title: MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis.
abstract: Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidence have shown that microRNAs (miRs) can have an important role in cancer metastasis. Using isogenic pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149 to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G-protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of focal adhesion kinase and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and α5β1 integrin via proteasome and lysosome pathways, respectively. Moreover, we found that GIT1 depletion in metastatic breast cancer cells greatly reduced α5β1-integrin-mediated cell adhesion to fibronectin and collagen. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer, as well as with lymph node metastasis. We conclude that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149-GIT1 pathway in clinical diagnosis and therapeutics.
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli, Taiwan.
authors.forename: S-H
authors.initials: SH
authors.lastname: Chan
authors.affiliation: 1] Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli, Taiwan [2] Department of Life Science, National Central University, Taoyuan, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli, Taiwan.
authors.forename: J-W
authors.initials: JW
authors.lastname: Chang
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: K-J
authors.initials: KJ
authors.lastname: Chang
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: W-H
authors.initials: WH
authors.lastname: Kuo
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: M-Y
authors.initials: MY
authors.lastname: Wang
authors.affiliation: Chi Mei Medical Center, Department of Medical Research, Tainan, Taiwan.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Lin
authors.affiliation: Chi Mei Medical Center, Department of Medical Research, Tainan, Taiwan.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Uen
authors.affiliation: Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: M-F
authors.initials: MF
authors.lastname: Hou
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli, Taiwan.
authors.forename: C-M
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli, Taiwan.
authors.forename: T-H
authors.initials: TH
authors.lastname: Jang
authors.affiliation: Department of Surgery, Chiayi Christian Hospital, Chiayi, Taiwan.
authors.forename: C-W
authors.initials: CW
authors.lastname: Tu
authors.affiliation: Department of Medical Research, Chiayi Christian Hospital, Chiayi, Taiwan.
authors.forename: Y-R
authors.initials: YR
authors.lastname: Lee
authors.affiliation: Department of Pathology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.
authors.forename: M-T
authors.initials: MT
authors.lastname: Tien
authors.affiliation: 1] Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli, Taiwan [2] Department of Life Science, National Central University, Taoyuan, Taiwan [3] Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: L-H
authors.initials: LH
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C485647:GIT1 protein, human; D016023:Integrins; C551557:MIRN149 microRNA, human; D035683:MicroRNAs