The impact of the transcription factor ChREBP as well as Glycogen and Glycogen associated proteins in experimental and human hepatocarcinogenesis

• Applicant: Dr. Silvia Ribback
• Subject Area: Pathology
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 286541313

This application includes two main projects regarding experimental and human hepatocarcinogenesis:(1) Experimental hepatocarcinogenesis: Clear cell foci (CCF) of glycogen storing hepatocytes are constitutive preneoplastic lesions of hepatocellular carcinoma (HCC) in experimental hepatocarcinogenesis. The main event is the activation of the protooncogenic AKT/mTOR-pathway which induces glycolysis, glycogen storage and de-novo-liogenesis.In two previous mouse models (intraportal pancreatic islet transplantation and hydrodynamic gene transfer), we could substantiate that ChREBP, a glucose-dependent transcription factor mainly stimulating glycolysis and de-novo-lipogenesis, appears to be an essential component of AKT/mTOR mediated cell proliferation and the metabolic switch from a glycogenotic to lipogenic phenotype in those CCF. A knockout of ChREBP delayed and diminished the development of tumors in the liver.We want to confirm these results of the proposed oncogenic function of ChREBP in two further ChREBP-Knockout mouse models of hepatocarcinogenesis A) metabolic carcinogenesis after administration of a high fat diet (HFD) and a modificated choline-deficient high fat diet (CD-HFD) for the induction of steatosis and steatohepatitis, respectively, with subsequent fibrosis/cirrhosis und development of hepatocellular tumors. These models are suitable for the simulation of the frequent human situation of type 2 diabetes mellitus with slowly progressing insulin resistance, non-alcoholic steatohepatitis, fibrosis/cirrhosis and HCC development. B) chemical carcinogenesis after administration of Diethylnitrosamine (DEN), which also well represents human hepatocarcinogesis with the fibrosis/cirrhosis - carcinoma - sequence and reflects the genetic profil of human HCC.For these short- and long-time experiments (4 until 48 weeks) ChREBP-Knockout mice will be compared with C57Bl6/J-wildtype mice and mice with a liver specific ChREBP deletion (Alb-cre, ChREBPflox/flox).(2) Human hepatocarcinogenesis: In previous investigations, we could show, that CCF also often occur in humans in non cirrhotic liver tissue and reveal an activation of the AKT/mTOR-pathway, similar metabolic alterations and an increased proliferative activity and may therefore represent precursor lesions of human HCC as well. After proteomic and microarray analysis we could identify an altered expression of several proteins and genes with relations to glycogen metabolism, especially Starch-binding domain-containing protein 1 (STBD1), and also to proliferation and apoptosis, i.e. USP28 and WDR92/monad. In further in vitro investigations, we want to clarify the function and regulation of these proteins/genes in the context of glycogen metabolism and proliferation in primary human hepatocyte/HCC-cell lines

• DFG Programme: Research Grants