CAV-1 contributes to bladder cancer progression by inducing epithelial-to-mesenchymal transition
CAV-1 contributes to bladder cancer progression by inducing epithelial-to-mesenchymal transition
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CAV-1通过诱导上皮间质转化促进膀胱癌进展
DOI：
10.1016/j.urolonc.2014.01.005
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发表时间：
2014-08-01
影响因子：
2.7
通讯作者：
Xie, Wen-Lian
中科院分区：
文献类型：
--
作者：
Liang, Wu;Hao, Zheng;Xie, Wen-Lian
背景：上皮向间充质转化(EMT)是肿瘤转移的关键步骤。CAV-1已被证明是膀胱癌的癌基因。然而，CAV-1与EMT在膀胱癌转移中的关系尚不清楚。方法：采用免疫组织化学方法对膀胱癌患者肿瘤标本进行免疫组织化学分析。检测CAV-1和E-钙粘蛋白的表达水平，并与肿瘤分级和转移的临床特征进行相关性分析。用创伤愈合和体外跨孔侵袭实验检测膀胱癌细胞株(T24、UMUC3、HT1376和5637)的EMT，并利用小干扰RNA下调CAV-1和Slug的表达。结果：在本研究中，CAV-1的表达增加诱导膀胱癌细胞迁移并促进EMT，这是通过降低E-钙粘蛋白的表达、诱导N-钙粘素和波形蛋白的表达而决定的。用特定的小干扰RNA抑制CAV-1的表达可减少细胞迁移和EMT。从机制上讲，CAV-1诱导转录因子slug的表达。Slug基因敲除可消除CAV-1诱导的膀胱癌细胞EMT。我们进一步证明，Slug的表达是由CAV-1对PI3K/AKT信号的调节所介导的。结论：CAV-1通过上调Slug蛋白的表达促进膀胱癌细胞的侵袭表型，这一过程是通过激活PI3K/AKT信号通路实现的。CAV-1在促进膀胱癌转移中的这一新作用使CAV-1及其相关途径成为浸润性膀胱癌潜在的治疗靶点。(C)2014 Elsevier Inc.保留所有权利。
Background: The epithelial-to-mesenchymal transition (EMT) is a critical step in tumor metastasis. CAV-1 has been shown to be an oncogene in bladder cancer. However, little is known about the relationship between CAV-1 and EMT in bladder cancer metastasis.Methods: Immunohistochemical analysis was carried out retrospectively on tumor samples from patients treated for bladder cancer. CAV-1 and E-cadherin expression levels were measured and correlated with clinical features of tumor grade and metastasis. EMT was assessed in bladder cancer cell lines (T24, UMUC3, HT1376, and 5637) using wound healing and in vitro transwell invasion assays, and small interfering RNA was used to knock down CAV-1 and Slug expression.Results: In this study, we show that increased CAV-1 expression induces bladder cancer cell migration and promotes the EMT, which was determined by the reduction of E-cadherin expression and the induction of N-cadherin and vimentin expression. Knockdown of CAV-1 expression with specific small interfering RNA reduced cell migration and EMT. Mechanistically, CAV-1-induced expression of the transcription factor, Slug. Slug knockdown abolished the CAV-1-induced EMT in bladder cancer cells. We further show that Slug expression is mediated by the CAV-1 regulation of the PI3K/AKT signaling. In addition, positive CAV-1 expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in bladder cancer tissues.Conclusions: Our results suggest that CAV-1 promotes invasive phenotypes in bladder cancer cells by inducing EMT through up-regulation of Slug expression, which occurs through activation of the PI3K/AKT signaling pathway. This new role for CAV-1 in promoting bladder cancer metastasis presents CAV-1 and related pathways as potential therapeutic targets in invasive bladder cancer. (C) 2014 Elsevier Inc. All rights reserved.