title: ADAM9 enhances CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis.
abstract: Metastasis is the leading cause of death in cancer patients due to the difficulty of controlling this complex process. MicroRNAs (miRNA), endogenous noncoding short RNAs with important biological and pathological functions, may play a regulatory role during cancer metastasis, but this role has yet to be fully defined. We previously demonstrated that ADAM9 enhanced the expression of the pro-migratory protein CDCP1 to promote lung metastasis; however, the regulatory process remains unknown. Here we demonstrate that endogenous miR-218, which is abundant in normal lung tissue but suppressed in lung tumors, is regulated during the process of ADAM9-mediated CDCP1 expression. Suppression of miR-218 was associated with high migration ability in lung cancer cells. Direct interaction between miR-218 and the 3'-UTR of CDCP1 mRNAs was detected in luciferase-based transcription reporter assays. CDCP1 protein levels decreased as expression levels of miR-218 increased, and increased in cells treated with miR-218 antagomirs. Induction of miR-218 inhibited tumor cell mobility, anchorage-free survival, and tumor-initiating cell formation in vitro and delayed tumor metastases in mice. Our findings revealed an integrative tumor suppressor function of miR-218 in lung carcinogenesis and metastasis.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.|Division of Chest Medicine, Department of Internal Medicine, Taichung Tzu-Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan.|School of Post-baccalaureate Chinese Medicine, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Kuo-Liang
authors.initials: KL
authors.lastname: Chiu
authors.affiliation: Center for Molecular Medicine, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Kuo
authors.affiliation: Center for Molecular Medicine, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Qian-Yu
authors.initials: QY
authors.lastname: Kuok
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.|Division of Thoracic Surgery, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Yu-Sen
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.|Department of Otolaryngology, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Chung-Hung
authors.initials: CH
authors.lastname: Hua
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.|Division of Hematology and Oncology, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Chen-Yuan
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Gastroenterology and Hepatology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Pei-Yuan
authors.initials: PY
authors.lastname: Su
authors.affiliation: Graduate Institute of Physiology, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Liang-Chuan
authors.initials: LC
authors.lastname: Lai
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.|Center for Molecular Medicine, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Yuh-Pyng
authors.initials: YP
authors.lastname: Sher
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000951:Antigens, Neoplasm; D001483:Base Sequence; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; C547471:MIRN218 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051722:ADAM Proteins; C098339:ADAM9 protein, human