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Hepatology
Original article
Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis
  1. Jun Ho Lee1,
  2. Jae Hee Suh2,
  3. Soo Youn Choi1,
  4. Hyun Je Kang1,
  5. Hwan Hee Lee1,
  6. Byeong Jin Ye1,
  7. Gap Ryol Lee3,
  8. Seok Won Jung4,
  9. Chang Jae Kim1,
  10. Whaseon Lee-Kwon1,
  11. Jiyoung Park1,
  12. Kyungjae Myung1,5,
  13. Neung Hwa Park4,
  14. Hyug Moo Kwon1,5
  1. 1 School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
  2. 2 Department of Pathology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
  3. 3 Department of Life Science, Sogang University, Seoul, Republic of Korea
  4. 4 Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
  5. 5 Center for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea
  1. Correspondence to Professor Neung Hwa Park, Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan 44033, Republic of Korea; nhparkmd{at}gmail.com and Professor Hyug Moo Kwon, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea; hmkwon{at}unist.ac.kr

Abstract

Objectives Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse aetiological agents and wide heterogeneity in individual tumours impede effective and personalised treatment. Tonicity-responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of proinflammatory genes. Although inflammation is intimately associated with the pathogenesis of HCC, the role of TonEBP is unknown. We aimed to identify function of TonEBP in HCC.

Design Tumours with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analysed by quantitative reverse transcription–quantitative real-time PCR (RT-PCR) and immunohfistochemical analyses of tissue microarrays. Mice with TonEBP haplodeficiency, and hepatocyte-specific and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines.

Results TonEBP expression is higher in tumours than in adjacent non-tumour tissues in 92.6% of patients with HCC regardless of aetiology associated. The TonEBP expression in tumours and adjacent non-tumour tissues predicts recurrence, metastasis and death in multivariate analyses. TonEBP drives the expression of cyclo-oxygenase-2 (COX-2) by stimulating the promoter. In mouse models of HCC, three common sites of TonEBP action in response to diverse aetiological agents leading to tumourigenesis and tumour growth were found: cell injury and inflammation, induction by oxidative stress and stimulation of the COX-2 promoter.

Conclusions TonEBP is a key component of the common pathway in tumourigenesis and tumour progression of HCC in response to diverse aetiological insults. TonEBP is involved in multiple steps along the pathway, rendering it an attractive therapeutic target as well as a prognostic biomarker.

  • TonEBP (NFAT5)
  • hepatocellular carcinoma
  • poor prognosis
  • inflammation
  • COX-2

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2017-315348

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    Footnotes

    • Contributors JHL, NHP and HMK conceived, directed and interpreted results and wrote the manuscript. JHL designed, performed and analysed most of the experiments. SYC helped to design and to interpret results and wrote the manuscript. JHS performed histological analysis and performed and analysed tissue array and IHC. NHP and JHS provided human HCC samples. HJK, HHL, BJY, SWJ and CJK contributed to the performance experiments. GRL provided YY1 constructs. KM, WL-K and JP provided intellectual input. NHP and HMK supervised experiments.

    • Funding This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government (Ministry of Science and ICT) (NRF-2011-0020163, NRF-2010-0029621, NRF-2016R1D1A1B03932335, NRF-2012R1A1A2043693, NRF-2017R1E1A1A01074673), Health Technology R&D Project grant of Korea (HI16C1837) and the Institute for Basic Science (IBS-R022-D1-2016) of Korea. This work was also supported by UNIST fund (1.170068.01). JHL was supported by Global PhD Fellowship of Korea (NRF-2014H1A2A1019656).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval This research was approved by the Institutional Review Board at the Ulsan University Hospital (UUH 2015-12-018).

    • Provenance and peer review Not commissioned; externally peer reviewed.