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.
Highlights
Lung cancer still remains as the most common cause of cancer death worldwide and presents a 5-year relative survival of around 18% [1, 2]
High TMPRSS4 protein expression is significantly associated with reduced Relapse free survival (RFS) and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with squamous histology
NSCLC patients were dichotomized into two groups: high (n=40) and low (n=39) TMPRSS4 expression, according to the median value of the H-score
Summary
Lung cancer still remains as the most common cause of cancer death worldwide and presents a 5-year relative survival of around 18% [1, 2]. Among the different tumor subtypes, non-small cell lung cancer (NSCLC) is the most common one (accounting approximately for 85% of the cases) and comprises two major histological groups: adenocarcinomas (ADC, ~50%), and squamous cell carcinomas (SCC, ~30%). It has been shown that earlier detection in screening programs mediated by spiral computed tomography reduces lung cancer deaths [3]. Current therapeutic regimes are not sufficiently effective to significantly increase long term survival. For most patients with early NSCLC, surgical resection is the appropriate therapeutic option, a considerable percentage of them (~30-70%, depending on the stage) will relapse overtime [2]
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