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本帖最后由 StephenW 于 2018-2-3 14:13 编辑
Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis
Jun Ho Lee1, Jae Hee Suh2, Soo Youn Choi1, Hyun Je Kang1, Hwan Hee Lee1, Byeong Jin Ye1, Gap Ryol Lee3, Seok Won Jung4, Chang Jae Kim1, Whaseon Lee-Kwon1, Jiyoung Park1, Kyungjae Myung1,5, Neung Hwa Park4, Hyug Moo Kwon1,5
Author affiliations
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
Department of Pathology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
Department of Life Science, Sogang University, Seoul, Republic of Korea
Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
Center for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea
Correspondence to Professor Neung Hwa Park, Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan 44033, Republic of Korea; [email protected] and Professor Hyug Moo Kwon, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea; [email protected]
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.
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/
http://dx.doi.org/10.1136/gutjnl-2017-315348
Significance of this study
What is already known on this subject?
Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. HCC is widely heterogeneous and diverse imposing formidable challenges to effective treatment and personalised therapy.
Tonicity-responsive enhancer-binding protein (TonEBP) is a critical regulator in many inflammatory diseases such as rheumatoid arthritis and atherosclerosis. While inflammation is intimately implicated in the pathogenesis of HCC, the role of TonEBP is unknown.
What are the new findings?
TonEBP is involved at multiple steps of the common pathway of HCC development and tumour progression: cell injury, induction by oxidative stress and inflammation.
TonEBP stimulated hepatic inflammation including prostaglandin E2 production which contributes to tumour growth and progression.
Expression of TonEBP is elevated in tumours in more than 90% of patients with HCC regardless of aetiology associated.
In patients with HCC who received resection, higher hepatic TonEBP expression is associated with recurrence, metastasis and survival in multivariate analyses.
How might it impact on clinical practice in the foreseeable future?Examination of TonEBP expression in hepatic tissues from patients who received resection of HCC would provide the patients with valuable prognostic information regarding recurrence and metastasis. TonEBP is an attractive target for therapeutic agents to prevent recurrence and metastasis as well as tumourigenesis.
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发表于 2018-2-3 13:52