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.