Methylation-induced downregulation of TFPI-2 causes TMPRSS4 overexpression and contributes to oncogenesis in a subset of non-small-cell lung carcinoma.
Bottom Line: Interestingly, we found that TMPRSS4 expression was associated with tissue factor pathway inhibitor 2 (TFPI-2) expression in these clinical samples.Knockdown of TMPRSS4 reduced the proliferation rate in several lung cancer cell lines.We found a novel molecular mechanism that TFPI-2 negatively regulates cell growth by inhibiting transcription of TMPRSS4.
Affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan.Show MeSH
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Mentions: We initially carried out mRNA profiling of 90 Japanese NSCLC patients (54 adenocarcinomas [AC], 24 squamous cell carcinomas [SCC], and 12 other lung cancers; patient characteristics are shown in Table S1), and identified 120 genes that were commonly upregulated more than twofold with a ratio P-value <0.001 in >75% of the samples (Fig.1a). With these criteria, approximately 1700 probes had a greater than twofold change, and of these, 163 probes were upregulated. Eliminating overlapping genes and expressed sequence tags, we obtained 120 genes as unique, upregulated genes. Among these 120 genes, 15 genes were found to have druggable domain(s) (Table1), as determined by the Gene Set Annotator (Rosetta Inpharmatics). We prioritized these 15 genes in terms of cancer relevance and unknown mechanism for tumorigenesis. TMPRSS4 overexpression has been reported in various cancers including lung cancer.5,7,23 We also confirmed that TMPRSS4 was overexpressed not only in clinical lung cancer samples but also in several lung cancer cell lines (Fig.1b,c). It is reported that TMRPSS4 promotes tumor growth, invasion, metastasis, and the epithelial–mesenchymal transition process and regulates in vitro cell growth24,25; however, only limited mechanisms for tumorigenesis by TMPRSS4 have been clarified.
Affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan.