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

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

doi:10.1111/cas.12569

Cited by 17 publications

(9 citation statements)

References 29 publications

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“…Hamamoto et al , have shown that TMPRSS4 is upregulated in NSCLC by epigenetic silencing of the tissue factor pathway inhibitor-2 [23]. We now provide evidence showing epigenetic changes that elicit TMPRSS4 promoter hypomethylation in NSCLC.…”

Section: Discussionsupporting

confidence: 63%

Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients

et al. 2016

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which highlights the need of innovative therapeutic options. Although targeted therapies can be successfully used in a subset of patients with lung adenocarcinomas (ADC), they are not appropriate for patients with squamous cell carcinomas (SCC). In addition, there is an unmet need for the identification of prognostic biomarkers that can select patients at risk of relapse in early stages. Here, we have used several cohorts of NSCLC patients to analyze the prognostic value of both protein expression and DNA promoter methylation status of the prometastatic serine protease TMPRSS4. Moreover, expression and promoter methylation was evaluated in a panel of 46 lung cancer cell lines. We have demonstrated that a high TMPRSS4 expression is an independent prognostic factor in SCC. Similarly, aberrant hypomethylation in tumors, which correlates with high TMPRSS4 expression, is an independent prognostic predictor in SCC. The inverse correlation between expression and methylation status was also observed in cell lines. In vitro studies showed that treatment of cells lacking TMPRSS4 expression with a demethylating agent significantly increased TMPRSS4 levels. In conclusion, TMPRSS4 is a novel independent prognostic biomarker regulated by epigenetic changes in SCC and a potential therapeutic target in this tumor type, where targeted therapy is still underdeveloped.

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Section: Discussionsupporting

confidence: 63%

Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients

et al. 2016

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“…1 ). Among these, 5 DEGs were found to be significantly overexpressed in LUAD, and TMPRSS4, a gene contributing to oncogenesis in NSCLC, was selected as our target gene ( 17 , 19 ).…”

Section: Resultsmentioning

confidence: 99%

The upregulation of TMPRSS4, partly ascribed to the downregulation of miR‑125a‑5p, promotes the growth of human lung adenocarcinoma via the NF‑κB signaling pathway

et al. 2018

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In this study, with the aid of microarray technology, transmembrane protease serine 4 (TMPRSS4), a novel member of the serine protease family, was found to be upregulated in the majority of lung adenocarcinoma (LUAD) tissues compared to normal lung tissues. Of note, the clinical significance of TMPRSS4 in LUAD has not yet been reported, at least to the best of our knowledge. Through immunohistochemistry assays, we found that TMPRSS4 was overexpressed in LUAD tissues and that the TMPRSS4 expression level was also proportionally associated with the AJCC clinical stage, T stage and pathological grade. Moreover, a high expression of TMPRSS4 was found to be associated with adverse outcomes and was a significant independent factors predicting a poor prognosis. To elucidate the possible mechanisms responsible for the overexpression of TMPRSS4, we examined at microRNAs (miRNAs or miRs), which are small non-coding RNAs commonly dysregulated in human malignancies and are known to promote carcinogenesis by interacting with other types of RNAs. By means of bioinformatics analysis, a miRNA potentially targeting TMPRSS4 mRNA, namely miR-125a-5p, was selected. Dual luciferase reporter gene assays were then performed to verify the interaction. The results of MTT assays and apoptotic assays revealed that miR-125a-5p significantly inhibited cell growth and enhanced apoptosis, and the silencing of TMPRSS4 had similar effects. Furthermore, we observed that either the overexpression of miR-125a-5p or the silencing of TMPRSS4 prevented the activation of the nuclear factor (NF)-κB signaling pathway. On the whole, our findings illustrate that TMPRSS4 may be a candidate oncogene and may thus serve as a prognostic biomarker for LUAD, and its overexpression may be partly ascribed to the downregulation of miR-125a-5p. The dysregulation of miR-125a-5p and TMPRSS4 affect the biological function of LUAD cells via the NF-κB signaling pathway. The miR-125a-5p/TMPRSS4/NF-κB axis may thus provide novel insight into the pathogenic mechanisms of LUAD and may be used in the development of novel treatment strategies for LUAD.

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“…Because of this broad expression profile in cancer, TMPRSS4 has been a focal point of anti-cancer research in recent years. TMPRSS4 has been shown to promote proliferative processes in lung and thyroid cancer cells, while shRNA targeting of TMPRSS4 transcripts causes reductions in proliferation (Guan et al, 2015; Hamamoto et al, 2015; de Aberasturi et al, 2016). Work using cultured lung cancer cells demonstrated that TMPRSS4 promotes a mesenchymal and invasive phenotype, suggesting a role for epithelial to mesenchymal transition (EMT) (de Aberasturi et al, 2016).…”

Section: Tmprss2 and Tmprss4mentioning

confidence: 99%

“…Several reports have suggested that TMPRSS4 associates with poor prognosis and survival in a variety of different cancers (Cheng et al, 2013a,b; Wu et al, 2014; de Aberasturi and Calvo, 2015; Wang et al, 2015), which may be a result of an increase in the CSCs population, although the factors leading to TMPRSS4 upregulation are still not identified. One recent finding suggests that increased TMPRSS4 in cancer may result from gene-silencing of tissue factor pathway inhibitor 2 (TFPI-2), a consequence of improper methylation (Hamamoto et al, 2015). However, the mechanism which connects TFPI-2 and TMPRSS4 expression remains unknown.…”

Section: Tmprss2 and Tmprss4mentioning

confidence: 99%

Type II transmembrane serine proteases as potential targets for cancer therapy

Murray

Varela

List

2016

Biological Chemistry

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Carcinogenesis is accompanied by increased protein and activity levels of extracellular cell-surface proteases that are capable of modifying the tumor micro-environment by directly cleaving the extracellular matrix, as well as activating growth factors and proinflammatory mediators involved in proliferation and invasion of cancer cells, and recruitment of inflammatory cells. These complex processes ultimately potentiate neoplastic progression leading to local tumor cell invasion, entry into the vasculature, and metastasis to distal sites. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression. In this review the knowledge collected over the past two decades about the molecular mechanisms underlying the pro-cancerous properties of selected TTSPs will be summarized. Furthermore, we will discuss how these insights may facilitate the translation into clinical settings in the future by specifically targeting TTSPs as part of novel cancer treatment regimens.

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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

Cited by 17 publications

References 29 publications

Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients

Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients

The upregulation of TMPRSS4, partly ascribed to the downregulation of miR‑125a‑5p, promotes the growth of human lung adenocarcinoma via the NF‑κB signaling pathway

Type II transmembrane serine proteases as potential targets for cancer therapy

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