Methylation‐induced downregulation of TFPI‐2 causes TMPRSS4 overexpression and contributes to oncogenesis in a subset of non‐small‐cell lung carcinoma. Issue 1 (8th December 2014)

• Record Type: Journal Article
• Authors: Hamamoto, Junko; Soejima, Kenzo; Naoki, Katsuhiko; Yasuda, Hiroyuki; Hayashi, Yuichiro; Yoda, Satoshi; Nakayama, Sohei; Satomi, Ryosuke; Terai, Hideki; Ikemura, Shinnosuke; Sato, Takashi; Arai, Daisuke; Ishioka, Kota; Ohgino, Keiko; Betsuyaku, Tomoko
• Is Part Of: Cancer science. Volume 106:Issue 1(2015:Jan.)
• Page Start: 34
• Page End: 42
• Publication Date: 2014-12-08
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12569
• Languages: English
• ISSNs: 1347-9032

Abstract

<abstract abstract-type="main" id="cas12569-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>We identified transmembrane protease<italic>, </italic> serine 4 (<italic>TMPRSS4</italic>) as a putative, druggable target by screening surgically resected samples from 90 Japanese non‐small‐cell lung cancer (NSCLC) patients using cDNA microarray. <italic>TMPRSS4</italic> has two druggable domains and was upregulated in 94.5% of the lung cancer specimens. Interestingly, we found that <italic>TMPRSS4</italic> expression was associated with tissue factor pathway inhibitor 2 (<italic>TFPI‐2</italic>) expression in these clinical samples. In contrast to <italic>TMPRSS4, TFPI‐2</italic> expression was downregulated in NSCLC samples. The <italic>in vitro</italic> induction of <italic>TFPI‐2</italic> in lung cancer cell lines decreased the expression of <italic>TMPRSS4 </italic>mRNA levels. Reporter assay showed that <italic>TFPI‐2</italic> inhibited transcription of <italic>TMPRSS4</italic>, although partially. Knockdown of <italic>TMPRSS4</italic> 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 <italic>TMPRSS4 </italic>mRNA expression levels were also reduced through the upregulation of <italic>TFPI‐2</italic> by decreasing its methylation <italic>in vitro</italic>. The <italic>TFPI‐2</italic> methylation level in the low <italic>TMPRSS4</italic> group appeared to be significantly low in NSCLC samples (<italic>P</italic> = 0.02). We found a novel molecular mechanism that <italic>TFPI‐2</italic> negatively regulates cell growth by inhibiting transcription of <italic>TMPRSS4</italic>. We suggest that <italic>TMPRSS4</italic> is upregulated by silencing of <italic>TFPI‐2</italic> through aberrant DNA methylation and contributes to oncogenesis in NSCLC.</p> </abstract>