Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces beta-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma

作者：Burkhalter Rebecca J; Westfall Suzanne D; Liu Yueying; Stack M Sharon

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290(36): 22143-22154.

DOI：10.1074/jbc.M115.641092

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.

• 出版日期2015-9-4