Tonicity-responsive enhancer binding protein promotes hepatocellular carcinogenesis, recurrence, and metastasis
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- Tonicity-responsive enhancer binding protein promotes hepatocellular carcinogenesis, recurrence, and metastasis
- Jun Ho Lee; Jae Hee Suh; Soo Youn Choi; Hyun Je Kang; Hwan Hee Lee; Byeong Jin Ye; Gap Ryol Lee; Seok Won Jung; Chang Jae Kim; Whaseon Lee-Kwon; Jiyoung Park; Kyungjae Myung; Neung Hwa Park; Hyug Moo Kwon
- GUT, v.29, no.2, pp.492 - 504
- B M J PUBLISHING GROUP
- 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 T umours with surrounding hepatic tissues were
obtained from 296 patients with HCC who received
completion resection. TonEBP expression was analysed
by quantitative reverse transcription–quantitative realtime
PCR (RT -PCR) and immunohfistochemical analyses
of tissue microarrays. Mice with TonEBP haplo
deficiency, and hepatocyte-specific and myeloid-specific
TonEBP deletion were used along with HCC and
hepatocyte cell lines.
Results T onEBP 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 T onEBP 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.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
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