Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China.
Biomed Res Int. 2013;2013:570909. doi: 10.1155/2013/570909. Epub 2013 Aug 20.
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.
肝细胞癌 (HCC) 是全球最常见的肿瘤之一。干扰素-α (IFN-α) 已广泛用于 HCC 的治疗，但患者最终会产生耐药性。ISG15 泛素样修饰物 (ISG15) 是一种由 IFN-α 转录调控的泛素样蛋白，具有抗病毒和抗肿瘤活性。然而，ISG15 的确切作用尚不清楚。在本研究中，我们表明 IFN-α 显著诱导 ISG15 表达，但未能诱导 HepG2 细胞凋亡，而 ISG15 的瞬时过表达则显著增加了 HepG2 细胞凋亡。ISG15 过表达增加了总蛋白泛素化，但在 IFN-α诱导的 ISG15 表达细胞中未观察到，这表明 IFN-α 治疗不仅诱导了 ISG15 的表达，而且抑制了 ISG15 介导的泛素化。肿瘤抑制因子 p53 和 p21 蛋白是细胞对 DNA 损伤等应激信号存活和死亡的关键调节因子。我们表明，p53 或 p21 仅在 HepG2 细胞中异位表达 ISG15 时上调，而在 IFN-α诱导的 ISG15 存在时则不上调。我们的结果表明，过表达 ISG15 可以开发成治疗 IFN-α 耐药性 HCC 的强大基因治疗工具。
