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

Cancer Science

Junko Hamamoto²  Kenzo Soejima²  Katsuhiko Naoki²  Hiroyuki Yasuda²  Yuichiro Hayashi¹  Satoshi Yoda²  Sohei Nakayama²  Ryosuke Satomi²  Hideki Terai²  Shinnosuke Ikemura²  Takashi Sato²  Daisuke Arai²  Kota Ishioka²  Keiko Ohgino² 

[1] Department of Pathology, School of Medicine, Keio University, Tokyo, Japan;Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan

关键词: Aberrant DNA methylation;    druggable domain;    non‐small‐cell lung carcinoma;    TFPI‐2;    TMPRSS4;   

DOI  :  10.1111/cas.12569

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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