MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis
Journal
Oncogene
Journal Volume
33
Journal Issue
36
Pages
4496-4507
Date Issued
2014
Author(s)
Chan S.-H.
Huang W.-C.
Chang J.-W.
Wang M.-Y.
Lin K.-Y.
Uen Y.-H.
Hou M.-F.
Lin C.-M.
Jang T.-H.
Tu C.-W.
Lee Y.-R.
Lee Y.-H.
Tien M.-T.
Wang L.-H.
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. ? 2014 Macmillan Publishers Limited All rights reserved.
SDGs
Other Subjects
cell cycle protein; GIT1 protein, human; integrin; microRNA; MIRN149 microRNA, human; signal transducing adaptor protein; article; breast tumor; female; gene expression regulation; gene silencing; genetics; human; metabolism; metastasis; pathology; signal transduction; tumor cell culture; tumor invasion; Adaptor Proteins, Signal Transducing; Breast Neoplasms; Cell Cycle Proteins; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Integrins; MicroRNAs; Neoplasm Invasiveness; Neoplasm Metastasis; Signal Transduction; Tumor Cells, Cultured
Publisher
Nature Publishing Group
Type
journal article