부산대학교 도서관

Aims: HNF4-alpha expression is associated with tumor suppression in hepatocellular carcinoma (HCC). However, the molecules involved in its signaling pathway remain elucidative. Therefore, the aim of this study was to identify the downstream of HNF4-alpha during tumor progression in HCC. Methods: HNF4-alpha expression was investigated by western blot and immunohistochemistry (IHC) analyses in HCC cell lines and HCC tissues, respectively. Colony forming ability and tumorigenicity were examined in vitro and in mouse model system. Further, I assessed FoxH1 expression during the progression of HCC cells and examined its functional significance by performing in vitro cell experiments and using in vivo animal models. Results: HNF4-alpha expression inhibited tumorigenicity of SH-J1-luc cells and its knockdown enhanced tumorigenicity of Alenxander cells, in vitro and in vivo. Protein-binding activity of differentially expressed transcription factors (TFs) was confirmed by Western Blot and Luciferase Reporter Gene Assay. FoxH1 were rapidly decreased upon HNF4-alpha expression in the nuclear of the HCC cell lines. In addition, ectopic overexpression of FoxH1 enhanced tumor cell growth and proliferation in liver cancer cells, whereas FoxH1 silencing reduced cell growth ability in vitro and in vivo. HNF4-alpha suppresses the β-catenine activation by inhibition of FoxH1 expression. Conclusions: HNF4-alpha suppresses hepatocarcinogenesis through inhibition of FoxH1 -mediated β-catenine activation. Therefore, this downstream signaling pathway may be a potential therapeutic target in HCC.