title: ISG15 inhibits IFN-α-resistant liver cancer cell growth.
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.
authors.affiliation: Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China.
authors.forename: Xin-xing
authors.initials: XX
authors.lastname: Wan
authors.forename: Han-chun
authors.initials: HC
authors.lastname: Chen
authors.forename: Md Asaduzzaman
authors.initials: MA
authors.lastname: Khan
authors.forename: Ai-hua
authors.initials: AH
authors.lastname: Xu
authors.forename: Fu-lan
authors.initials: FL
authors.lastname: Yang
authors.forename: Yun-yi
authors.initials: YY
authors.lastname: Zhang
authors.forename: Dian-zheng
authors.initials: DZ
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D016207:Cytokines / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014452:Ubiquitins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C074034:ISG15 protein, human
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