title: TMPRSS4 regulates levels of integrin α5 in NSCLC through miR-205 activity to promote metastasis.
abstract: BACKGROUND
  TMPRSS4 is a membrane-anchored protease involved in cell migration and invasion in different cancer types including lung cancer. TMPRSS4 expression is increased in NSCLC and its inhibition through shRNA reduces lung metastasis. However, molecular mechanisms leading to the protumorigenic regulation of TMPRSS4 in lung cancer are unknown.
  
  
  METHODS
  miR-205 was identified as an overexpressed gene upon TMPRSS4 downregulation through microarray analysis. Cell migration and invasion assays and in vivo lung primary tumour and metastasis models were used for functional analysis of miR-205 overexpression in H2170 and H441 cell lines. Luciferase assays were used to identify a new miR-205 direct target in NSCLC.
  
  
  RESULTS
  miR-205 overexpression promoted an epithelial phenotype with increased E-cadherin and reduced fibronectin. Furthermore, miR-205 expression caused a G0/G1 cell cycle arrest and inhibition of cell growth, migration, attachment to fibronectin, primary tumour growth and metastasis formation in vivo. Integrin α5 (a proinvasive protein) was identified as a new miR-205 direct target in NSCLC. Integrin α5 downregulation in lung cancer cells resulted in complete abrogation of cell migration, a decreased capacity to adhere to fibronectin and reduced in vivo tumour growth, compared with control cells. TMPRSS4 silencing resulted in a concomitant reduction of integrin α5 levels.
  
  
  CONCLUSIONS
  We have demonstrated for the first time a new molecular pathway that connects TMPRSS4 and integrin α5 through miR-205 to regulate cancer cell invasion and metastasis. Our results will help designing new therapeutic strategies to inhibit this novel pathway in NSCLC.
authors.affiliation: Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Larzabal
authors.affiliation: 1] Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain [2] Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
authors.forename: A L
authors.initials: AL
authors.lastname: de Aberasturi
authors.affiliation: Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Redrado
authors.affiliation: Ingenasa Inc, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Rueda
authors.affiliation: Ingenasa Inc, Madrid, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Rodriguez
authors.affiliation: Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
authors.forename: M E
authors.initials: ME
authors.lastname: Bodegas
authors.affiliation: 1] Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain [2] Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Montuenga
authors.affiliation: 1] Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain [2] Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Calvo
mesh_terms: D015820:Cadherins / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005353:Fibronectins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015820:Cadherins; D005353:Fibronectins; D039482:Integrin alpha5; D008565:Membrane Proteins; D035683:MicroRNAs; D012697:Serine Endopeptidases; C534425:MIR205, human; C528837:TMPRSS4 protein, human