Abstract
2 min read// Maria Villalba 1, 2, * , Angel Diaz-Lagares 3, * , Miriam Redrado 2 , Arrate L. de Aberasturi 1, 2 , Victor Segura 4 , Maria Elena Bodegas 1 , Maria J. Pajares 1, 2 , Ruben Pio 2, 5 , Javier Freire 6 , Javier Gomez-Roman 6 , Luis M. Montuenga 1, 2 , Manel Esteller 3 , Juan Sandoval 7, # , Alfonso Calvo 1, 2, # 1 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain 2 IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain 3 Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain 4 IDISNA and Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain 5 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Navarra, Spain 6 Department of Pathology, University Hospital Marques de Valdecilla, IDIVAL, Santander, Spain 7 Department of Personalized Medicine, Epigenomics Unit, Medical Research Institute La Fe, Valencia, Spain * Both authors should be considered as first authors # Both authors should be considered as senior authors Correspondence to: Juan Sandoval, e-mail: epigenomica@iislafe.es Alfonso Calvo, e-mail: acalvo@unav.es Keywords: TMPRSS4, epigenetics, promoter hypomethylation, squamous cell carcinoma, prognosis Abbreviations: NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma; ADC, adenocarcinoma; TCGA, The Cancer Genome Atlas; TSS, Transcription Start Site Received: December 02, 2015 Accepted: February 18, 2016 Published: March 14, 2016 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.
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