RT Journal Article
SR Electronic
T1 Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 347
OP 358
DO 10.1136/gutjnl-2017-315348
VO 68
IS 2
A1 Jun Ho Lee
A1 Jae Hee Suh
A1 Soo Youn Choi
A1 Hyun Je Kang
A1 Hwan Hee Lee
A1 Byeong Jin Ye
A1 Gap Ryol Lee
A1 Seok Won Jung
A1 Chang Jae Kim
A1 Whaseon Lee-Kwon
A1 Jiyoung Park
A1 Kyungjae Myung
A1 Neung Hwa Park
A1 Hyug Moo Kwon
YR 2019
UL http://gut.bmj.com/content/68/2/347.abstract
AB 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.