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.

Jung-Hyun Cho,Ah-Young Oh,Min-Ho Yoon,Nam-Chul Ha,Jihwan Hwang,Bum-Joon Park,So-Mi Kang,Ho-Young Lee,Soyoung Park,Tae-Gyun Woo,Shin-Deok Hong

doi:10.1158/1535-7163.mct-17-1210

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.

Highlights

NF2 (Neurofibromatosis type 2) syndrome is a very rare genetic disorder, where patients are afflicted by Schwannoma in the peripheral nervous system [1]
Mouse schwann cells derived from NF2flox mice [14] were subjected to in vitro Cre-mediated deletion and cells were transduced with pMSCV-hygro retroviral rescue constructs encoding either full-length Merlin isoform 1 (MSchw-wild-type mouse (WT)), the truncated version that was encoded by the SKYmutant allele (MSchw-SKY), or the empty vector (MSchw-KO)
ACHN cells (NF2-mutated kidney cancer cell line; 28) were resistant to physical stimulus (Supplementary Fig. S1C), and HCT116 was partially resistant to physical stimulation [29]

Summary

Introduction

NF2 (Neurofibromatosis type 2) syndrome is a very rare genetic disorder, where patients are afflicted by Schwannoma (benign tumor of Schwann cell) in the peripheral nervous system [1]. Loss of hearing is common feature of NF2 syndrome, due to presence of tumor in the vestibular nervous system. Tumors are detected in the spinal ganglion in patients with NF2 [2]. Genetic alteration of NF2 is revealed a loss of the NF2/Merlin [2]. NF2/Merlin functions as a linker between the cytoskeleton and membrane [3, 4]. It is suggested to be a negative regulator of the Hippo/YAP pathway [5], Ras signaling cascade, and mTORC2 [6]. According to previous literatures, it is clear that NF2/Merlin is an important tumor

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Results

Conclusion