TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Nuernberger, Vincent
A1  - Mortoga, Sharif
A1  - Metzendorf, Christoph
A1  - Burkert, Christian
A1  - Ehricke, Katrina
A1  - Knuth, Elisa
A1  - Zimmer, Jenny
A1  - Singer, Stephan
A1  - Nath, Neetika
A1  - Karim, Majedul
A1  - Yasser, Mohd
A1  - Calvisi, Diego F.
A1  - Dombrowski, Frank
A1  - Ribback, Silvia
ED  - Taddei, Maria Letizia
T1  - Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice
JF  - Cells
N2  - Objective: In the rat, the pancreatic islet transplantation model is an established method to induce hepatocellular carcinomas (HCC), due to insulin-mediated metabolic and molecular alterations like increased glycolysis and de novo lipogenesis and the oncogenic AKT/mTOR pathway including upregulation of the transcription factor Carbohydrate-response element-binding protein (ChREBP). ChREBP could therefore represent an essential oncogenic co-factor during hormonally induced hepatocarcinogenesis. Methods: Pancreatic islet transplantation was implemented in diabetic C57Bl/6J (wild type, WT) and ChREBP-knockout (KO) mice for 6 and 12 months. Liver tissue was examined using histology, immunohistochemistry, electron microscopy and Western blot analysis. Finally, we performed NGS-based transcriptome analysis between WT and KO liver tumor tissues. Results: Three hepatocellular carcinomas were detectable after 6 and 12 months in diabetic transplanted WT mice, but only one in a KO mouse after 12 months. Pre-neoplastic clear cell foci (CCF) were also present in liver acini downstream of the islets in WT and KO mice. In KO tumors, glycolysis, de novo lipogenesis and AKT/mTOR signalling were strongly downregulated compared to WT lesions. Extrafocal liver tissue of diabetic, transplanted KO mice revealed less glycogen storage and proliferative activity than WT mice. From transcriptome analysis, we identified a set of transcripts pertaining to metabolic, oncogenic and immunogenic pathways that are differentially expressed between tumors of WT and KO mice. Of 315 metabolism-associated genes, we observed 199 genes that displayed upregulation in the tumor of WT mice, whereas 116 transcripts showed their downregulated expression in KO mice tumor. Conclusions: The pancreatic islet transplantation model is a suitable method to study hormonally induced hepatocarcinogenesis also in mice, allowing combination with gene knockout models. Our data indicate that deletion of ChREBP delays insulin-induced hepatocarcinogenesis, suggesting a combined oncogenic and lipogenic function of ChREBP along AKT/mTOR-mediated proliferation of hepatocytes and induction of hepatocellular carcinoma.
KW  - -
KW  - hepatocarcinogenesis
KW  - hepatocellular carcinoma
KW  - ChREBP
KW  - PI3K/AKT/mTOR
KW  - intraportal pancreatic islet transplantation
KW  - clear cell foci of altered hepatocytes
KW  - preneoplastic foci
Y1  - 2021
UN  - https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-57209
SN  - 2073-4409
SS  - 2073-4409
U6  - https://doi.org/10.3390/cells10102787
DO  - https://doi.org/10.3390/cells10102787
VL  - 10
IS  - 10
PB  - MDPI
ER  -