TrCP 和 β-catenin 表达水平可预测患者肺癌术后复发。通过各种方法刺激 SLIT2 表达，由于其转录抑制因子 SNAI1 减弱而导致 E-钙粘蛋白水平升高。相反，通过协调调节 AKT/GSK3 β/β TrCP 通路中的 β-catenin 和 E-cadherin/SNAI1 的失调，敲低 SLIT2 的表达会增加细胞迁移并减少细胞粘附。我们的研究结果表明，SLIT2 抑制肺癌进展，将其定义为一种新型“治疗诊断”因子，有潜力作为肺癌的治疗靶点和预后预测因子。癌症研究； 70(2)； 543-51。 (C)2010 AACR。
Chromosome 4p15.3 is frequently deleted in late-stage lung cancer. We investigated the significance of the SLIT2 gene located in this region to lung cancer progression. SLIT2 encodes an extracellular glycoprotein that can suppress breast cancer by regulating beta-catenin. In this study, we examined alterations in the structure or expression of SLIT2, its receptor ROBO1, and beta-catenin, along with the AKT/glycogen synthase kinase 3 beta (GSK3 beta)/beta-transducin repeat-containing protein (beta TrCP) pathway in lung cancer cell lines and patients. Low SLIT2 expression correlated with an upward trend of pathological stage and poorer survival in lung cancer patients. Importantly, SLIT2, beta TrCP, and beta-catenin expression levels predicted postoperative recurrence of lung cancer in patients. Stimulating SLIT2 expression by various methods increased the level of E-cadherin caused by attenuation of its transcriptional repressor SNAI1. Conversely, knocking down SLIT2 expression increased cell migration and reduced cell adhesion through coordinated deregulation of beta-catenin and E-cadherin/SNAI1 in the AKT/GSK3 beta/beta TrCP pathway. Our findings indicate that SLIT2 suppresses lung cancer progression, defining it as a novel "theranostic" factor with potential as a therapeutic target and prognostic predictor in lung cancer. Cancer Res; 70(2); 543-51. (C)2010 AACR.