Loss Of Nf2 Induces Tgf Beta Receptor 1-Mediated Noncanonical And Oncogenic Tgf Beta Signaling: Implication Of The Therapeutic Effect Of Tgf Beta Receptor 1 Inhibitor On Nf2 Syndrome

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 TGF beta receptor 2 (T beta R2) expression, and an overwhelming expression of TGF beta receptor 1 (T beta R1) is activated by physical stimuli such as pressure or heavy materials. Activated T beta R1 induces the phosphorylation and degradation of RKIP. RKIP reduction consequently results in MAPK activation as well as Snailmediated p53 suppression and occurrence of EMT in NF2-deficient cells by physical stimuli. Thus, T beta R1 kinase inhibitors restore cell differentiation and induce growth suppression in NF2-deficient Schwannoma cell line and MEF. Moreover, TEW7197, a specific T beta R1 kinase inhibitor, reduces tumor formation in the NF2-model mouse (Postn-Cre;NF2(f/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 T beta R2 or NF2 induces the T beta R1-mediated oncogenic pathway, and therefore inhibition of the unbalanced TGF beta signaling is a putative strategy for NF2-related cancers (NF2 syndrome and mesothelioma) and T beta R2-mutated advanced cancers. (C) 2018 AACR.