Identification of transcriptional mechanisms downstream of nf1 gene defeciency in malignant peripheral nerve sheath tumors

摘要

Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of mutations in the neurofibromatosis type I gene (Nf1) as well as sporadically. Plexiform neurofibromas in NF1 patients have a significant risk of developing into MPNSTs leading to increased morbidity and mortality from this syndrome. Surgery is the primary intervention but it is not always effective due to the tendency of MPNSTs to infiltrate the surrounding tissue or grow in an inoperable location. Neurofibromin, the protein coded by the Nf1 gene, functions as a GTPase activating protein (GAP) whose mutation leads to constitutive activation of RAS and mitogen-activated protein kinase (MAPK) signaling in NF1 patientsf tumors. However, therapeutic targeting of RAS and MAPK have had limited success (Kalamarides, et al., 2012).In this study, we modulated NRAS, MEK1/2 and neurofibromin levels in MPNST cell lines and determined the global gene expression changes that were associated with each experimental condition. Furthermore, gene expression changes due to neurofibromin deficiency but independent of NRAS and MEK1/2 regulation were characterized for the first time in MPNST cell lines, with a focus on bone morphogenetic protein 2 (Bmp2). Experimental evidence indicated that the BMP2-SMAD1/5 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or shRNA to BMP2 decreased the motility and invasion of NF1-associated MPNST cells in vitro.The stratification of gene changes according to pathway responses has provided a clarification of one mechanism within the complex effects of neurofibromin in MPNST pathology and some novel targets for future therapeutic intervention.