ncRNA basic information
ncRNA ID:
MI0000268
ncRNA Database:
miRBase
ncRNA Name:
miR-34a
ncRNA Type:
miRNA
ncRNA Expression:
up-regulated
ncRNA Method:
RT-PCR
ncRNA Target Gene:
MAGE-A2,MAGE-A3,MAGE-A6,and MAGE-A12
ncRNA Pathway:
p53 signaling pathway
Evidence (ncRNA-drug):
validated
drug basic information
Drug ID:
DB00515 (APRD00359)
Drug Name:
Cisplatin
Drug Method:
In the study, 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 3 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.
Drug Response:
sensitive
Cancer basic information
Cancer:
medulloblastoma
Tissue/Cell:
cell line (R262, UW228, UW426, and R300 )
Other information
Title:
miR-34a confers chemosensitivity through modulation of MAGE-A and p53 in medulloblastoma.
Journal:
Neuro Oncol
Published:
2011
PubMed ID:
21177782