MicroRNA-92a negatively regulates neurofibromin 2 and inhibits its tumor suppressive function

Inactivation of the tumor suppressor Merlin leads to the development of benign nervous system tumors of neurofibromatosis type 2. Merlin deficiency is also observed in human malignancies including colorectal and lung cancers. Causes of Merlin inactivation include deleterious mutations in the encoding neurofibromin 2 gene (NF2) and aberrant Merlin proteasomal degradation. Here, we show that NF2 is also regulated by microRNAs (miRNAs) through interaction with evolutionarily conserved miRNA response elements (MREs) within its 3-untranslated region (3 UTR). Dual luciferase assays in HCT116 and A549 show downregulation of wild type NF2 by miR-92a via its 3UTR but not NF2-3UTR with mutated MRE. HCT116 cells transfected with miR-92a show significant downregulation of endogenous NF2 mRNA and protein levels, which were rescued by co-transfection of a target protector oligonucelotide specific for the miR-92a binding site within NF2-3UTR. MiR-92a overexpression in HCT116 and A549 resulted in increased migration and proliferation, apoptosis resistance, and altered F-actin organization compared to controls. This study provides functional proof of the unappreciated role of miRNAs in NF2 regulation and tumor progression.