NF2 blocks Snail-mediated p53 suppression in mesothelioma

Our plain-English summary of NF2 blocks Snail-mediated p53 suppression in mesothelioma, by J.H. Cho, S.J. Lee, A.Y. Oh, et al (Oncotarget, 2015).

The study

• Authors: J.H. Cho, S.J. Lee, A.Y. Oh, M.H. Yoon, T.G. Woo, B.J. Park
• Journal: Oncotarget
• Published: 2015;6(12):10073-85
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Although asbestos causes malignant pleural mesothelioma (MPM), rising from lung mesothelium, the molecular mechanism has not been suggested until now. Extremely low mutation rate in classical tumor suppressor genes (such as p53 and pRb) and oncogenes (including Ras or myc) indicates that there would be MPM-specific carcinogenesis pathway. To address this, we treated silica to mimic mesothelioma carcinogenesis in mesothelioma and non-small cell lung cancer cell lines (NSCLC). Treatment of silica induced p-Erk and Snail through RKIP reduction. In addition, p53 and E-cadherin were decreased by silica-treatment. Elimination of Snail restored p53 expression. We found that NF2 (frequently deleted in MPM) inhibited Snail-mediated p53 suppression and was stabilized by RKIP. Importantly, GN25, an inhibitor of p53-Snail interaction, induced p53 and apoptosis. These results indicate that MPM can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail. Thus, the p53-Snail binding inhibitor such as GN25 is a drug candidate for MPM.

In plain English

This was a laboratory study of human cell lines, carried out at Pusan National University. The authors wanted to understand how malignant pleural mesothelioma develops. They stated that restrictions prevented them from using asbestos, so they exposed cells to silica (silicon dioxide) instead. They used two mesothelioma cell lines, H28 (sarcomatoid) and H2452 (epithelial), plus several lung cancer and non-cancerous lung cell lines. In lung cancer cells, silica lowered a protein called RKIP in a dose-dependent way and raised a protein called Snail; it also lowered RKIP in non-cancerous lung cells. RKIP was very low in H28 cells. In H28, removing Snail or adding a protein called NF2 increased the tumor-suppressor protein p53. In a separate test with A549 lung cancer cell extracts, NF2 blocked Snail from binding p53. An experimental compound, GN25, raised p53 and lowered cell viability in H28 and A549 cells, but did not raise p53 in H2452. The authors proposed that silica or asbestos retained in the lung may promote tumors by lowering RKIP, and suggested GN25 as a possible treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) experiment on cultured human cell lines
• Who was studied: Two human malignant pleural mesothelioma cell lines (H28, sarcomatoid; H2452, epithelial), plus non-small cell lung cancer lines (including A549), small cell lung cancer lines, non-cancerous lung cell lines (WI26, L132) and some other cell lines; no people or animals
• Exposure: Silica (silicon dioxide, bought from a chemical supplier), used in place of asbestos, given at 10 µg/ml in some experiments; asbestos was not used. The cells were also treated with the experimental compound GN25.
• Main results:
  • In the mesothelioma cell lines, silica-induced p-Erk (an activated growth-signal protein) did not fall at later times, and silica did not change how fast the mesothelioma cells grew
  • Silica reduced RKIP in non-small cell lung cancer cell lines in a dose-dependent manner
  • Silica also reduced RKIP in non-transformed (non-cancerous) lung cells
  • RKIP was very low in the H28 mesothelioma cell line
  • Silica increased Snail, and removing Snail increased p53 in H28 cells
  • Adding NF2 to H28 cells increased p53 in the cell nucleus
  • In a binding test using whole-cell extracts from A549 lung cancer cells (not H28), NF2 blocked the interaction between Snail and p53
  • GN25 increased p53 in H28 but not in H2452, and decreased cell viability in H28 and A549 cells
• The authors' conclusion: The authors concluded that silica or asbestos retained in the lung may promote tumors in human pleural mesothelioma through reduction of RKIP, which leads to loss of NF2, a rise in Snail and suppression of p53. They suggested that inhibitors of Snail-p53 binding such as GN25 would be useful for treatment.
• Limitations the authors state:
  • Asbestos could not be used; silica was used instead
  • The authors do not know how silica reduces RKIP
  • The finding that RKIP raised p53 in A549 cells should be interpreted carefully, because A549 cells carry oncogenic K-Ras
  • The proposed pathway did not apply to the H2452 mesothelioma cell line, which the authors suggest arose by a different mechanism

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Mesothelium, Tumor Suppressor Gene, Carcinogenesis, Non-Small Cell Lung Cancer, Apoptosis.

Related studies

• Loss of NF2 Induces TGFβ Receptor 1-mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome — J.H. Cho, A.Y. Oh, et al. (2018)
• Expression of snail, twist, and Zeb1 in malignant mesothelioma — H. Merikallio, P. Pääkkö, et al. (2013)
• Snail expression is associated with a poor prognosis in malignant pleural mesotheliomas — M. Kobayashi, C.L. Huang, et al. (2013)
• The p53/mouse double minute 2 homolog complex deregulation in merlin-deficient tumours — S. Ammoun, M.C. Schmid, et al. (2015)
• Establishment and characterization of CRISPR/Cas9-mediated NF2-/- human mesothelial cell line: Molecular insight into fibroblast growth factor receptor 2 in malignant pleural mesothelioma — M. Wahiduzzaman, S. Karnan, et al. (2019)
• P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma — C. Costa, P. Indovina, et al. (2020)

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