Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma
Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma
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DOI：
10.1074/jbc.m115.641092
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发表时间：
2015-09-04
影响因子：
4.8
通讯作者：
Stack, M. Sharon
中科院分区：
文献类型：
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作者：
Burkhalter, Rebecca J.;Westfall, Suzanne D.;Stack, M. Sharon
在肿瘤进展期间，上皮性卵巢癌（EOC）细胞经历上皮向间质转化（EMT），这影响转移成功。Wnt/β-连环蛋白信号的突变依赖性激活与几种实体瘤的间充质表型获得和分化丧失有关;然而，在大多数EOC组织型中，类似的突变是罕见的。尽管如此，已经报道了EOC中激活的Wnt/β-连环蛋白信号的证据，并且人EOC肿瘤的免疫组织化学分析显示所有组织型中都有核染色。本研究提出了一个假设，即EOC微环境中普遍存在的生物活性脂质溶血磷脂酸（LPA），其功能是调节EOC中的EMT。我们的研究结果表明，LPA诱导连接β-连环蛋白的损失，刺激β 1整合素的聚集，并增强表面β 1整合素的构象活性群体。此外，LPA处理启动β-连环蛋白的核转位和Wnt/β-连环蛋白靶基因的转录激活，导致间充质标志物表达的获得。总之，这些数据表明，LPA通过Wnt/β-连环蛋白信号的β 1-整联蛋白依赖性激活启动卵巢肿瘤中的EMT，为EOC进展中该途径的突变非依赖性激活提供了一种新的机制。
During tumor progression, epithelial ovarian cancer (EOC) cells undergo epithelial-to-mesenchymal transition (EMT), which influences metastatic success. Mutation-dependent activation of Wnt/beta-catenin signaling has been implicated in gain of mesenchymal phenotype and loss of differentiation in several solid tumors; however, similar mutations are rare in most EOC histotypes. Nevertheless, evidence for activated Wnt/beta-catenin signaling in EOC has been reported, and immunohistochemical analysis of human EOC tumors demonstrates nuclear staining in all histotypes. This study addresses the hypothesis that the bioactive lipid lysophosphatidic acid (LPA), prevalent in the EOC microenvironment, functions to regulate EMT in EOC. Our results demonstrate that LPA induces loss of junctional beta-catenin, stimulates clustering of beta 1 integrins, and enhances the conformationally active population of surface beta 1 integrins. Furthermore, LPA treatment initiates nuclear translocation of beta-catenin and transcriptional activation of Wnt/beta-catenin target genes resulting in gain of mesenchymal marker expression. Together these data suggest that LPA initiates EMT in ovarian tumors through beta 1-integrin-dependent activation of Wnt/beta-catenin signaling, providing a novel mechanism for mutation-independent activation of this pathway in EOC progression.