Original Article

Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

Wen Lei, Hong-bin Liu, Shi-bing Wang, Xiu-mei Zhou, Shui-di Zheng, Ke-ni Guo, Bu-yun Ma, Yu-long Xia, Wen-song Tan, Xin-yuan Liu, Yi-gang Wang
DOI: 10.1038/aps.2012.196


Wen LEI1, #, Hong-bin LIU1, #, Shi-bing WANG1, Xiu-mei ZHOU1, Shui-di ZHENG1, Ke-ni GUO1, Bu-yun MA1, Yu-long XIA1, Wen-song TAN2, Xin-yuan LIU1, 3, Yi-gang WANG1, 2, *

1Xinyuan Institute of Medicine and Biotechnology, College of Biological Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China; 2State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; 3State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Aim: The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer, and frequently inactivated in primary non-small cell lung cancer (NSCLC). In this study, we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer, and the mechanisms underlying the antitumor actions.
Methods: The recombinant virus Ad·sp-E1A(∆24)-TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·sp-E1A(∆24) vector, which contained the survivin promoter and a 24 bp deletion within E1A. The antitumor effects of Ad·sp-E1A(∆24)-TSLC1 were evaluated in NCI-H460, A549, and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5, as well as in A549 xenograft model in nude mice. Cell viability was assessed using MTT assay. The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses. The tumor tissues from the xenograft models were examined using H&E staining, IHC, TUNEL, and TEM analyses.

Results: Infection of A549 lung cancer cells with Ad·sp-E1A(∆24)-TSLC1 induced high level expression of TSLC1. Furthermore, the Ad·sp-E1A(∆24)-TSLC1 virus dose-dependently suppressed the viability of NCI-H460, A549, and H1299 lung cancer cells, and did not affect MRC-5 normal fibroblast cells. Infection of NCI-H460, A549, and H1299 lung cancer cells with Ad·sp-E1A(∆24)-TSLC1 induced apoptosis, and increased activation of caspase-8, caspase-3 and PARP. In A549 xenograft model in nude mice, intratumoral injection of Ad·sp-E1A(∆24)-TSLC1 significantly suppressed the tumor volume, and increased the survival rate (from less than 15% to 87.5% at d 60). Histological studies showed that injection of Ad·sp-E1A(∆24)-TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues.

Conclusion: The oncolytic adenovirus Ad·sp-E1A(∆24)-TSLC1 exhibits specific antitumor effects, and is a promising agent for the treatment of lung cancer.

Keywords: lung cancer; tumor suppressor in lung cancer-1; oncolytic adenovirus; survivin; apoptosis; caspase signaling pathway; tumor xenograft model

This work was supported by the National Natural Science Foundation of China (No 81272687), the Hi-Tech Research Development Program of China (863 Program, No 2012AA020806), the Open Funding Project of the State Key Laboratory of Bioreactor Engineering and Zhejiang Sci-Tech University Study Start-up grants (1016834-Y and 1016845-Y).
# These authors contributed equally to this paper.
* To whom correspondence should be addressed.
E-mail wangyigang43@163.com
Received 2012-07-28 Accepted 2012-12-20

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