TY - JOUR
T1 - A functional screen identifies miRs that induce radioresistance in glioblastomas
AU - Moskwa, Patryk
AU - Zinn, Pascal O.
AU - Choi, Young Eun
AU - Shukla, Sachet A.
AU - Fendler, Wojciech
AU - Chen, Clark C.
AU - Lu, Jun
AU - Golub, Todd R.
AU - Hjelmeland, Anita
AU - Chowdhury, Dipanjan
N1 - Publisher Copyright:
©2014 American Association for Cancer Research.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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 TGFb signaling. Finally, it is demonstrated that expression of miR1 and miR125a can be induced by TGFb and antagonized by a TGFb 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 TGFb inhibitors in radiotherapy.
AB - 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 TGFb signaling. Finally, it is demonstrated that expression of miR1 and miR125a can be induced by TGFb and antagonized by a TGFb 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 TGFb inhibitors in radiotherapy.
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U2 - 10.1158/1541-7786.MCR-14-0268
DO - 10.1158/1541-7786.MCR-14-0268
M3 - Article
C2 - 25256711
AN - SCOPUS:84919344088
SN - 1541-7786
VL - 12
SP - 1767
EP - 1778
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 12
ER -