1. Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation.
- Author
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Wu J, Keng VW, Patmore DM, Kendall JJ, Patel AV, Jousma E, Jessen WJ, Choi K, Tschida BR, Silverstein KA, Fan D, Schwartz EB, Fuchs JR, Zou Y, Kim MO, Dombi E, Levy DE, Huang G, Cancelas JA, Stemmer-Rachamimov AO, Spinner RJ, Largaespada DA, and Ratner N
- Subjects
- Animals, Carcinogenesis metabolism, Carcinogenesis pathology, DNA Helicases genetics, DNA Helicases metabolism, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins metabolism, Disease Models, Animal, Female, Glycogen Synthase Kinase 3 beta antagonists & inhibitors, Glycogen Synthase Kinase 3 beta genetics, Glycogen Synthase Kinase 3 beta metabolism, Histones genetics, Histones metabolism, Humans, Mice, Mice, Nude, Mutagenesis, Insertional, N-Terminal Acetyltransferase A antagonists & inhibitors, N-Terminal Acetyltransferase A metabolism, Neoplasm Transplantation, Neural Stem Cells metabolism, Neural Stem Cells pathology, Neurofibromatosis 1 metabolism, Neurofibromatosis 1 pathology, Neurofibromin 1 genetics, Neurofibromin 1 metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Peripheral Nervous System Neoplasms metabolism, Peripheral Nervous System Neoplasms pathology, Phosphorylation, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor metabolism, Schwann Cells metabolism, Schwann Cells pathology, Signal Transduction, Transcription Factors genetics, Transcription Factors metabolism, beta Catenin metabolism, Carcinogenesis genetics, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic, N-Terminal Acetyltransferase A genetics, Neurofibromatosis 1 genetics, Peripheral Nervous System Neoplasms genetics, STAT3 Transcription Factor genetics, beta Catenin genetics
- Abstract
To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b to increase β-catenin. Knockdown of Arid1b or Gsk3β in Stat3(fl/fl);Nf1(fl/fl);DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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