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.Material and 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.Conclusion: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.

TMPRSS4 correlates with colorectal cancer pathological stage and regulates cell proliferation and self-renewal ability

“…In breast cancer, higher expression of TMPRSS4 was associated with positive lymph node metastasis, larger tumor size, advanced pathological grade, and shorter overall and disease-free survival; 16 in non-small cell lung cancer, overexpression of TMPRSS4 in patients with squamous histology was associated with poor prognosis; 24 in malignant thyroid neoplasm, TMPRSS4 was identified to be a diagnostic marker. 25 Of note, Jung et al had reported TMPRSS4 was upregulated in colon cancer.…”

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

“…Moreover, we showed that increased TMPRSS4 mRNA levels were associated with poor prognosis in SCC patients [7]. TMPRSS4 has also been found upregulated in colon, pancreas, breast, cervix, thyroid and liver tumors [8, 9, 10, 11].…”

Prognostic significance of TMPRSS4 in gastric cancer

“…Subsequebt data show that TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin alpha5 and its signaling pathways [15]. Recent studies indicate that overexpression of TMPRSS4 is significantly associated with reduced overall survival of patients with non-small cell lung cancer and breast cancer and may represent a potential therapeutic target [10][11]16]. However, to date, there is no report to clarify the prognostic impact of TMPRSS4 expression in GC.…”