Methylation-induced downregulation of TFPI-2 causes TMPRSS4 overexpression and contributes to oncogenesis in a subset of non-small-cell lung carcinoma.

Abstract

We identified transmembrane protease, serine 4 (TMPRSS4) as a putative, druggable target by screening surgically resected samples from 90 Japanese non-small-cell lung cancer (NSCLC) patients using cDNA microarray. TMPRSS4 has two druggable domains and was upregulated in 94.5% of the lung cancer specimens. Interestingly, we found that TMPRSS4 expression was associated with tissue factor pathway inhibitor 2 (TFPI-2) expression in these clinical samples. In contrast to TMPRSS4, TFPI-2 expression was downregulated in NSCLC samples. The in vitro induction of TFPI-2 in lung cancer cell lines decreased the expression of TMPRSS4 mRNA levels. Reporter assay showed that TFPI-2 inhibited transcription of TMPRSS4, although partially. Knockdown of TMPRSS4 reduced the proliferation rate in several lung cancer cell lines. When lung cancer cell lines were treated with 5-aza-2'-deoxycytidine or trichostatin A, their proliferation rate and TMPRSS4 mRNA expression levels were also reduced through the upregulation of TFPI-2 by decreasing its methylation in vitro. The TFPI-2 methylation level in the low TMPRSS4 group appeared to be significantly low in NSCLC samples (P = 0.02). We found a novel molecular mechanism that TFPI-2 negatively regulates cell growth by inhibiting transcription of TMPRSS4. We suggest that TMPRSS4 is upregulated by silencing of TFPI-2 through aberrant DNA methylation and contributes to oncogenesis in NSCLC.

• Authors: Junko Hamamoto, Kenzo Soejima, Katsuhiko Naoki, Hiroyuki Yasuda, Yuichiro Hayashi, Satoshi Yoda, Sohei Nakayama, Ryosuke Satomi, Hideki Terai, Shinnosuke Ikemura, Takashi Sato, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Tomoko Betsuyaku
• Journal: Cancer science (Cancer Sci) Vol. 106 Issue 1 Pg. 34-42 (Jan 2015) ISSN: 1349-7006 [Electronic] England
• PMID: 25414083 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• Glycoproteins
• Membrane Proteins
• tissue-factor-pathway inhibitor 2
• Serine Endopeptidases
• TMPRSS4 protein, human

Topics

• Carcinogenesis (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• DNA Methylation
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Glycoproteins (genetics, metabolism)
• Humans
• Lung Neoplasms (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Serine Endopeptidases (genetics, metabolism)