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: Because TMPRSS4 is a serine protease and TFPI-2 encodes a broad-spectrum serine protease inhibitor, we speculated that there is some relationship between TMPRSS4 and TFPI-2. Although we first hypothesized that TFPI-2 inhibits the protease activity of TMPRSS4, surprisingly, we found that the mRNA expression level of TMPRSS4 was reduced when TFPI-2 was overexpressed by plasmid transfection in NCI-H358, NCI-H520, and NCI-H1975 cells (Fig.3a,b). We checked whether the reporter activity of endogenous TMPRSS4 is inhibited by the overexpression of TFPI-2. The reporter activity of the TMPRSS4 promoter region was partially inhibited by TFPI-2 in these three cell lines (Fig.3c). Conversely, the knockdown of TFPI-2 by siRNA induced an increase in TMPRSS4 mRNA expression (Fig.3d,e).
Affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan.