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Cancer upregulated gene 2, a novel oncogene, confers resistance to oncolytic vesicular stomatitis virus through STAT1-OASL2 signaling

Cancer Gene Therapy volume 20, pages 125–132 (2013)Cite this article

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Abstract

We have recently found a novel oncogene, named cancer upregulated gene 2 (CUG2), which activates Ras and mitogen-activated protein kinases (MAPKs), including ERK, JNK and p38 MAPK. Because activation of these signaling pathways has previously been shown to enhance cancer cell susceptibility to oncolysis by certain viruses, we examined whether vesicular stomatitis virus (VSV) could function as a potential therapeutic agent by efficiently inducing cytolysis in cells transformed by CUG2. Unexpectedly, NIH3T3 cells stably expressing CUG2 (NIH-CUG2) were resistant to VSV because of the activation of signal transducers and activators of transcription 1 (STAT1). The result was supported by evidence showing that suppression of STAT1 with short interference RNA (siRNA) renders cells susceptible to VSV. Furthermore, 2′–5′ oligoadenylate synthetase-like (OASL) 2 was the most affected by STAT1 expression level among anti-viral proteins and furthermore suppression of OASL2 mRNA level caused NIH-CUG2 cells to succumb to VSV as seen in NIH-CUG2 cells treated with STAT1 siRNA. In addition, Colon26L5 carcinoma cells stably expressing CUG2 (Colon26L5-CUG2) exhibited resistance to VSV, whereas Colon26L5 stably expressing a control vector yielded to VSV infection. Moreover, Colon26L5-CUG2 cells stably suppressing STAT1 succumbed to VSV infection, resulting in apoptosis. Taken together, we propose that VSV treatment combined with the selective regulation of genes such as STAT1 and OASL2 will improve therapeutic outcomes for CUG2-overexpressing tumors.

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Acknowledgements

This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1120140) and the World Class University Program (R31-2008-000-20004-0) through the National Research Foundation funded by the Korean government.

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Authors and Affiliations

  1. Department of Cogno-Mechatronics Engineering, WCU, Pusan National University, Busan, Republic of Korea

    W Malilas, R Srisuttee, W Boonying, I-R Cho & Y-H Chung

  2. Department of Functional Genomics, Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea

    S S Koh

  3. School of Biological Sciences, Ulsan University, Ulsan, Republic of Korea

    C-S Jeong

  4. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada

    R N Johnston

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  1. W Malilas
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Correspondence to Y-H Chung.

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Malilas, W., Koh, S., Srisuttee, R. et al. Cancer upregulated gene 2, a novel oncogene, confers resistance to oncolytic vesicular stomatitis virus through STAT1-OASL2 signaling. Cancer Gene Ther 20, 125–132 (2013). https://doi.org/10.1038/cgt.2012.96

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