Methylation-induced downregulation of TFPI-2 causes TMPRSS4 overexpression and contributes to oncogenesis in a subset of non-small-cell lung carcinoma.
Bottom Line: Interestingly, we found that TMPRSS4 expression was associated with tissue factor pathway inhibitor 2 (TFPI-2) expression in these clinical samples.Knockdown of TMPRSS4 reduced the proliferation rate in several lung cancer cell lines.We found a novel molecular mechanism that TFPI-2 negatively regulates cell growth by inhibiting transcription of TMPRSS4.
Affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan.Show MeSH
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Mentions: As aberrant methylation of the TFPI-2 gene in various cancers has been reported, we carried out MethyLight analysis of 87 clinical lung cancer samples, with the exception of three samples that were omitted from the analysis because their β-actin methylation status could not be detected. We observed that TFPI-2 was methylated in lung cancer specimens. Because we did not see an apparent correlation between the level of TMPRSS4 mRNA and that of TFPI-2 methylation, we divided the lung cancer patients into two groups based on their TMPRSS4 expression levels. We found that the average expression level of TMPRSS4 in the low TMPRSS4 group (n = 45) was 0.5 (log10 ratios to average expression level of non-malignant region) and in the high TMPRSS4 group (n = 45), it was 1.3 (Fig.5a, P < 0.001). The average methylation level of TFPI-2 in the low TMPRSS4 group was 6.0% in H1975 cells (cells in which TFPI-2 was most methylated among the tested lung cancer cell lines), and in the high TMPRSS4 group it was 18.3% (Fig.5a, P = 0.13). We also found that the methylation level of TFPI-2 was significantly higher in SCC patients compared to those with AC, corresponding to the inverse expression level of mRNA in these histological subtypes (Fig. S1b,c).
Affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan.