Stimulation of Interferon-Stimulated Gene 20 by Thyroid Hormone Enhances Angiogenesis in Liver Cancer

Abstract

Thyroid hormone, 3,3′,5-triiodo-l-thyronine (T3), mediates several physiological processes, including embryonic development, cellular differentiation and cell proliferation, via binding to its nuclear thyroid receptors (TR). Previous microarray and Chromatin immunoprecipitation (ChIP)-on-ChIP analyses have revealed that interferon-stimulated gene 20 kDa (ISG20), an exoribonuclease involved in the antiviral function of interferon, is up-regulated by T3 in HepG2-TR cells. However, the underlying mechanisms of ISG20 action in tumor progression remain unknown to date. Here, we verified induction of ISG20 mRNA and protein expression by T3 in HepG2-TR cells. Based on the ChIP-on-ChIP database, potential thyroid hormone responsive element of the ISG20 promoter region was predicted, and the result confirmed with the ChIP assay. Functional assays showed that forced expression of ISG20 leads to significant promotion of metastasis and angiogenesis, both in vitro and in vivo. Furthermore, the angiogenic-related protein, interleukin-8 (IL-8), was up-regulated through a T3-mediated increase in ISG20, as determined using a human angiogenesis array kit. Induction of IL-8 signaling activated the p-JAK2/p-STAT3 pathway, in turn, leading to promotion of tumor metastasis and angiogenesis. Furthermore, ISG20 overexpression in hepatocellular carcinoma (HCC) specimens was positively correlated with clinical parameters, including vascular invasion, α-fetoprotein and tumor size. Higher ISG20 expression was significantly correlated with poorer recurrence-free survival in HCC patients. Our results collectively indicate higher TR-dependent expression of ISG20 in a subset of HCC, supporting an oncogenic role in HCC progression.

Interferon-stimulated gene 20 kDa protein serum levels and clinical outcome of hepatitis B virus-related liver diseases

“…In addition, ISG20 mRNA expression is up-regulated in HCC tumour compared to adjacent non-tumour tissues. These results, which are compatible with a previous study showing overexpression of ISG20 mRNA in cancerous compared to adjacent tissues [ 13 ], indicate that ISG20 is involved in the development of HBV-related HCC. Differential expression patterns of ISG20 have been shown in the biopsies of various malignancies, including virus-related cancers like glioblastoma and HCC [ 30 ].…”

“…Importantly, our study shows that ISG20 levels are strongly associated with liver function tests in patients with HCC, also indicating that ISG20 may contribute to the pathogenesis of HBV-related HCC. In support of our observations, a previous study has shown that ISG20 overexpression in HCC tumours was correlated with clinical parameters, such as vascular invasion, AFP levels and tumour sizes, as well as with poorer recurrence-free survival in HCC patients [ 13 ]. In addition, ISG20 levels are correlated with AFP levels in LC patients and are different between CHB patients with AFP levels lower and higher than 5 IU/mL as well as between LC patients with AFP levels lower and higher than 25 IU/mL.…”

“…Differential expression patterns of ISG20 have been shown in the biopsies of various malignancies, including virus-related cancers like glioblastoma and HCC [ 30 ]. A recent study has shown that forced expression of ISG20 promotes metastases and angiogenesis via the IL-8/p-JAK2/p-STAT3 signalling pathway, both in liver cancer cell lines and in animal models, suggesting a pro-tumour role of ISG20 [ 13 , 31 ]. However, the precise mechanism by which ISG20 triggers tumours and contributes to cancer development is far from being clear.…”

“…Among the ISG family, the interferon-stimulated gene 20 kDa protein (ISG20), also known as human estrogen regulated transcript 45 (HEM45), is a protein belonging to the DEDDh subgroup of the DEDD exonuclease superfamily, defined by three aspartates (D) and one glutamate (E) [ 9 , 10 ]. ISG20 is encoded by the ISG20 gene located on chromosome 15q26.1 (NC_000015.10), and is induced by both type I and II interferons [ 9 ], double-stranded RNA [ 11 ], estrogen and thyroid hormones [ 12 , 13 ], as well as by virus-encoded transcription factors [ 14 ]. ISG20 displays a strong 3’ to 5’ exonuclease activity, mainly targeting single-stranded rather than double-stranded RNA or single-stranded DNA [ 11 ].…”

Development and validation of an interferon signature predicting prognosis and treatment response for glioblastoma

“…45 ISG20 was reported as a pro-angiogenic factor in liver cancer. 46 On the other hand, IRF9 was termed as a key factor for eliciting the anti-proliferative activity of interferon alpha. 18,47 Additionally, NLRC5 is a critical player in maintaining immune surveillance.…”