A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma

Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRa and PDGFR beta signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRa and PDGFR beta and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFR beta but not PDGFRa, is involved in PDGFR beta signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFR beta and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFR beta 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 PDGFR beta-driven signaling cascade and a potential therapeutic target.