Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRalpha and PDGFRbeta signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRalpha and PDGFRbeta and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRbeta but not PDGFRalpha, is involved in PDGFRbeta signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFRbeta and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFRbeta and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients. Our study may resolve the controversy on the role of PDGFRs in MB and unveils JAG2 as a key downstream effector of a PDGFRbeta-driven signaling cascade and a potential therapeutic target.
Wang, FengfeiRemke, MarcBhat, KruttikaWong, Eric TZhou, ShuangRamaswamy, VijayDubuc, AdrianFonkem, EkokobeSalem, SaeedZhang, HongbingHsieh, Tze-ChenO'Rourke, Stephen TWu, LiziLi, David WHawkins, CynthiaKohane, Isaac SWu, Joseph MWu, MinTaylor, Michael DWu, ErxiengP20 RR020151/RR/NCRR NIH HHS/P20GM103505/GM/NIGMS NIH HHS/R01 DE023641/DE/NIDCR NIH HHS/R01 EY018380/EY/NEI NIH HHS/R01CA148699/CA/NCI NIH HHS/R01CA159859/CA/NCI NIH HHS/R01DE023641/DE/NIDCR NIH HHS/Canadian Institutes of Health Research/CanadaResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't2015/01/13 06:00Oncotarget. 2015 Feb 20;6(5):2709-24.