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Int. J. Mol. Sci. 2015, 16(6), 12243-12260; doi:10.3390/ijms160612243

Human Papillomavirus E6/E7-Specific siRNA Potentiates the Effect of Radiotherapy for Cervical Cancer in Vitro and in Vivo

1
Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
2
ABION Inc. R&D Center, 9th Floor, HanWha Biz Metro Bldg, 242 Digital-ro, Guro-gu, Seoul 152-733, Korea
3
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
4
Department of Radiology, Kangwon National University Hospital, Kangwon-do 200-722, Korea
5
Department of Radiation Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, Korea
6
The Center for Anti-cancer CDx, N-Bio, Seoul National University, Seoul 151-742, Korea
7
Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul 151-742, Korea
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Michael R. Ladomery
Received: 10 March 2015 / Revised: 2 May 2015 / Accepted: 12 May 2015 / Published: 29 May 2015
(This article belongs to the Special Issue RNA Interference)
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Abstract

The functional inactivation of TP53 and Rb tumor suppressor proteins by the HPV-derived E6 and E7 oncoproteins is likely an important step in cervical carcinogenesis. We have previously shown siRNA technology to selectively silence both E6/E7 oncogenes and demonstrated that the synthetic siRNAs could specifically block its expression in HPV-positive cervical cancer cells. Herein, we investigated the potentiality of E6/E7 siRNA candidates as radiosensitizers of radiotherapy for the human cervical carcinomas. HeLa and SiHa cells were transfected with HPV E6/E7 siRNA; the combined cytotoxic effect of E6/E7 siRNA and radiation was assessed by using the cell viability assay, flow cytometric analysis and the senescence-associated β-galactosidase (SA-β-Gal) assay. In addition, we also investigated the effect of combined therapy with irradiation and E6/E7 siRNA intravenous injection in an in vivo xenograft model. Combination therapy with siRNA and irradiation efficiently retarded tumor growth in established tumors of human cervical cancer cell xenografted mice. In addition, the chemically-modified HPV16 and 18 E6/E7 pooled siRNA in combination with irradiation strongly inhibited the growth of cervical cancer cells. Our results indicated that simultaneous inhibition of HPV E6/E7 oncogene expression with radiotherapy can promote potent antitumor activity and radiosensitizing activity in human cervical carcinomas. View Full-Text
Keywords: E6; E7; siRNA; Concurrent Chemoradiation therapy (CCRT); radiotherapy; radiosensitizer; cervical cancer E6; E7; siRNA; Concurrent Chemoradiation therapy (CCRT); radiotherapy; radiosensitizer; cervical cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Jung, H.S.; Rajasekaran, N.; Song, S.Y.; Kim, Y.D.; Hong, S.; Choi, H.J.; Kim, Y.S.; Choi, J.-S.; Choi, Y.-L.; Shin, Y.K. Human Papillomavirus E6/E7-Specific siRNA Potentiates the Effect of Radiotherapy for Cervical Cancer in Vitro and in Vivo. Int. J. Mol. Sci. 2015, 16, 12243-12260.

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