Liver regeneration is an important survival process that occurs after liver injury
e.g. viral infection, toxins or hepatectomy. This process involves a variety of specific
cytokines, growth factors and transcription factors. In the liver, hepatocyte nuclear
factors (HNFs) play a central role during liver regeneration. These include the HNF3
transcription factors, also termed forkhead box (Fox) family. Additionally, it has
been shown that Foxa2 (HNF-3β) expression is induced in regenerating mouse livers
after partial hepatectomy as well as in livers from patients with hepatocellular carcinoma
HCC. Furthermore, we have shown that Augmenter of Liver Regeneration (ALR) is significantly
increased in hepatocellular carcinoma. In addition, increased expression levels of
ALR were shown in a Foxa2- transgenic mouse model. The aim of our study was to identify
transciption factors that regulate the expression of ALR. Promoter studies of ALR
revealed potential binding sites for Foxa2, IL-6 RE, CEBP/β, YY1 and HNF-4α. The promoter
activity of ALR was significantly induced over the control after co-transfection of
Foxa2 in HepG2 cells. To verify whether the putative Foxa2 element is capable of binding
Foxa2 protein, Electrophoresis Mobility Shift Assays (EMSA) were performed. Supershift
analysis using α-Foxa2 antibody indicates the specific binding of Foxa2 to ALR promoter.
This binding was inducible when the cells were simultaneously stimulated with IL-6.
This increased binding after Foxa2-transfection was confirmed by elevated ALR protein
levels using Western Blot technique. On the other hand, no binding was observed with
IL-6 RE, CEBP/β and YY1. In conclusion, we demonstrated that Foxa2 enhances the expression
of ALR. We assumed that ALR might be regulated by Foxa2, and this regulation could
be amplified by simultaneously activation using IL-6. Taken together, both IL-6 and
Foxa2 induce the expression of ALR, and Foxa2 is necessary in the IL-6 response of
ALR promoter.
Augmenter of Liver Regeneration - Foxa2 - HCC - Liver regeneration - hepatic transcription
factor
