Research Papers:

Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients

Maria Villalba, Angel Diaz-Lagares, Miriam Redrado, Arrate L. de Aberasturi, Victor Segura, Maria Elena Bodegas, Maria J. Pajares, Ruben Pio, Javier Freire, Javier Gomez-Roman, Luis M. Montuenga, Manel Esteller, Juan Sandoval _ and Alfonso Calvo

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Oncotarget. 2016; 7:22752-22769. https://doi.org/10.18632/oncotarget.8045

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Maria Villalba1,2,*, Angel Diaz-Lagares3,*, Miriam Redrado2, Arrate L. de Aberasturi1,2, Victor Segura4, Maria Elena Bodegas1, Maria J. Pajares1,2, Ruben Pio2,5, Javier Freire6, Javier Gomez-Roman6, Luis M. Montuenga1,2, Manel Esteller3, Juan Sandoval7,#, Alfonso Calvo1,2,#

1Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain

2IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain

3Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet, Catalonia, Spain

4IDISNA and Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain

5Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Navarra, Spain

6Department of Pathology, University Hospital Marques de Valdecilla, IDIVAL, Santander, Spain

7Department 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: [email protected]

Alfonso Calvo, e-mail: [email protected]

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


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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