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Thyroid hormone protects hepatocytes from HBx-induced carcinogenesis by enhancing mitochondrial turnover

Oncogene volume 36, pages 5274–5284 (2017)Cite this article

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Abstract

Infection by hepatitis B virus (HBV) accounts for 50–80% of hepatocellular carcinoma (HCC) development worldwide, in which the HBV-encoded X protein (HBx) has critical role in the induction of carcinogenesis. Several studies have shown that thyroid hormone (TH) suppresses HCC development and protects hepatocytes from HBx-induced damage, thus it is of interest to examine whether TH can protect hepatocytes from HBx-induced carcinogenesis. By treating HBx- transgenic mice with or without TH, we confirmed the protective effects of TH on HBx-induced hepatocarcinogenesis, which was achieved via reduction of reactive oxygen species (ROS) inflicted DNA damage. We further found that TH induced biogenesis of mitochondria (MITO) and autophagy of HBx-targeted MITO simultaneously, consequently leading to suppression of HBx-promoted ROS and carcinogenesis. Using microarray data analysis, this protective effect of TH was found to be mediated via activation of PTEN-induced kinase 1 (PINK1) in hepatocytes. PINK1, in turn, activated and recruited Parkin, an E3 ligase, to ubiquitinate MITO-associated HBx protein and trigger selective mitophagy. The pathological significance of the TH/PINK1 pathway in liver protection was confirmed by the concomitant decrease in expression of both TR and PINK1 in matched HCC tumor tissues and negatively correlated with aggressive progression of cancer and poor prognosis. Our data indicate that TH/PINK1/Parkin pathway has a critical role in protecting hepatocytes from HBx-induced carcinogenesis. Notably, several liver-targeting therapeutic derivatives of TH facilitating prevention or therapy of steatosis have been identified. Furthermore, our proof-of-concept experiments suggest that application of T3 constitutes an effective novel therapeutic or preventive option for HCC. Thus, the utilization of the agonists of TRs could be the meaningful strategy in liver relative diseases, ranging from simple hepatic steatosis to HCC.

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Abbreviations

TH:

thyroid hormone

HBx:

hepatitis B virus X

TR:

thyroid hormone receptor

MITO:

mitochondria

PINK1:

PTEN-induced kinase 1

OXPHOS:

oxidative phosphorylation

ROS:

reactive oxygen species

NRFs:

nuclear respiratory factors

Δψm:

mitochondrial membrane potential

OMM:

outer mitochondrial membrane

HBV:

hepatitis B virus

HCC:

hepatocellular carcinoma

γ-H2AX:

phospho-histone H2AX

OCR:

oxygen consumption rate

PPARs:

peroxisome proliferator-activated receptors

CQ:

chloroquine.

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Acknowledgements

This work was supported by grants from Chang Gung Memorial Hospital, Taoyuan, Taiwan (CRRPD1F0011, CRRPD1F0012) and from the Ministry of Science and Technology of the Republic of China (MOST 103-2320-B-182-018-MY3, 103-2320-B-182-017-MY3, 105-2811-B-182-018, 105-2321-B-182-002-MY3). Accession number of transcript profiling: GEO accession: GSE14520.

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Authors and Affiliations

  1. Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    H-C Chi, S-L Lin, Y-H Lin & K-H Lin

  2. Department of Life Sciences, National Central University, Jhongli, Taiwan

    S-L Chen

  3. Kidney Research Center and Department of Nephrology, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    C-Y Tsai

  4. Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan

    W-Y Chuang

  5. Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Y-H Huang, C-T Yeh & K-H Lin

  6. Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan

    M-M Tsai

  7. Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan

    M-M Tsai

  8. Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan

    K-H Lin

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Chi, HC., Chen, SL., Lin, SL. et al. Thyroid hormone protects hepatocytes from HBx-induced carcinogenesis by enhancing mitochondrial turnover. Oncogene 36, 5274–5284 (2017). https://doi.org/10.1038/onc.2017.136

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