Journal
NEURO-ONCOLOGY
Volume 13, Issue 2, Pages 165-175Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/noq179
Keywords
chemosensitivity; MAGE-A; medulloblastoma; miR-34a; p53; positive feedback mechanism
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Funding
- US National Institutes of Health [R01-CA109467, P30-HD018655]
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Recent studies have established miR-34a as a key effector of the p53 signaling pathway and have implicated its role in multiple cancer types. Here, we establish that miR-34a induces apoptosis, G2 arrest, and senescence in medulloblastoma and renders these cells more sensitive to chemotherapeutic agents. These effects are mediated in part by the direct post-transcriptional repression of the oncogenic MAGE-A gene family. We demonstrate that miR-34a directly targets the 31 untranslated regions of MAGE-A genes and decreases MAGE-A protein levels. This decrease in MAGE-A results in a concomitant increase in p53 and its associated transcriptional targets, p21/WAF1/CIP1 and, importantly, miR-34a. This establishes a positive feedback mechanism where miR-34a is not only induced by p53 but increases p53 mRNA and protein levels through the modulation of MAGE-A genes. Additionally, the forced expression of miR-34a or the knockdown of MAGE-A genes by small interfering RNA similarly sensitizes medulloblastoma cells to several classes of chemotherapeutic agents, including mitomycin C and cisplatin. Finally, the analysis of mRNA and micro-RNA transcriptional profiles of a series of primary medulloblastomas identifies a subset of tumors with low miR-34a expression and correspondingly high MAGE-A expression, suggesting the coordinate regulation of these genes. Our work establishes a role for miR-34a in modulating responsiveness to chemotherapy in medulloblastoma and presents a novel positive feedback mechanism involving miR-34a and p53, via direct targeting of MAGE-A.
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