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BioMed Research International
Volume 2013 (2013), Article ID 570909, 8 pages
http://dx.doi.org/10.1155/2013/570909
Research Article

ISG15 Inhibits IFN-α-Resistant Liver Cancer Cell Growth

1Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China
2Department of Biochemistry/Molecular Biology, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USA

Received 1 April 2013; Revised 2 July 2013; Accepted 2 July 2013

Academic Editor: John N. Plevris

Copyright © 2013 Xin-xing Wan et al. 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.

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide. Interferon-α (IFN-α) has been widely used in the treatment of HCC, but patients eventually develop resistance. ISG15 ubiquitin-like modifier (ISG15) is a ubiquitin-like protein transcriptionally regulated by IFN-α which shows antivirus and antitumor activities. However, the exact role of ISG15 is unknown. In the present study, we showed that IFN-α significantly induced ISG15 expression but failed to induce HepG2 cell apoptosis, whereas transient overexpression of ISG15 dramatically increased HepG2 cell apoptosis. ISG15 overexpression increased overall protein ubiquitination, which was not observed in cells with IFN-α-induced ISG15 expression, suggesting that IFN-α treatment not only induced the expression of ISG15 but also inhibited ISG15-mediated ubiquitination. The tumor suppressor p53 and p21 proteins are the key regulators of cell survival and death in response to stress signals such as DNA damage. We showed that p53 or p21 is only up regulated in HepG2 cells ectopically expressing ISG15, but not in the presence of IFN-α-induced ISG15. Our results suggest that ISG15 overexpression could be developed into a powerful gene-therapeutic tool for treating IFN-α-resistant HCC.