ADAM9 enhances CDCP1 by inhibiting miR-1 through EGFR signaling activation in lung cancer metastasis

// Kuo-Liang Chiu 1, 4, 5, * , Yu-Sen Lin 1, 8, * , Ting-Ting Kuo 7 , Chia-Chien Lo 7 , Yu-Kai Huang 7 , Hsien-Fang Chang 6 , Eric Y. Chuang 6 , Ching-Chan Lin 1, 9 , Wei-Chung Cheng 2, 3 , Yen-Nien Liu 10 , Liang-Chuan Lai 6, 11 and Yuh-Pyng Sher 1, 2, 7 1 Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan 2 Graduate Institute of BioMedical Sciences, China Medical University, Taichung 404, Taiwan 3 Research Center for Tumor Medical Science, China Medical University, Taichung 404, Taiwan 4 Division of Chest Medicine, Department of Internal Medicine, Taichung Tzu-Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan 5 School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 970, Taiwan 6 Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei 100, Taiwan 7 Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan 8 Division of Thoracic Surgery, China Medical University Hospital, Taichung 404, Taiwan 9 Division of Hematology and Oncology, China Medical University Hospital, Taichung 404, Taiwan 10 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan 11 Graduate Institute of Physiology, National Taiwan University, Taipei 106, Taiwan * These authors contributed equally to this work Correspondence to: Yuh-Pyng Sher, email: ypsher@mail.cmu.edu.tw Liang-Chuan Lai, email: llai@ntu.edu.tw Keywords: lung cancer, ADAM9, EGFR, miR-1, CDCP1 Received: November 30, 2016 Accepted: April 19, 2017 Published: May 07, 2017 ABSTRACT MicroRNAs (miRNAs), which are endogenous short noncoding RNAs, can regulate genes involved in important biological and pathological functions. Therefore, dysregulation of miRNAs plays a critical role in cancer progression. However, whether the aberrant expression of miRNAs is regulated by oncogenes remains unclear. We previously demonstrated that a disintegrin and metalloprotease domain 9 (ADAM9) promotes lung metastasis by enhancing the expression of a pro-migratory protein, CUB domain containing protein 1 (CDCP1). In this study, we found that this process occurred via miR-1 down-regulation. miR-1 expression was down-regulated in lung tumors, but increased in ADAM9 -knockdown lung cancer cells, and was negatively correlated with CDCP1 expression as well as the migration ability of lung cancer cells. Luciferase-based reporter assays showed that miR-1 directly bound to the 3′-untranslated region of CDCP1 and inhibited its translation. Treatment with a miR-1 inhibitor restored CDCP1 protein levels and enhanced tumor cell mobility. Overexpression of miR-1 decreased tumor metastases and increased the survival rate in mice. ADAM9 knockdown reduced EGFR signaling and increased miR-1 expression. These results revealed that ADAM9 down-regulates miR-1 via activating EGFR signaling pathways, which in turn enhances CDCP1 expression to promote lung cancer progression.