Abstract 4726: TonEBP promotes hepatocellular carcinoma and is associated with poor prognosis
Authors: Lee Jun Ho , Suh Jae hee , Choi Soo Youn , Kang Hyun Je , Lee Gap Ryol , Lee-Kwon Whaseon , Park Neung Hwa , Kwon Hyug Moo 
Published: July 2017

Carcinogenesis is initiated by genetic changes due to aberrant processing of genetic information. Tumor microenvironment, however, should not be overlooked as cancer risk because they influence the development and progression. Indeed, the role of inflammation has received a lot of attention lately. Specifically, hepatocellular carcinoma (HCC) has been considered as an inflammation-associated tumor like colorectal cancer and lung cancer. In addition, high rate of recurrence is the major feature of HCC, and there is a need to identify novel biomarkers for post-operative prognosis of HCC patients Tonicity-responsive enhancer binding protein (TonEBP), also known as nuclear factor of activated T cell 5 (NFAT5), is a key transcriptional cofactor for the expression of pro-inflammatory genes such as TNF-α, IL-1β, and cyclooxygenase 2 (COX-2). Since chronic hepatic inflammation is essential for hepatocellular carcinogenesis, we asked whether TonEBP plays a role in HCC. To investigate the relevance of TonEBP in HCC development, TonEBP expression in hepatic tumors and their adjacent normal tissues were analyzed from of HCC patients. TonEBP expression was higher in tumors than adjacent normal hepatic tissues in 94% of HCC patients (n = 104). In a mouse model of diethylnitrosamine (DEN)-induced HCC, TonEBP expression was also higher in 100% of the tumors. Downregulation of miR-223 was responsible for the elevated TonEBP expression. miR-223 targeted the 3’-UTR of TonEBP gene and suppressed TonEBP translation. Interestingly, univariate analyses revealed that TonEBP expression in normal tissues adjacent to HCC was significantly associated with tumor size, tumor grade, vascular invasion, viral DNA replication, α-fetoprotein, PIVKA-II, recurrence, metastasis, and death. In addition, Kaplan-Meier estimation and multivariate analyses showed that the TonEBP expression was an independent prognostic marker for recurrence and death in HCC patients. In mice, TonEBP haplo-deficiency reduced both DEN- and DEN/high-fat diet (HFD)-induced HCC in association with lower COX-2 transcription and milder hepatic inflammation. Acute hepatic inflammation induced by DEN or lipopolysaccharide was also reduced in hepatocyte- or myeloid-specific TonEBP knockout mice. TonEBP-mediated activation of hepatic COX-2 promoter was dependent on the transcription factor Yin Yang 1 (YY1). TonEBP interacted with YY1 through the Rel-homology domain of TonEBP and spacer domain of YY1. In aggregate, our data demonstrate that TonEBP-mediated hepatic inflammation is a critical regulator of hepatocarcinogenesis. The miR-223-YY1/TonEBP-COX-2 pathway drives hepatic inflammation and commits the stressed hepatocytes to malignant fate. Thus, TonEBP promotes HCC via COX-2 expression and is a strong post-operative prognosticator of poor outcome in HCC patients.

Citation Format: Jun Ho Lee, Jae hee Suh, Soo Youn Choi, Hyun Je Kang, Gap Ryol Lee, Whaseon Lee-Kwon, Neung Hwa Park, Hyug Moo Kwon. TonEBP promotes hepatocellular carcinoma and is associated with poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4726. doi:10.1158/1538-7445.AM2017-4726