Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with poor prognosis. IFN-stimulated genes 15 (ISG15) is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. However, the role of ISG15 in HCC remains unclear. In this study, we investigated the function of ISG15 during HCC progression and related mechanism using clinicopathological data, cell line and xenograft model. Our results indicated that ISG15 is highly expressed in HCC tissues and multiple HCC cell lines. ISG15 expression is significantly associated with the differentiation grade, metastatic of tumor and survival of HCC patients. However, the expression of ISG15 is not affected by HBV infection. ISG15 promotes the proliferation and migration of hepatocarcinoma cells through maintaining Survivin protein stabilization via sequestering XIAP from interacting with Survivin. Knowing down ISG15 with SiRNA inhibited the xenografted tumor growth and prolonged the lifespan of tumor-bearing mice. All these results support that ISG15 high expression is an intrinsic feature for HCC and a trigger for tumorigenesis and metastasis. ISG15 may be a prognostic biomarker and the inhibition of ISG15 could provide a therapeutic advantage for HCC patients over-expressing ISG15.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common solid neoplasm and the leading cause of cancer-related death in the world with 55% occurring in China [1,2,3]
We determined whether IFN-stimulated genes 15 (ISG15) www.impactjournals.com/oncotarget overexpressed in HCC specimens compared to nontumor counterparts
ISG15 is a type I interferon regulated gene that is induced by viral infection through the JAK/STAT signaling pathway [29, 30]
Summary
Hepatocellular carcinoma (HCC) is the sixth most common solid neoplasm and the leading cause of cancer-related death in the world with 55% occurring in China [1,2,3]. According to a recent report from the International Agency for Research on Cancer, HCC has become the second most common cause of cancerrelated death and accounts for 9.1% (0.8 million) of the global cancer-related deaths in 2012 [4]. Despite advance in the treatment of HCC, there is currently no curative option for this life-threatening disease and the overall 5-year survival is about 40% for patients treated with major hepatectomy [5]. Chronic hepatitis B virus (HBV) infection accounts for 52% of the causes of HCC, followed by chronic infection with hepatitis C virus and alcoholic liver disease [6]. HBV is a well-known predominant etiologic risk factor and its carriers have a 100-fold relative risk for developing HCC with an annual incidence rate of 2–6% in cirrhotic patients [7]. Sustained inflammation caused by chronic HBV infection is involved in hepatocarcinogenesis, and plays critical roles in the recurrence and metastasis of HCC after www.impactjournals.com/oncotarget
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