title: Alpha-smooth muscle actin (ACTA2) is required for metastatic potential of human lung adenocarcinoma.
abstract: OBJECTIVE
  Metastatic relapse of primary lung cancer leads to therapeutic resistance and unfavorable clinical prognosis; therefore, identification of key molecules associated with metastatic conversion has significant clinical implications. We previously identified a link between early brain metastasis of lung adenocarcinoma and amplification of the α-smooth muscle actin (ACTA2) gene. The aim of present study was to investigate the prognostic and functional significance of ACTA2 expression in cancer cells for the metastatic potential of lung adenocarcinomas.
  
  
  METHODS
  ACTA2 expression was analyzed in tumor cells from 263 patients with primary lung adenocarcinomas by immunohistochemistry, and was correlated with clinicopathologic parameters. The expression of ACTA2 in human lung adenocarcinoma cells was modulated with short hairpin RNAs (shRNA) and siRNAs specifically targeting ACTA2.
  
  
  RESULTS
  The patients with lung adenocarcinomas with high ACTA2 expression in tumor cells showed significantly enhanced distant metastasis and unfavorable prognosis. ACTA2 downregulation remarkably impaired in vitro migration, invasion, clonogenicity, and transendothelial penetration of lung adenocarcinoma cells without affecting proliferation. Consistent with the in vitro results, depletion of ACTA2 in human lung adenocarcinoma PC14PE6 cells significantly reduced their metastatic potential without altering their tumorigenic potential. Expression of c-MET and FAK in lung adenocarcinoma cells was also reduced by ACTA2-targeting siRNAs and shRNAs, and was accompanied by a loss of mesenchymal characteristics.
  
  
  CONCLUSIONS
  These findings indicate that ACTA2 regulates c-MET and FAK expression in lung adenocarcinoma cells, which positively and selectively influence metastatic potential. Therefore, ACTA2 could be a promising prognostic biomarker and/or therapeutic target for metastatic lung adenocarcinoma.
authors.affiliation: Authors' Affiliations: Cancer Stem Cell Research Center and Department of Neurosurgery, Samsung Medical Center; Graduate School, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University; Samsung Biomedical Research Institute, Department of Anatomy and Cell Biology, Department of Molecular Cell Biology, Center for Genome Research, and Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Lee
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Park
authors.forename: Se Jeong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Cho
authors.forename: Duk-Hwan
authors.initials: DH
authors.lastname: Kim
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Lee
authors.forename: Myung-Soo
authors.initials: MS
authors.lastname: Kang
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Seol
authors.forename: Young Mog
authors.initials: YM
authors.lastname: Shim
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D034622:RNA Interference
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D019859:Proto-Oncogene Proteins c-met; D051416:Focal Adhesion Protein-Tyrosine Kinases