Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2016; 22(23): 5342-5352
Published online Jun 21, 2016. doi: 10.3748/wjg.v22.i23.5342
Tumor-specific expression of shVEGF and suicide gene as a novel strategy for esophageal cancer therapy
Ting Liu, Hai-Jun Wu, Yu Liang, Xu-Jun Liang, Hui-Chao Huang, Yan-Zhong Zhao, Qing-Chuan Liao, Ya-Qi Chen, Ai-Min Leng, Wei-Jian Yuan, Gui-Ying Zhang, Jie Peng, Yong-Heng Chen
Ting Liu, Ya-Qi Chen, Ai-Min Leng, Wei-Jian Yuan, Gui-Ying Zhang, Jie Peng, Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Ting Liu, Xu-Jun Liang, Hui-Chao Huang, Yong-Heng Chen, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Hai-Jun Wu, Yu Liang, Department of Oncology Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Yan-Zhong Zhao, Department of Medical Experimental center, the Third Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Qing-Chuan Liao, Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders of Hubei Province, Hubei University of Science and Technology, Xianning 437000, Hubei Province, China
Yong-Heng Chen, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410008, Hunan Province, China
Yong-Heng Chen, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510000, Guangdong Province, China
Author contributions: Liu T and Wu HJ contributed equally to this work; Peng J is the co-corresponding author of this article; Peng J and Chen YH designed the research; Liu T, Wu HJ and Liang Y performed the research; Liu T, Wu HJ, Chen YQ and Peng J wrote the paper; Liang Y, Liang XJ, Huang HC, Zhao YZ, Liao QC, Chen YQ, Leng AM, Yuan WJ and Zhang GY analyzed the data; all authors have seen and approved the final version of the manuscript.
Supported by National Natural Science Foundation of China, No. 81372904, No. 81272971, No. 81272735 and No. 30800518; and Science and Technology Department of Hunan Province, No. 2010CK3013.
Institutional review board statement: The study was reviewed and approved by the XiangYa Hospital Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the XiangYa Hospital.
Conflict-of-interest statement: No conflict of interest exists.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yong-Heng Chen, MD, PhD, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, No. 87 Xiangya Road, Changsha 410008, Hunan Province, China. yonghenc@163.com
Telephone: +86-731-84327608 Fax: +86-731-84327608
Received: December 2, 2015
Peer-review started: December 4, 2015
First decision: December 21, 2015
Revised: April 6, 2016
Accepted: April 20, 2016
Article in press: April 20, 2016
Published online: June 21, 2016
Processing time: 193 Days and 11.3 Hours
Abstract

AIM: To develop a potent and safe gene therapy for esophageal cancer.

METHODS: An expression vector carrying fusion suicide gene (yCDglyTK) and shRNA against vascular endothelial growth factor (VEGF) was constructed and delivered into EC9706 esophageal cancer cells by calcium phosphate nanoparticles (CPNP). To achieve tumor selectivity, expression of the fusion suicide gene was driven by a tumor-specific human telomerase reverse transcriptase (hTERT) promoter. The biologic properties and therapeutic efficiency of the vector, in the presence of prodrug 5-fluorocytosine (5-FC), were evaluated in vitro and in vivo.

RESULTS: Both in vitro and in vivo testing showed that the expression vector was efficiently introduced by CPNP into tumor cells, leading to cellular expression of yCDglyTK and decreased VEGF level. With exposure to 5-FC, it exhibited strong anti-tumor effects against esophageal cancer. Combination of VEGF shRNA with the fusion suicide gene demonstrated strong anti-tumor activity.

CONCLUSION: The shVEGF-hTERT-yCDglyTK/5-FC system provided a novel approach for esophageal cancer-targeted gene therapy.

Keywords: Esophageal cancer; Suicide gene; RNA interference; Vascular endothelial growth factor; Nanoparticles

Core tip: Esophageal cancer is a highly aggressive neoplasm with poor prognosis and low survival rates. In this study, an expression vector carrying a fusion suicide gene (yCDglyTK) and shRNA against vascular endothelial growth factor (VEGF) was constructed and delivered into EC9706 esophageal cancer cells by calcium phosphate nanoparticles (CPNP). To achieve tumor selectivity, the expression of the fusion suicide gene was driven by a tumor-specific human telomerase reverse transcriptase promoter. Our results showed that the novel expression vector was efficiently introduced into EC9706 cells by CPNP, leading to cellular expression of yCDglyTK and decreased VEGF level. With exposure to 5-fluorocytosine, it exhibited strong anti-tumor effects against esophageal cancer both in vitro and in vivo. Combination of VEGF shRNA with the fusion suicide gene demonstrated strong anti-cancer effects. Our study provides a novel approach for esophageal cancer-targeted gene therapy.