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ISG15 inhibits IFN-α-resistant liver cancer cell growth
Xin-xing Wan1, Han-chun Chen, Md Asaduzzaman Khan
1Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China.
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.
Insights
Interferon-alfa (IFN-α) resistance in liver cancer (HCC) may be overcome by ISG15 ubiquitin-like modifier (ISG15) gene therapy. Overexpressing ISG15, not IFN-α, induces cancer cell death and upregulates tumor suppressors.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Hepatocellular carcinoma (HCC) is a major global cancer.
- Interferon-alfa (IFN-α) is a standard HCC treatment but often fails due to resistance.
- ISG15 ubiquitin-like modifier (ISG15) is IFN-α-regulated and has antitumor potential, but its role in HCC is unclear.
Purpose of the Study:
- To investigate the role of ISG15 in HCC, particularly in IFN-α-resistant cells.
- To compare the effects of IFN-α-induced ISG15 expression versus ectopic ISG15 overexpression on HCC cells.
- To explore ISG15's potential as a therapeutic agent for IFN-α-resistant HCC.
Main Methods:
- HepG2 cells were treated with IFN-α to induce ISG15 expression.
- ISG15 was ectopically overexpressed in HepG2 cells.
- Cell apoptosis, protein ubiquitination, and levels of p53 and p21 were assessed.
Main Results:
- IFN-α induced ISG15 expression but did not cause HepG2 cell apoptosis.
- Ectopic ISG15 overexpression significantly increased HepG2 cell apoptosis.
- ISG15 overexpression, unlike IFN-α-induced ISG15, enhanced overall protein ubiquitination and upregulated p53 and p21.
Conclusions:
- IFN-α treatment may inhibit ISG15's tumor-suppressive functions.
- Ectopic ISG15 overexpression demonstrates potent anti-HCC activity by promoting apoptosis and upregulating tumor suppressors.
- ISG15 gene therapy holds promise for treating IFN-α-resistant HCC.
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