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

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 - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan.

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Upregulation of TMPRSS4 and downregulation of TFPI-2 in lung cancer samples. (a) Pseudocolor image showing log10 expression ratios to the average expression level of the control lung region of 90 specimens for each of approximately 1700 probes (x-axis) across the 90 specimens (y-axis) tested by microarray. Red indicates upregulation; green indicates downregulation. AC, adenocarcinoma; SCC, squamous cell carcinoma. (b) Average relative mRNA expression levels of TMPRSS4 or TFPI-2 in 90 clinical lung cancer samples. Results are expressed as fold change to the average expression level of non-malignant regions, mean ± SEM. *P < 0.05 compared to non-malignant control. (c) Expression levels of TMPRSS4/β-actin mRNA in lung cancer cell lines were measured by RT-PCR. Relative TMPRSS4 expression mRNA level to β-actin was calculated by the −ΔCt method. Results are expressed as the mean ± SD. (d) Expression levels of TFPI-2/β-actin mRNA in lung cancer cell lines were measured by RT-PCR as in (c). Experiments were carried out in technically triplicate (c, d).
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fig01: Upregulation of TMPRSS4 and downregulation of TFPI-2 in lung cancer samples. (a) Pseudocolor image showing log10 expression ratios to the average expression level of the control lung region of 90 specimens for each of approximately 1700 probes (x-axis) across the 90 specimens (y-axis) tested by microarray. Red indicates upregulation; green indicates downregulation. AC, adenocarcinoma; SCC, squamous cell carcinoma. (b) Average relative mRNA expression levels of TMPRSS4 or TFPI-2 in 90 clinical lung cancer samples. Results are expressed as fold change to the average expression level of non-malignant regions, mean ± SEM. *P < 0.05 compared to non-malignant control. (c) Expression levels of TMPRSS4/β-actin mRNA in lung cancer cell lines were measured by RT-PCR. Relative TMPRSS4 expression mRNA level to β-actin was calculated by the −ΔCt method. Results are expressed as the mean ± SD. (d) Expression levels of TFPI-2/β-actin mRNA in lung cancer cell lines were measured by RT-PCR as in (c). Experiments were carried out in technically triplicate (c, d).

Mentions: We initially carried out mRNA profiling of 90 Japanese NSCLC patients (54 adenocarcinomas [AC], 24 squamous cell carcinomas [SCC], and 12 other lung cancers; patient characteristics are shown in Table S1), and identified 120 genes that were commonly upregulated more than twofold with a ratio P-value <0.001 in >75% of the samples (Fig.1a). With these criteria, approximately 1700 probes had a greater than twofold change, and of these, 163 probes were upregulated. Eliminating overlapping genes and expressed sequence tags, we obtained 120 genes as unique, upregulated genes. Among these 120 genes, 15 genes were found to have druggable domain(s) (Table1), as determined by the Gene Set Annotator (Rosetta Inpharmatics). We prioritized these 15 genes in terms of cancer relevance and unknown mechanism for tumorigenesis. TMPRSS4 overexpression has been reported in various cancers including lung cancer.5,7,23 We also confirmed that TMPRSS4 was overexpressed not only in clinical lung cancer samples but also in several lung cancer cell lines (Fig.1b,c). It is reported that TMRPSS4 promotes tumor growth, invasion, metastasis, and the epithelial–mesenchymal transition process and regulates in vitro cell growth24,25; however, only limited mechanisms for tumorigenesis by TMPRSS4 have been clarified.


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

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 - Cancer Sci. (2014)

Upregulation of TMPRSS4 and downregulation of TFPI-2 in lung cancer samples. (a) Pseudocolor image showing log10 expression ratios to the average expression level of the control lung region of 90 specimens for each of approximately 1700 probes (x-axis) across the 90 specimens (y-axis) tested by microarray. Red indicates upregulation; green indicates downregulation. AC, adenocarcinoma; SCC, squamous cell carcinoma. (b) Average relative mRNA expression levels of TMPRSS4 or TFPI-2 in 90 clinical lung cancer samples. Results are expressed as fold change to the average expression level of non-malignant regions, mean ± SEM. *P < 0.05 compared to non-malignant control. (c) Expression levels of TMPRSS4/β-actin mRNA in lung cancer cell lines were measured by RT-PCR. Relative TMPRSS4 expression mRNA level to β-actin was calculated by the −ΔCt method. Results are expressed as the mean ± SD. (d) Expression levels of TFPI-2/β-actin mRNA in lung cancer cell lines were measured by RT-PCR as in (c). Experiments were carried out in technically triplicate (c, d).
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fig01: Upregulation of TMPRSS4 and downregulation of TFPI-2 in lung cancer samples. (a) Pseudocolor image showing log10 expression ratios to the average expression level of the control lung region of 90 specimens for each of approximately 1700 probes (x-axis) across the 90 specimens (y-axis) tested by microarray. Red indicates upregulation; green indicates downregulation. AC, adenocarcinoma; SCC, squamous cell carcinoma. (b) Average relative mRNA expression levels of TMPRSS4 or TFPI-2 in 90 clinical lung cancer samples. Results are expressed as fold change to the average expression level of non-malignant regions, mean ± SEM. *P < 0.05 compared to non-malignant control. (c) Expression levels of TMPRSS4/β-actin mRNA in lung cancer cell lines were measured by RT-PCR. Relative TMPRSS4 expression mRNA level to β-actin was calculated by the −ΔCt method. Results are expressed as the mean ± SD. (d) Expression levels of TFPI-2/β-actin mRNA in lung cancer cell lines were measured by RT-PCR as in (c). Experiments were carried out in technically triplicate (c, d).
Mentions: We initially carried out mRNA profiling of 90 Japanese NSCLC patients (54 adenocarcinomas [AC], 24 squamous cell carcinomas [SCC], and 12 other lung cancers; patient characteristics are shown in Table S1), and identified 120 genes that were commonly upregulated more than twofold with a ratio P-value <0.001 in >75% of the samples (Fig.1a). With these criteria, approximately 1700 probes had a greater than twofold change, and of these, 163 probes were upregulated. Eliminating overlapping genes and expressed sequence tags, we obtained 120 genes as unique, upregulated genes. Among these 120 genes, 15 genes were found to have druggable domain(s) (Table1), as determined by the Gene Set Annotator (Rosetta Inpharmatics). We prioritized these 15 genes in terms of cancer relevance and unknown mechanism for tumorigenesis. TMPRSS4 overexpression has been reported in various cancers including lung cancer.5,7,23 We also confirmed that TMPRSS4 was overexpressed not only in clinical lung cancer samples but also in several lung cancer cell lines (Fig.1b,c). It is reported that TMRPSS4 promotes tumor growth, invasion, metastasis, and the epithelial–mesenchymal transition process and regulates in vitro cell growth24,25; however, only limited mechanisms for tumorigenesis by TMPRSS4 have been clarified.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus