LIM and SH3 Protein 1 Induces TGFβ-Mediated Epithelial-Mesenchymal Transition in Human Colorectal Cancer by Regulating S100A4 Expression
LIM and SH3 Protein 1 Induces TGFβ-Mediated Epithelial-Mesenchymal Transition in Human Colorectal Cancer by Regulating S100A4 Expression
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DOI：
10.1158/1078-0432.ccr-14-0485
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发表时间：
2014-11-15
影响因子：
11.5
通讯作者：
Zhao, Liang
中科院分区：
文献类型：
--
作者：
Wang, Hui;Shi, Jiaolong;Zhao, Liang
目的：在结直肠癌病例中，LIM和SH3蛋白1 （LASP1）的表达上调，从而促进结直肠癌细胞的侵袭性表型。然而，我们仍然不能破译与结直肠癌转移相关的潜在分子机制。实验设计：本研究采用免疫组化方法研究人类结直肠癌组织中蛋白的表达。Western blot分析lasp1诱导的信号通路。利用双向凝胶电泳技术筛选LASP1调控蛋白，揭示LASP1的分子机制。TGF - β诱导上皮-间质转化（EMT）。结果：在临床结直肠癌样本中，LASP1表达与间充质标志物vimentin相关，与上皮标志物E-cadherin、β -catenin呈负相关。功能增益和功能丧失实验表明，LASP1在体外和体内诱导emt样表型。S100A4被鉴定为LASP1调控蛋白，被LASP1上调。此外，它在结直肠癌中经常与LASP1共表达。EMT需要S100A4， LASP1诱导结直肠癌细胞侵袭性增加。此外，TGF β的刺激导致Smad通路激活，增加LASP1和S100A4的表达。LASP1或S100A4表达的缺失抑制了TGF β信号通路。显著削弱TGF β对结直肠癌细胞的促侵袭作用。结论：这些发现阐明了LASP1在TGF β介导的EMT过程中的核心作用，为晚期结直肠癌患者的临床干预提供了潜在的靶点。(c) 2014年aacr。
Purpose: The expression of LIM and SH3 protein 1 (LASP1) was upregulated in colorectal cancer cases, thereby contributing to the aggressive phenotypes of colorectal cancer cells. However, we still cannot decipher the underlying molecular mechanism associated with colorectal cancer metastasis.Experimental Design: In this study, IHC was performed to investigate the expression of proteins in human colorectal cancer tissues. Western blot analysis was used to assess the LASP1-induced signal pathway. Two-dimensional difference gel electrophoresis was performed to screen LASP1-modulated proteins and uncover the molecular mechanism of LASP1. TGF beta was used to induce an epithelial-mesenchymal transition (EMT).Results: LASP1 expression was correlated with the mesenchymal marker vimentin and was inversely correlated with epithelial markers, namely, E-cadherin and beta-catenin, in clinical colorectal cancer samples. The gain- and loss-of-function assay showed that LASP1 induces EMT-like phenotypes in vitro and in vivo. S100A4, identified as a LASP1-modulated protein, was upregulated by LASP1. Moreover, it is frequently coexpressed with LASP1 in colorectal cancer. S100A4 was required for EMT, and an increased cell invasiveness of colorectal cancer cell is induced by LASP1. Furthermore, the stimulation of TGF beta resulted in an activated Smad pathway that increased the expression of LASP1 and S100A4. The depletion of LASP1 or S100A4 expression inhibited the TGF beta signaling pathway. Moreover, it significantly weakened the proinvasive effects of TGF beta on colorectal cancer cells.Conclusion: These findings elucidate the central role of LASP1 in the TGF beta-mediated EMT process and suggest a potential target for the clinical intervention in patients with advanced colorectal cancer. (C) 2014 AACR.