Burkhalter Rebecca J, Westfall Suzanne D, Liu Yueying, Stack M Sharon
From the Departments of Medical Pharmacology and Physiology and the Harper Cancer Research Institute.
Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri 65212 and.
J Biol Chem. 2015 Sep 4;290(36):22143-54. doi: 10.1074/jbc.M115.641092. Epub 2015 Jul 14.
During tumor progression, epithelial ovarian cancer (EOC) cells undergo epithelial-to-mesenchymal transition (EMT), which influences metastatic success. Mutation-dependent activation of Wnt/β-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/β-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 β-catenin, stimulates clustering of β1 integrins, and enhances the conformationally active population of surface β1 integrins. Furthermore, LPA treatment initiates nuclear translocation of β-catenin and transcriptional activation of Wnt/β-catenin target genes resulting in gain of mesenchymal marker expression. Together these data suggest that LPA initiates EMT in ovarian tumors through β1-integrin-dependent activation of Wnt/β-catenin signaling, providing a novel mechanism for mutation-independent activation of this pathway in EOC progression.
在肿瘤进展过程中，上皮性卵巢癌（EOC）细胞会经历上皮-间质转化（EMT），这会影响转移的成功。Wnt/β-连环蛋白信号通路的突变依赖性激活与几种实体瘤中间质表型的获得和分化的丧失有关；然而，在大多数EOC组织类型中，类似的突变很少见。尽管如此，已有报道称EOC中存在激活的Wnt/β-连环蛋白信号通路的证据，对人类EOC肿瘤的免疫组织化学分析显示所有组织类型中均有核染色。本研究探讨了生物活性脂质溶血磷脂酸（LPA）在EOC微环境中普遍存在，其作用是调节EOC中的EMT这一假说。我们的结果表明，LPA诱导连接性β-连环蛋白的丧失，刺激β1整合素的聚集，并增加表面β1整合素的构象活性群体。此外，LPA处理引发β-连环蛋白的核转位和Wnt/β-连环蛋白靶基因的转录激活，导致间质标志物表达增加。这些数据共同表明，LPA通过β1整合素依赖性激活Wnt/β-连环蛋白信号通路在卵巢肿瘤中启动EMT，为EOC进展中该通路的非突变依赖性激活提供了一种新机制。
