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Mol Cancer Res. 2014 Dec;12(12):1767-78. doi: 10.1158/1541-7786.MCR-14-0268. Epub 2014 Sep 25.

A functional screen identifies miRs that induce radioresistance in glioblastomas.

Author information

1
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Internal Medicine A, Medical University of Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, Germany.
2
Department of Neurosurgery, Baylor College of Medicine and M Anderson Cancer Center, Houston, Texas.
3
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
4
Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
5
Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.
6
Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, San Diego, California.
7
Yale Stem Cell Center and Department of Genetics, Yale University, New Haven, Connecticut.
8
Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Howard Hughes Medical Institute, Chevy Chase, Maryland.
9
Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham, Birmingham, Alabama.
10
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. dipanjan_chowdhury@dfci.harvard.edu.

Abstract

The efficacy of radiotherapy in many tumor types is limited by normal tissue toxicity and by intrinsic or acquired radioresistance. Therefore, it is essential to understand the molecular network responsible for regulating radiosensitivity/resistance. Here, an unbiased functional screen identified four microRNAs (miR1, miR125a, miR150, and miR425) that induce radioresistance. Considering the clinical importance of radiotherapy for patients with glioblastoma, the impact of these miRNAs on glioblastoma radioresistance was investigated. Overexpression of miR1, miR125a, miR150, and/or miR425 in glioblastoma promotes radioresistance through upregulation of the cell-cycle checkpoint response. Conversely, antagonizing with antagomiRs sensitizes glioblastoma cells to irradiation, suggesting their potential as targets for inhibiting therapeutic resistance. Analysis of glioblastoma datasets from The Cancer Genome Atlas (TCGA) revealed that these miRNAs are expressed in glioblastoma patient specimens and correlate with TGFβ signaling. Finally, it is demonstrated that expression of miR1 and miR125a can be induced by TGFβ and antagonized by a TGFβ receptor inhibitor. Together, these results identify and characterize a new role for miR425, miR1, miR125, and miR150 in promoting radioresistance in glioblastomas and provide insight into the therapeutic application of TGFβ inhibitors in radiotherapy.

IMPLICATIONS:

Systematic identification of miRs that cause radioresistance in gliomas is important for uncovering predictive markers for radiotherapy or targets for overcoming radioresistance.

PMID:
25256711
PMCID:
PMC4386891
DOI:
10.1158/1541-7786.MCR-14-0268
[Indexed for MEDLINE]
Free PMC Article
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