[ RadSafe ] Disabling cancer cells' defenses against radiation
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Thu Mar 15 22:58:01 CDT 2012
Disabling cancer cells' defenses against radiation
Woodruff Health Sciences Center | March 13, 2012
RNAi-Mediated Targeting of Noncoding and Coding Sequences in DNA Repair Gene
Messages Efficiently Radiosensitizes Human Tumor Cells
1. Zhiming Zheng1,2,
2. Wooi Loon Ng2,
3. Xiangming Zhang2,
4. Jeffrey J. Olson3,
5. Chunhai Hao4,
6. Walter J. Curran2, and
7. Ya Wang2
+ Author Affiliations
1. Authors' Affiliations:1Department of Neurosurgery, Provincial Hospital
affiliated to Shandong University, Shandong University, Jinan, China; and
Departments of 2Radiation Oncology, 3Neurosurgery, and 4Pathology and Laboratory
Medicine, Emory University School of Medicine, Winship Cancer Institute of Emory
University, Atlanta, Georgia
1. Corresponding Author:
Ya Wang, Department of Radiation Oncology, Emory University School of Medicine,
1365 Clifton Rd, NE, Atlanta, GA 30322. Phone: 404-778-1832; Fax: 404-778-1750;
E-mail: ywang94 at emory.edu
Human tumor cell death during radiotherapy is caused mainly by ionizing
radiation (IR)–induced DNA double-strand breaks (DSB), which are repaired by
either homologous recombination repair (HRR) or nonhomologous end-joining
(NHEJ). Although siRNA-mediated knockdown of DNA DSB repair genes can sensitize
tumor cells to IR, this approach is limited by inefficiencies of gene silencing.
In this study, we show that combining an artificial miRNA (amiR) engineered to
target 3′-untranslated regions of XRCC2 (an HRR factor) or XRCC4 (an NHEJ
factor) along with an siRNA to target the gene coding region can improve
silencing efficiencies to achieve more robust radiosensitization than a single
approach alone. Mechanistically, the combinatorial knockdown decreased targeted
gene expression through both a reduction in mRNA stability and a blockade to
mRNA translation. Together, our findings establish a general method of gene
silencing that is more efficient and particularly suited for suppressing genes
that are difficult to downregulate by amiR- or siRNA-based methods alone. Cancer
Res; 72(5); 1221–8. ©2012 AACR.
* Received August 16, 2011.
* Revision received December 20, 2011.
* Accepted December 26, 2011.
* ©2012 American Association for Cancer Research.
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