title: CD151-α3β1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling.
abstract: Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated. Knocking down Slug partially restores CD151-α3β1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of β-catenin and Axin-2 as well as resistance to the inhibition in β-catenin-dependent transcriptional complexes. Together, our study demonstrates that CD151-α3β1 integrin complexes regulate ovarian tumor growth by repressing Slug-mediated EMT and Wnt signaling.
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Department of Pathology & Laboratory Medicine, University of Kentucky, College of Medicine, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Baldwin
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Department of Pathology & Laboratory Medicine, University of Kentucky, College of Medicine, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: John T
authors.initials: JT
authors.lastname: Hoff
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Department of Pathology & Laboratory Medicine, University of Kentucky, College of Medicine, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Jason
authors.initials: J
authors.lastname: Lefringhouse
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Michael
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Changhe
authors.initials: C
authors.lastname: Jia
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Zeyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Sonia
authors.initials: S
authors.lastname: Erfani
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Qing-Bai
authors.initials: QB
authors.lastname: She
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Department of Pathology & Laboratory Medicine, University of Kentucky, College of Medicine, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: John R
authors.initials: JR
authors.lastname: van Nagell
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Rina
authors.initials: R
authors.lastname: Plattner
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaetzel
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Lu
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Department of Pathology & Laboratory Medicine, University of Kentucky, College of Medicine, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Dava
authors.initials: D
authors.lastname: West
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Department of Pathology & Laboratory Medicine, University of Kentucky, College of Medicine, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Ueland
authors.affiliation: Department of Cancer Biology and Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Binhua P
authors.initials: BP
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY.
authors.forename: Xiuwei H
authors.initials: XH
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D060185:Tetraspanin 24 / Q000378:metabolism*; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: C554715:CD151 protein, human; D039201:Integrin alpha3beta1; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D060185:Tetraspanin 24; D014157:Transcription Factors