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

Our plain-English summary of 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, by J.H. Cho, A.Y. Oh, S. Park, et al (Molecular Cancer Therapeutics, 2018).

The study

• Authors: J.H. Cho, A.Y. Oh, S. Park, S.M. Kang, M.H. Yoon, T.G. Woo, S.D. Hong, J. Hwang, N.C. Ha, H.Y. Lee, B.J. Park
• Journal: Molecular Cancer Therapeutics
• Published: 2018;17(11):2271-2284
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Neurofibromatosis type 2 (NF2) syndrome is a very rare human genetic disease, and there has been no proper treatment for it until now. In our recent study, it has been reported that the loss of NF2 activates MAPK signaling through reduction of RKIP in a mesothelioma model. Here, we show that loss of NF2 induces reduction of the TGFβ receptor 2 (TβR2) expression, and an overwhelming expression of TGFβ receptor 1 (TβR1) is activated by physical stimuli such as pressure or heavy materials. Activated TβR1 induces the phosphorylation and degradation of RKIP. RKIP reduction consequently results in MAPK activation as well as Snail-mediated p53 suppression and occurrence of EMT in NF2-deficient cells by physical stimuli. Thus, TβR1 kinase inhibitors restore cell differentiation and induce growth suppression in NF2-deficient Schwannoma cell line and MEF. Moreover, TEW7197, a specific TβR1 kinase inhibitor, reduces tumor formation in the NF2-model mouse (Postn-Cre;NF2f/f). Gene expression profiling reveals that TEW7197 treatment induces the expression of lipid metabolism-related gene set, such as NF2-restored cells in HEI-193 (NF2-deficient Schwannoma). Our results indicate that reduction or deletion of TβR2 or NF2 induces the TβR1-mediated oncogenic pathway, and therefore inhibition of the unbalanced TGFβ signaling is a putative strategy for NF2-related cancers (NF2 syndrome and mesothelioma) and TβR2-mutated advanced cancers. Mol Cancer Ther; 17(11); 2271-84. ©2018 AACR.

©2018 American Association for Cancer Research.

In plain English

This was a laboratory study of the tumour suppressor NF2 (Merlin) and TGF-β receptor signalling, using human and mouse cell lines and an NF2 mouse model. Because asbestos use is banned, the authors used silica, together with pressure applied by overlaying cells with a cover glass, as the physical stimulus. In mouse embryonic fibroblasts, deleting NF2 made cells resistant to pressure-induced loss of viability and abolished the pressure-induced rise in p53 and RKIP. Of the cell-surface proteins tested, only TβR1 co-precipitated with silica (and with FeO2). Silica lowered RKIP and NF2 in TβR2-deficient HCT116 cells but not in TβR1-null LNCaP cells, and did not activate Smad or Hippo/YAP readouts. Knocking down NF2 reduced TβR2, and NF2 extended the TβR2 half-life. The TβR1 kinase inhibitor TEW7197 raised RKIP and p53 in the NF2-deficient Schwannoma line HEI-193, the mesothelioma line H28 and HCT116, and reduced tumour formation in Postn-Cre;NF2f/f mice. Microarray showed 1183 genes commonly altered by NF2 transfection and TEW7197, many in lipid metabolism.

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 cell-line and in vivo mouse) experimental study
• Who was studied: Human and mouse cell lines (including NF2-deficient Schwannoma HEI-193, mesothelioma NCI-H28 and NCI-H2452, HCT116, LNCaP, HEK293, A549, ACHN, mouse Schwann cells and MEF) plus Postn-Cre;NF2f/f mice; laboratory study in Korea
• Exposure: Physical stimuli: silica (silicon dioxide) particles used as a replacement for asbestos, FeO2, and pressure from an overlaid cover glass; plus TβR1 kinase inhibitors (TEW7197, SB431542, Alectinib, PF-06463922, Certinib, Crizotinib)
• Main results:
  • In Ubc-Cre-ER;NF2f/f mouse embryonic fibroblasts, removing NF2 with 4-OHT increased viability under pressure, and the pressure-induced p53 and RKIP induction seen in normal MEF did not occur
  • Among E-cadherin, TβR1, TβR2 and Her2/Neu, only TβR1 co-precipitated with silica; FeO2 also co-precipitated with TβR1
  • Silica lowered RKIP and NF2 in TβR2-deficient HCT116 cells but not in TβR1-deleted LNCaP cells
  • Silica did not activate canonical TGF-β (3TP-luciferase, R-Smad phosphorylation/translocation) or the Hippo/YAP CTGF promoter readout
  • Knockdown or knockout of NF2 reduced TβR2 expression, and NF2 lengthened the TβR2 half-life
  • The RKIP T101A mutant (resistant to TβR1-mediated phosphorylation) was not reduced by silica and blocked the NF2 reduction, while the phospho-mimetic T101D mutant had low protein stability
  • TEW7197 dose-dependently induced RKIP and p53 in Schwannoma (HEI-193), mesothelioma (H28) and HCT116 cells; in mesothelioma it acted together with adriamycin on p53 and growth suppression
  • Microarray of HEI-193: TEW7197 altered about 5000 genes and NF2 transfection 4229 genes, with 1183 commonly altered, many grouped as cholesterol biosynthesis or adipose tissue formation
  • In Postn-Cre;NF2f/f mice, PET/CT and histology showed fewer tumours after TEW7197; large dorsal root ganglion tumours seen in vehicle mice were not detected in treated mice
• The authors' conclusion: The authors concluded that loss of NF2 or TβR2 allows TβR1-mediated oncogenic signalling, and that inhibiting this unbalanced TGF-β signalling is a putative strategy for NF2-related cancers, including NF2 syndrome and mesothelioma, and TβR2-mutated cancers
• Limitations the authors state:
  • Asbestos itself could not be used, so silica was substituted as the physical stimulus
  • The authors state the mechanism by which TβR1 recognises silica or heavy material remains unknown
  • Microarray RNA came from HEI-193 with only about 60% transfection yield for NF2

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

Related studies

• NF2 blocks Snail-mediated p53 suppression in mesothelioma — J.H. Cho, S.J. Lee, et al. (2015)
• Multi-walled carbon nanotubes directly induce epithelial-mesenchymal transition in human bronchial epithelial cells via the TGF-β-mediated Akt/GSK-3β/SNAIL-1 signalling pathway — M. Polimeni, G.R. Gulino, et al. (2016)
• Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis — J. Cooper, Q. Xu, et al. (2017)
• Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis — M. Myllärniemi, P. Lindholm, et al. (2008)
• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship — I.M. Shapiro, V.N. Kolev, et al. (2014)

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