Abstract 1519: TonEBP promotes hepatocellular carcinogenesis, recurrence, and metastasis
Authors: Lee Jun Ho , Suh Jae Hee , Choi Soo Youn , Kang Hyun Je , Lee Hwan Hee , Lee-Kwon Whaseon , Park Jiyoung , Myung Kyungjae , Park Neung Hwa , Kwon Hyug Moo 
Published: August 2018

Abstract
Introduction: Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse etiological agents and wide heterogeneity in individual tumors impede effective and personalized treatment. Tonicity-responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of pro-inflammatory 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.
Methods: Tumors with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analyzed by qRT-PCR and immunohistochemical analyses of tissue microarrays. Mice with TonEBP haplo-deficiency, and hepatocyte- and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines.
Results: TonEBP expression is higher in tumors than in adjacent non-tumor tissues in 92.6% of 296 patients with HCC regardless of etiology associated and DEN-induced mouse HCC. Hepatic induction of TonEBP is mediated by a fall in the miR-223 abundance. The TonEBP expression in tumors and adjacent non-tumor tissues predicts recurrence, metastasis, and death in multivariate analyses. Univariate analysis of two layers of patients showed that higher TonEBP expression was significantly associated with bigger tumor, advanced tumor grade, and vascular invasion. TonEBP promotes HCC initiation and growth via oxidative stress and inflammation in various mouse models of HCC. The association between TonEBP and inflammation was confirmed from analysis of the RNA-seq dataset from TCGA. TonEBP-dependent stimulation of tumor growth was dependent on COX-2. TonEBP drives the expression of COX-2 by stimulating the promoter in association with transcription factor YY1 and histone acetyltransferase p300. TonEBP is required for the recruitment of both YY1 and p300 to the promoter in situ. The interaction between TonEBP and YY1 is mediated by RHD and spacer domain. TonEBP deficiency resulted in reduced COX-2 expression leading to reduced production of prostaglandin E2 in various animal models of HCC and acute liver injury. In addition, self-renewal of hepatic cancer stem cells (hCSCs) contributing to recurrence was driven by TonEBP in association with ERCC1. In mouse models of HCC and acute liver injury, three common sites of TonEBP action in response to diverse etiological agents leading to tumorigenesis and tumor progression 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 tumorigenesis and tumor progression of HCC in response to diverse etiological insults. TonEBP is involved in multiple steps along the pathway rendering it an attractive therapeutic target as well as a prognostic biomarker.
Citation Format: Jun Ho Lee, Jae Hee Suh, Soo Youn Choi, Hyun Je Kang, Hwan Hee Lee, Whaseon Lee-Kwon, Jiyoung Park, Kyungjae Myung, Neung Hwa Park, Hyug Moo Kwon. TonEBP promotes hepatocellular carcinogenesis, recurrence, and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1519.