title: Overexpression of TMPRSS4 in non-small cell lung cancer is associated with poor prognosis in patients with squamous histology.
abstract: BACKGROUND
  Mortality rates in lung cancer patients have not decreased significantly in recent years, even with the implementation of new therapeutic regimens. One of the main problems is that a large proportion of patients present local or distant metastasis at the time of diagnosis. The need for identification of novel biomarkers and therapeutic targets for a more effective management of lung cancer led us to investigate TMPRSS4, a protease reported to promote tumour growth and metastasis.
  
  
  METHODS
  In all, 34 lung cancer cell lines were used to evaluate the TMPRSS4 expression. Cell migration and clonogenic assays, and an in-vivo lung metastasis model were used for functional analysis of the TMPRSS4 downregulation in H358, H441 and H2170 cell lines. The TMPRSS4 expression analysis in normal and malignant lung tissue samples was performed by qPCR. Five different microarray-based publicly available expression databases were used to validate our results and to study prognosis.
  
  
  RESULTS
  The TMPRSS4 knock down in H358, H441 and H2170 cells resulted in a significant reduction in proliferation, clonogenic capacity and invasion. A significant (P<0.05) decrease in the lung colonisation and growth was found when mice were injected with TMPRSS4-depleated H358-derived clones, as compared with controls. Expression of TMPRSS4 showed a >30-fold increase (P<0.001) in tumours in comparison with non-malignant samples. Levels in tumours with squamous cell carcinoma (SCC) histology were found to be significantly higher (P<0.001) than those with adenocarcinoma (AC) histology, which was confirmed in data retrieved from the microarrays. Kaplan-Meier curves demonstrated that high levels of TMPRSS4 were significantly associated (P=0.017) with reduced overall survival in the patients with SCC histology, whereas no correlation was found for the AC histology.
  
  
  CONCLUSIONS
  Our results demonstrate that TMPRSS4 has a role in the lung cancer development. The potential use of TMPRSS4 as a biomarker for lung cancer detection or as a predictor of patient's outcome warrants further investigation.
authors: Laboratory of Novel Therapeutic Targets, Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors: L
authors: L
authors: Larzabal
authors: P A
authors: PA
authors: Nguewa
authors: R
authors: R
authors: Pio
authors: D
authors: D
authors: Blanco
authors: B
authors: B
authors: Sanchez
authors: M J
authors: MJ
authors: Rodríguez
authors: M J
authors: MJ
authors: Pajares
authors: R
authors: R
authors: Catena
authors: L M
authors: LM
authors: Montuenga
authors: A
authors: A
authors: Calvo
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human