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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.

cancer science

Methylation‐induced downregulation of   TFPI ‐2  causes   TMPRSS 4  overexpression and contributes to oncogenesis in a subset of non‐small‐cell lung carcinoma