CD151-α3β1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling

// Lauren A. Baldwin 1,2,* , John T. Hoff 1,2,* , Jason Lefringhouse 1,2,* , Michael Zhang 1 , Changhe Jia 1 , Zeyi Liu 1 , Sonia Erfani 1 , Hongyan Jin 1 , Mei Xu 1 , Qing-Bai She 1 , John R. van Nagell 2 , Chi Wang 1 , Li Chen 1 , Rina Plattner 1 , David M. Kaetzel 3 , Jia Luo 1 , Michael Lu 4 , Dava West 2 , Chunming Liu 1 , Fred R. Ueland 2 , Ronny Drapkin 5 , Binhua P. Zhou 1 and Xiuwei H. Yang 1 1 Department of Pharmacology and Nutritional Science, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY 2 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 3 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 4 Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States of America 5 Department of Cancer Biology and Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA * These authors contributed equally to this work Correspondence: Xiuwei H. Yang, email: // Keywords : CD151, integrin, EMT, tumor growth, ovarian cancer Received : September 02, 2014 Accepted : October 22, 2014 Published : October 22, 2014 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.