microRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes

By Yunqing Li, F. Guessous, Ying Zhang, C. Dipierro, B. Kefas, E. Johnson, Lukasz Marcinkiewicz, Jinmai Jiang, Yanzhi Yang, Thomas D. Schmittgen and 4 more. Cancer Research, 2009

634 citations recorded by the source corpus.

microRNA-34a (miR-34a) is a transcriptional target of p53 that is down-regulated in some cancer cell lines. We studied the expression, targets and functional effects of miR-34a in brain tumor cells and human gliomas. Transfection of miR-34a down-regulated c-Met in human glioma and medulloblastoma cells and Notch-1, Notch-2 and CDK6 protein expressions in glioma cells. miR-34a expression inhibited c-Met reporter activities in glioma and medulloblastoma cells and Notch-1 and Notch-2 3′UTR reporter activities in glioma cells and stem cells. Analysis of human specimens showed that miR-34a expression is down-regulated in glioblastoma tissues as compared to normal brain and in mutant p53 gliomas as compared to wild-type p53 gliomas. miR-34a levels in human gliomas inversely correlated to c-Met levels measured in the same tumors. Transient transfection of miR-34a into glioma and medulloblastoma cell lines strongly inhibited cell proliferation, cell cycle progression, cell survival and cell invasion, but transfection of miR-34a into human astrocytes did not affect cell survival and cell cycle status. Forced expression of c-Met or Notch1/Notch2 transcripts lacking the 3′UTR sequences partially reversed the effects of miR-34a on cell cycle arrest and cell death in glioma cells and stem cells, respectively. Also, transient expression of miR-34a in glioblastoma cells strongly inhibited in vivo glioma xenograft growth. Together, these findings represent the first comprehensive analysis of the role of miR-34a in gliomas. They show that miR-34a suppresses brain tumor growth by targeting c-Met and Notch. The results also suggest that miR-34a could serve as a potential therapeutic agent for brain tumors.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6917922240800359b1af0520561a8cf4857484c2

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Citations in the corpus

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. (2014, positive): “Interestingly, NOTCH1 represents a miR-34a target (50).”
Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma (2010, background): “pl?acc=MI0000268">miR-34a , which is typically downregulated in glioblastoma, suppresses gliomagenesis by directly targeting the expression of the aforementioned oncoproteins MET and CDK6, along with Notch receptor 1and Notch receptor 2, which seem to have crucial roles in glioma stem cell survival ”
MicroRNAs in development and disease. (2011, background): “Meanwhile, miR-34a (365) and miR-326 (294) are also downregulated and result in an increase in their common target Notch-1, which is known to enhance the expression of EGFR (496).”
Identification of miR-34a as a potent inhibitor of prostate cancer progenitor cells and metastasis by directly repressing CD44 (2011, positive): “Cyclin D1, CDK4 and 6, E2F3, N-Myc, c-MET and BCL-2 have been reported to be direct targets of miR-34”