Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice
Abstract
:1. Background
1.1. Preneoplastic and Neoplastic Hepatocellular Lesions in Rodent Models and Humans
1.2. Role of Carbohydrate-Response Element-Binding Protein in Hepatocellular Metabolism and Carcinogenesis
2. Methods
2.1. Immunohistochemistry
2.2. Morphologic and Proliferation Kinetic Investigations
2.3. Glycogen Quantification (Automated PAS-Quantification)
2.4. Ultrastructural Analysis
2.5. RNA Extraction, Quality Control and RNA-seq Transcriptomic Data Analysis
2.6. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)
2.7. Statistical Analysis
3. Results
3.1. Hormonally Induced Hepatocarcinogenesis Leads to CCF of Altered Hepatocytes
3.1.1. ChREBP Is Associated with Distinct Morphological Alterations
3.1.2. Proliferative Activity
3.2. CCF Signature Leads to Hepatocellular Adenomas (HCAs) and Carcinomas (HCCs)
3.2.1. HCAs and HCCs Are Associated with Distinct Morphological Alterations
3.2.2. Immunohistochemical Expression Patterns of Glycolytic, Lipogenic and Molecular Pathways
3.3. Glycogen Storage in Unaltered Liver Tissue
3.4. Proliferative Activity of Unaltered Liver Tissue
3.5. Blood Glucose Level, Body Weight, and Serum ALT and AST Levels
3.6. Transcriptional Profiling of Liver Tissues (Tumor and Extrafocal Liver Tissue) to Characterize Prominent Dysregulated Genes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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6 Months | 12 Months | |||||||
---|---|---|---|---|---|---|---|---|
Transplantation | Control | Transplantation | Control | |||||
Diabetic | Nondiabetic | Diabetic | Nondiabetic | Diabetic | Nondiabetic | Diabetic | Nondiabetic | |
Wildtype C57Bl/6J | n = 36 | n = 20 | n = 20 | n = 19 | n = 33 | n = 19 | n = 13 | n = 20 |
ChREBP-knockout | n = 18 | n = 19 | n = 18 | n = 20 | n = 12 | n = 19 | n = 13 | n = 21 |
Experimental Groups | 6 Months (Mean ± S.E.M. (n)) | 12 Months (Mean ± S.E.M. (n)) |
---|---|---|
WT diabetic transplanted | 8.76 ± 0.90% (20) 1 | 10.63 ± 1.77% (20) 2 |
KO diabetic transplanted | 5.16 ± 1.04% (9) 1 | 2.24 ± 0.61% (9) 2 |
WT transplanted | 1.35 ± 0.27% (10) | 1.49 ± 0.43% (10) |
KO transplanted | 6.10 ± 2.51% (10) | 3.89 ± 2.33% (10) |
WT diabetic | 6.11 ± 2.18% (6) | 2.57 ± 0.93% (9) |
KO diabetic | 2.11 ± 0.60% (9) | 4.20 ± 1.31% (8) |
WT non-diabetic | 1.54 ± 0.33% (10) | 1.03 ± 0.21% (10) |
KO non-diabetic | 2.21 ± 0.87% (10) | 1.69 ± 0.47% (15) |
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Nuernberger, V.; Mortoga, S.; Metzendorf, C.; Burkert, C.; Ehricke, K.; Knuth, E.; Zimmer, J.; Singer, S.; Nath, N.; Karim, M.; et al. Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice. Cells 2021, 10, 2787. https://doi.org/10.3390/cells10102787
Nuernberger V, Mortoga S, Metzendorf C, Burkert C, Ehricke K, Knuth E, Zimmer J, Singer S, Nath N, Karim M, et al. Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice. Cells. 2021; 10(10):2787. https://doi.org/10.3390/cells10102787
Chicago/Turabian StyleNuernberger, Vincent, Sharif Mortoga, Christoph Metzendorf, Christian Burkert, Katrina Ehricke, Elisa Knuth, Jenny Zimmer, Stephan Singer, Neetika Nath, Majedul Karim, and et al. 2021. "Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice" Cells 10, no. 10: 2787. https://doi.org/10.3390/cells10102787