RAS/MEK-independent gene expression reveals BMP2-related malignant phenotypes in the Nf1-deficient MPNST.

Abstract

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.

• Authors: Daochun Sun, Ramsi Haddad, Janice M Kraniak, Steven D Horne, Michael A Tainsky
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 6 Pg. 616-27 (Jun 2013) ISSN: 1557-3125 [Electronic] United States
• PMID: 23423222 (Publication Type: Journal Article)
• Copyright: ©2013 AACR.

Chemical References

• Bone Morphogenetic Protein 2
• LDN 193189
• Membrane Proteins
• Neurofibromin 1
• Pyrazoles
• Pyrimidines
• RNA, Small Interfering
• Smad Proteins
• Mitogen-Activated Protein Kinase Kinases
• GTP Phosphohydrolases
• NRAS protein, human

Topics

• Bone Morphogenetic Protein 2 (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• GTP Phosphohydrolases (metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Membrane Proteins (metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Neoplasm Invasiveness
• Nerve Sheath Neoplasms (enzymology, genetics, pathology)
• Neurofibromin 1 (deficiency, metabolism)
• Phenotype
• Phosphorylation (drug effects)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• RNA, Small Interfering (metabolism)
• Signal Transduction (drug effects, genetics)
• Smad Proteins (metabolism)