title: 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.affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Hamamoto
authors.forename: Kenzo
authors.initials: K
authors.lastname: Soejima
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Naoki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoda
authors.forename: Sohei
authors.initials: S
authors.lastname: Nakayama
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Satomi
authors.forename: Hideki
authors.initials: H
authors.lastname: Terai
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Ikemura
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Daisuke
authors.initials: D
authors.lastname: Arai
authors.forename: Kota
authors.initials: K
authors.lastname: Ishioka
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohgino
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
mesh_terms: D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D008565:Membrane Proteins; C021240:tissue-factor-pathway inhibitor 2; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human
keywords: Aberrant DNA methylation; TFPI-2; TMPRSS4; druggable domain; non-small-cell lung carcinoma