title: Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma.
abstract: 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.
authors.affiliation: From the Departments of Medical Pharmacology and Physiology and the Harper Cancer Research Institute.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Burkhalter
authors.affiliation: Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri 65212 and.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Westfall
authors.affiliation: the Harper Cancer Research Institute, Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana 46617.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: the Harper Cancer Research Institute, Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana 46617 sstack@nd.edu.
authors.forename: M Sharon
authors.initials: MS
authors.lastname: Stack
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051820:TCF Transcription Factors / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D019012:Integrin beta1; D008246:Lysophospholipids; D011518:Proto-Oncogene Proteins; D049368:Receptors, Lysophosphatidic Acid; D051820:TCF Transcription Factors; D014746:Vimentin; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; C032881:lysophosphatidic acid
keywords: LPA; Wnt signaling; integrin; lysophospholipid; ovarian cancer; β-catenin (β-catenin)