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

Syuan Ling Lin, Sheng Ming Wu, I. Hsiao Chung, Yang Hsiang Lin, Ching Ying Chen, Hsiang Cheng Chi, Tzu Kang Lin, Chau Ting Yeh, Kwang Huei Lin

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)57-68
Number of pages12
JournalNeoplasia (United States)
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

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Liver Neoplasms
Thyroid Hormones
Interferons
Chromatin Immunoprecipitation
Genes
Hepatocellular Carcinoma
Thyroid Gland
Interleukin-8
Exoribonucleases
Angiogenic Proteins
Cell Proliferation
Thyronines
Fetal Proteins
Physiological Phenomena
Neoplasm Metastasis
Neoplasms
Cytoplasmic and Nuclear Receptors
Genetic Promoter Regions
Embryonic Development
Antiviral Agents

ASJC Scopus subject areas

  • Cancer Research

Cite this

Stimulation of Interferon-Stimulated Gene 20 by Thyroid Hormone Enhances Angiogenesis in Liver Cancer. / Lin, Syuan Ling; Wu, Sheng Ming; Chung, I. Hsiao; Lin, Yang Hsiang; Chen, Ching Ying; Chi, Hsiang Cheng; Lin, Tzu Kang; Yeh, Chau Ting; Lin, Kwang Huei.

In: Neoplasia (United States), Vol. 20, No. 1, 01.01.2018, p. 57-68.

Research output: Contribution to journalArticle

Lin, Syuan Ling ; Wu, Sheng Ming ; Chung, I. Hsiao ; Lin, Yang Hsiang ; Chen, Ching Ying ; Chi, Hsiang Cheng ; Lin, Tzu Kang ; Yeh, Chau Ting ; Lin, Kwang Huei. / Stimulation of Interferon-Stimulated Gene 20 by Thyroid Hormone Enhances Angiogenesis in Liver Cancer. In: Neoplasia (United States). 2018 ; Vol. 20, No. 1. pp. 57-68.
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AU - Lin, Syuan Ling

AU - Wu, Sheng Ming

AU - Chung, I. Hsiao

AU - Lin, Yang Hsiang

AU - Chen, Ching Ying

AU - Chi, Hsiang Cheng

AU - Lin, Tzu Kang

AU - Yeh, Chau Ting

AU - Lin, Kwang Huei

PY - 2018/1/1

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AB - 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.

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