TonEBP Promotes Hepatocellular Carcinoma via Promotion of Inflammation = TonEBP Promotes Hepatocellular Carcinoma via Promotion of Inflammation

다국어 초록 (Multilingual Abstract)

Aims: Tonicity-responsive enhancer binding protein (TonEBP) is a key transcription cofactor in pro-inflammatory activation of macrophages. TonEBP is involved in inflammatory diseases such as rheumatoid arthritisand atherosclerosis. Since hepatic inflammation is required for the development of hepatocellular carcinoma (HCC), we asked whether TonEBP played a role in HCC. Methods: We studied liver section and tissue biopsy from patients with HBV-, HCV-, and non-viral-induced HCC, obtained from the University of Ulsan college of Medicine . Levels of protein expression and gene expression was measured by western blot analysis and qRT-PCR. Mice with whole body haplo-deficiency of TonEBP and their wild type littermates (C57BL6 background) were given injection of DEN at 2-week-old age and fed the high fat diet or normal control diet for 30 weeks. Mice of hepatocyte-specific (Albcre +/- or -/- floxed with TonEBP) or myeloid-specific TonEBP deletion(LysM cre +/- or -/- floxed with TonEBP) and their wild type littermates were injected DEN at 8-week-old age for 48 hrs. Results: Here we report that TonEBP haplo-insufficiency is resistant not only to diethylnitrosamine (DEN)-induced HCC but also to DEN/high fat diet induced HCC, through attenuation of COX-2 expression and inflammation. In hepatocytes, TonEBP interacts with transcription factor YY1 and histone acetyltransferase p300. This interaction promotes inflammatory stimuli-induced COX-2 expression. Interestingly, hepatic tumor shows higher expression of TonEBP than non-tumor liver in mice and HCC patients. This regulation is associated with miR-223 which expression is down-regulated upon HCC development. In addition, its expression was significantly associated with poor survival of HCC patients after resection. Conclusions: TonEBP is a novel transcription cofactor in COX-2 regulation through transcription factor YY1. With this mechanism, TonEBP is an independent determinant of HCC and novel target for HCC diagnosis and treatment.