Integrin β3 and CD44 levels determine the effects of the OPN-a splicing variant on lung cancer cell growth

// Shih-Jung Sun 1, * , Chun-Chi Wu 1, * , Gwo-Tarng Sheu 1 , Hui-Yi Chang 2 , Mei-Yu Chen 2 , Yu-Ying Lin 2 , Cheng-Yen Chuang 2, 3 , Shih-Lan Hsu 4 , Jinghua Tsai Chang 1, 2, 5 1 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC 2 Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC 3 Division of Thoracic Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, ROC 4 Department of Education & Research, Taichung Veterans General Hospital, Taichung, Taiwan, ROC 5 Department of Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC * These authors have contributed equally to this study Correspondence to: Jinghua Tsai Chang, email: jinghuat@csmu.edu.tw Keywords: OPN-a, Integrin β3, CD44, NF-kB Received: November 25, 2015     Accepted: June 07, 2016     Published: July 27, 2016 ABSTRACT Osteopontin (OPN), a phosphorylated glycoprotein, is frequently overexpressed in cancer. Among the three OPN isoforms, OPN-a is the most highly expressed in lung cancer cell lines and lung tumors. Overexpression of OPN-a greatly reduced CL1-5 lung adenocarcinoma cell growth, but had no effect on growth in A549 lung adenocarcinoma cells. Examination of the expression of integrins and CD44, which are possible OPN-a receptors, revealed that differences in integrin β3 levels might explain this discrepancy between CL1-5 and A549 cells. When integrin β3 was ectopically expressed in A549 cells, OPN-a inhibited their growth, whereas OPN-a increased cell growth following integrin β3 knockdown in CL1-5 cells. This OPN-a-induced increase in growth appeared to result from activation of the CD44/NFκB pathway. Our results demonstrated that OPN-a inhibits growth of cells with high integrin β3 levels and increases growth via activation of the CD44/NFκB pathway in cells with low integrin β3 levels. Thus, OPN-a, integrin β3, and CD44 interact to affect lung cancer cell growth, and this study may aid in the development of cancer treatment strategies involving these molecules.