title: Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma.
abstract: BACKGROUND
  Claudin (CLDN)-1, a key component of tight junction complexes, was down-regulated in human lung adenocarcinomas.
  
  
  OBJECTIVE
  To investigate the clinical significance of CLDN1 expression in patients with lung adenocarcinoma and its role in cancer invasion and metastasis.
  
  
  METHODS
  We examined the CLDN1 mRNA expression in tumor specimens from 64 patients with lung adenocarcinoma and protein expression by immunohistochemistry in an independent cohort of 67 patients with lung adenocarcinoma. CLDN1 functions in cancer cell migration, invasion, and metastatic colonization were studied by overexpression and knockdown of CLDN1. Affymetrix microarrays were performed to identify gene expression changes associated with CLDN1 overexpression.
  
  
  RESULTS
  We found that low-CLDN1 mRNA expression had shorter overall survival (P = 0.027, log-rank test) in 64 patients with lung adenocarcinoma, and we confirmed by immunohistochemistry that low CLDN1 expression had shorter overall survival (P = 0.024, log-rank test) in an independent cohort of 67 patients with lung adenocarcinoma. Overexpression of CLDN1 inhibited cancer cell dissociation in time-lapse imaging of wound healing, and suppressed cancer cell migration, invasion, and metastasis. Knockdown CLDN1 expression increased cancer cell invasive and metastatic abilities. Affymetrix microarrays identified a panel of genes altered by CLDN1 overexpression. CLDN1 increased expressions of cancer invasion/metastasis suppressors (e.g., connective tissue growth factor [CTGF], thrombospondin 1 [THBS1], deleted in liver cancer 1 [DLC1], occludin [OCLN], zona occludens 1 [ZO-1]) and suppressed expressions of invasion/metastasis enhancers (e.g., secreted phosphoprotein 1 [SPP1], cut-like homeobox 1 [CUTL1], transforming growth factor alpha [TGF-alpha], solute carrier family 2 [faciliated glucose transporter] member 3 [SLC2A3], placental growth factor [PGF]), supporting a role for CLDN1 as an invasion and metastasis suppressor.
  
  
  CONCLUSIONS
  CLDN1 is a cancer invasion/metastasis suppressor. CLDN1 is also a useful prognostic predictor and potential drug treatment target for patients with lung adenocarcinoma.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Chao
authors.forename: Szu-Hua
authors.initials: SH
authors.lastname: Pan
authors.forename: Shuenn-Chen
authors.initials: SC
authors.lastname: Yang
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.forename: Ting-Fang
authors.initials: TF
authors.lastname: Che
authors.forename: Chung-Wu
authors.initials: CW
authors.lastname: Lin
authors.forename: Mu-Shiun
authors.initials: MS
authors.lastname: Tsai
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.forename: Che-Hsiang
authors.initials: CH
authors.lastname: Wu
authors.forename: Yi-Ying
authors.initials: YY
authors.lastname: Wu
authors.forename: Yung-Chie
authors.initials: YC
authors.lastname: Lee
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D062445:Claudin-1; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; D012333:RNA, Messenger