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

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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. TMPRSS4 was up-regulated by silencing of TFPI-2 through aberrant DNA methylation and contributed to oncogenesis in NSCLC. It will provide novel therapeutic potential for NSCLC patients by suppressing TMPRSS4 through inhibiting TMPRSS4 directly or indirectly through demethylating TFPI-2.

Original languageEnglish
Pages (from-to)34-42
Number of pages9
JournalCancer science
Volume106
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1

Keywords

  • Aberrant DNA methylation
  • Druggable domain
  • Non-small-cell lung carcinoma
  • TFPI-2
  • TMPRSS4

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Hamamoto, J., Soejima, K., Naoki, K., Yasuda, H., Hayashi, Y., Yoda, S., Nakayama, S., Satomi, R., Terai, H., Ikemura, S., Sato, T., Arai, D., Ishioka, K., Ohgino, K., & Betsuyaku, T. (2015). Methylation-induced downregulation of TFPI-2 causes TMPRSS4 overexpression and contributes to oncogenesis in a subset of non-small-cell lung carcinoma. Cancer science, 106(1), 34-42. https://doi.org/10.1111/cas.12569