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
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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.
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