RAS/MEK-independent gene expression reveals BMP2-related malignant phenotypes in the Nf1-deficient MPNST. Mol Cancer Res 2013 Jun;11(6):616-27
Date
02/21/2013Pubmed ID
23423222DOI
10.1158/1541-7786.MCR-12-0593Scopus ID
2-s2.0-84879300153 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of germline mutations in Nf1 gene as well as sporadically. Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors. However, therapeutic targeting of RAS and MAPK have had limited success in this disease. In this study, we modulated NRAS, mitogen-activated protein/extracellular signal-regulated kinase (MEK)1/2, and neurofibromin levels in MPNST cells and determined gene expression changes to evaluate the regulation of signaling pathways in MPNST cells. Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in MPNST cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway. The BMP2-SMAD1/5/8 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or short hairpin RNA (shRNA) to BMP2 decreased the motility and invasion of NF1-associated MPNST cells. The pathway-specific gene changes provide a greater understanding of the complex role of neurofibromin in MPNST pathology and novel targets for drug discovery.
Author List
Sun D, Haddad R, Kraniak JM, Horne SD, Tainsky MAAuthor
Daochun Sun PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Bone Morphogenetic Protein 2Cell Line, Tumor
Cell Movement
GTP Phosphohydrolases
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Membrane Proteins
Mitogen-Activated Protein Kinase Kinases
Neoplasm Invasiveness
Nerve Sheath Neoplasms
Neurofibromin 1
Phenotype
Phosphorylation
Pyrazoles
Pyrimidines
RNA, Small Interfering
Signal Transduction
Smad Proteins
