title: Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients.
abstract: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which highlights the need of innovative therapeutic options. Although targeted therapies can be successfully used in a subset of patients with lung adenocarcinomas (ADC), they are not appropriate for patients with squamous cell carcinomas (SCC). In addition, there is an unmet need for the identification of prognostic biomarkers that can select patients at risk of relapse in early stages. Here, we have used several cohorts of NSCLC patients to analyze the prognostic value of both protein expression and DNA promoter methylation status of the prometastatic serine protease TMPRSS4. Moreover, expression and promoter methylation was evaluated in a panel of 46 lung cancer cell lines. We have demonstrated that a high TMPRSS4 expression is an independent prognostic factor in SCC. Similarly, aberrant hypomethylation in tumors, which correlates with high TMPRSS4 expression, is an independent prognostic predictor in SCC. The inverse correlation between expression and methylation status was also observed in cell lines. In vitro studies showed that treatment of cells lacking TMPRSS4 expression with a demethylating agent significantly increased TMPRSS4 levels. In conclusion, TMPRSS4 is a novel independent prognostic biomarker regulated by epigenetic changes in SCC and a potential therapeutic target in this tumor type, where targeted therapy is still underdeveloped.
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain.|IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Villalba
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Diaz-Lagares
authors.affiliation: IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Redrado
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain.|IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Arrate L
authors.initials: AL
authors.lastname: de Aberasturi
authors.affiliation: IDISNA and Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Bodegas
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain.|IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Pajares
authors.affiliation: IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.|Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
authors.affiliation: Department of Pathology, University Hospital Marques de Valdecilla, IDIVAL, Santander, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Freire
authors.affiliation: Department of Pathology, University Hospital Marques de Valdecilla, IDIVAL, Santander, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gomez-Roman
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain.|IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Department of Personalized Medicine, Epigenomics Unit, Medical Research Institute La Fe, Valencia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Sandoval
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain.|IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human
keywords: TMPRSS4; epigenetics; prognosis; promoter hypomethylation; squamous cell carcinoma