| First Author | Wu J | Year | 2016 |
| Journal | Cell Rep | Volume | 14 |
| Issue | 8 | Pages | 1979-90 |
| PubMed ID | 26904939 | Mgi Jnum | J:270438 |
| Mgi Id | MGI:6274200 | Doi | 10.1016/j.celrep.2016.01.074 |
| Citation | Wu J, et al. (2016) Insertional Mutagenesis Identifies a STAT3/Arid1b/beta-catenin Pathway Driving Neurofibroma Initiation. Cell Rep 14(8):1979-90 |
| abstractText | 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/beta-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 beta-catenin activity. beta-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and beta-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3beta and the SWI/SNF gene Arid1b to increase beta-catenin. Knockdown of Arid1b or Gsk3beta 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/beta-catenin pathway inhibitors in neurofibroma therapeutic trials. |
