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Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice

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 upregulatio...

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Autores principales: Nuernberger, Vincent, Mortoga, Sharif, Metzendorf, Christoph, Burkert, Christian, Ehricke, Katrina, Knuth, Elisa, Zimmer, Jenny, Singer, Stephan, Nath, Neetika, Karim, Majedul, Yasser, Mohd, Calvisi, Diego F., Dombrowski, Frank, Ribback, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534692/
https://www.ncbi.nlm.nih.gov/pubmed/34685767
http://dx.doi.org/10.3390/cells10102787
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author Nuernberger, Vincent
Mortoga, Sharif
Metzendorf, Christoph
Burkert, Christian
Ehricke, Katrina
Knuth, Elisa
Zimmer, Jenny
Singer, Stephan
Nath, Neetika
Karim, Majedul
Yasser, Mohd
Calvisi, Diego F.
Dombrowski, Frank
Ribback, Silvia
author_facet Nuernberger, Vincent
Mortoga, Sharif
Metzendorf, Christoph
Burkert, Christian
Ehricke, Katrina
Knuth, Elisa
Zimmer, Jenny
Singer, Stephan
Nath, Neetika
Karim, Majedul
Yasser, Mohd
Calvisi, Diego F.
Dombrowski, Frank
Ribback, Silvia
author_sort Nuernberger, Vincent
collection PubMed
description 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.
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spelling pubmed-85346922021-10-23 Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice Nuernberger, Vincent Mortoga, Sharif Metzendorf, Christoph Burkert, Christian Ehricke, Katrina Knuth, Elisa Zimmer, Jenny Singer, Stephan Nath, Neetika Karim, Majedul Yasser, Mohd Calvisi, Diego F. Dombrowski, Frank Ribback, Silvia Cells Article 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. MDPI 2021-10-18 /pmc/articles/PMC8534692/ /pubmed/34685767 http://dx.doi.org/10.3390/cells10102787 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nuernberger, Vincent
Mortoga, Sharif
Metzendorf, Christoph
Burkert, Christian
Ehricke, Katrina
Knuth, Elisa
Zimmer, Jenny
Singer, Stephan
Nath, Neetika
Karim, Majedul
Yasser, Mohd
Calvisi, Diego F.
Dombrowski, Frank
Ribback, Silvia
Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice
title Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice
title_full Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice
title_fullStr Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice
title_full_unstemmed Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice
title_short Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice
title_sort hormonally induced hepatocellular carcinoma in diabetic wild type and carbohydrate responsive element binding protein knockout mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534692/
https://www.ncbi.nlm.nih.gov/pubmed/34685767
http://dx.doi.org/10.3390/cells10102787
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