title: miRNA-491-5p and GIT1 serve as modulators and biomarkers for oral squamous cell carcinoma invasion and metastasis.
abstract: MicroRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells, established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression analysis to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of patients with OSCCs. miR-491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G-protein-coupled receptor kinase-interacting protein 1 (GIT1)-as a direct target gene for miR-491-5p control. GIT1 overexpression was sufficient to rescue miR-491-5p-mediated inhibition of migration/invasion and lung metastasis. Conversely, GIT1 silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GIT1 attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated extracellular signal-regulated kinase (ERK1/2) activation, and MMP2/9 levels and activities. In clinical specimens of OSCCs, GIT1 levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GIT1 correlated inversely in OSCCs, where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GIT1 as biomarkers for prognosis in this cancer.
authors: Authors' Affiliations: Institute of Molecular and Genomic Medicine, Division of Environmental Health and Occupational Medicine, National Health Research Institute, Miaoli; Department of Life Sciences, National Central University, Jhongli; Environment-Omics-Disease Research Center, China Medical University Hospital, Taichung; Departments of Medical Biotechnology, Chang Gung University; Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital; Head and Neck Oncology Group, Chang Gung Memorial Hospital, Taoyuan; Department of Oral and Maxillofacial Section, Chi-Mei Medical Center, Liouying; and Department of Oral Hygiene, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Wei-Chieh
authors: WC
authors: Huang
authors: Shih-Hsuan
authors: SH
authors: Chan
authors: Te-Hsuan
authors: TH
authors: Jang
authors: Jer-Wei
authors: JW
authors: Chang
authors: Ying-Chin
authors: YC
authors: Ko
authors: Tzu-Chen
authors: TC
authors: Yen
authors: Shang-Lun
authors: SL
authors: Chiang
authors: Wei-Fan
authors: WF
authors: Chiang
authors: Tien-Yu
authors: TY
authors: Shieh
authors: Chun-Ta
authors: CT
authors: Liao
authors: Jyh-Lyh
authors: JL
authors: Juang
authors: Hsueh-Chun
authors: HC
authors: Wang
authors: Ann-Joy
authors: AJ
authors: Cheng
authors: Ya-Ching
authors: YC
authors: Lu
authors: Lu-Hai
authors: LH
authors: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D022001:Focal Adhesions / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009062:Mouth Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051419:Paxillin / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C485647:GIT1 protein, human; C551410:MIRN491 microRNA, human; D035683:MicroRNAs; D051419:Paxillin; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9