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

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

SUBMITTER: Wang F

PROVIDER: S-EPMC4413612 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Wang Fengfei F Remke Marc M Bhat Kruttika K Wong Eric T ET Zhou Shuang S Ramaswamy Vijay V Dubuc Adrian A Fonkem Ekokobe E Salem Saeed S Zhang Hongbing H Hsieh Tze-Chen TC O'Rourke Stephen T ST Wu Lizi L Li David W DW Hawkins Cynthia C Kohane Isaac S IS Wu Joseph M JM Wu Min M Taylor Michael D MD Wu Erxi E

Oncotarget 20150201 5

Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRβ signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRβ and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRβ but not PDGFRα, is involved in PDGFRβ signaling associated with cell proliferation, cell death, and invas ...[more]

PMID: 25576913

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Project description:Medulloblastoma is a malignant pediatric brain tumor. Current treatment following patient stratification into standard and high-risk groups using clinical features has improved survival. However, a subset of patients with standard risk features have unanticipated aggressive disease, underscoring the need for a better understanding of tumor biology and the development of novel treatments. Poor differentiation, a hallmark of medulloblastomas is associated with elevated expression levels of the repressor of neuronal differentiation called repressor element 1-silencing transcription factor (REST). Here, we assessed whether elevated REST expression levels had prognostic significance and whether its pharmacologic manipulation would promote neurogenesis and block tumor cell growth. REST levels in patient tumors were measured by immunohistochemistry and stratified into negative, low/moderate- (+/++/+++), and high-REST (+++++) groups. Kaplan-Meier curves revealed that patients with high-REST tumors had worse overall and event-free survival compared with patients with REST-negative or REST-low tumors. Because histone deacetylases (HDAC) are required for REST-dependent repression of neurogenesis, we evaluated a panel of HDAC inhibitors (HDACI) for their effects on growth and differentiation of established and primary REST-positive cell lines. MS-275, trichostatin-A (TSA), valproic acid (VPA), and suberoylanilide hydroxamic acid (SAHA) upregulated expression of the REST-target neuronal differentiation gene, Syn1, suggesting a potential effect of these HDACIs on REST function. Interestingly, VPA and TSA substantially increased histone acetylation at the REST promoter and activated its transcription, whereas SAHA unexpectedly promoted its proteasomal degradation. A REST-dependent decrease in cell growth was also observed following SAHA treatment. Thus, our studies suggest that HDACIs may have therapeutic potential for patients with REST-positive tumors. This warrants further investigation.

Dataset Information

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

Publications

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

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