Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer
| Autor: | Damjana Rozman, Martina Perše, Kaja Blagotinšek Cokan, Cene Skubic, Gregor Lorbek, Peter Juvan, Tadeja Režen, Madlen Matz-Soja, Žiga Urlep, Jera Jeruc |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
hepatocelularni karcinom Cancer Research spolni dimorfizem cholesterol biosynthesis hepatocellular carcinoma lanosterol 14α-demethylase (CYP51) sex dimorphism Biology lcsh:RC254-282 Article Transcriptome 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine RAR-related orphan receptor gamma medicine ddc:610 Transcription factor PI3K/AKT/mTOR pathway udc:616-006 Cholesterol medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens digestive system diseases 030104 developmental biology Oncology Nuclear receptor chemistry 030220 oncology & carcinogenesis Hepatocellular carcinoma Cancer research lipids (amino acids peptides and proteins) biosinteza holesterola Liver cancer |
| Zdroj: | Cancers, Vol 12, Iss 3302, p 3302 (2020) Cancers Cancers, vol. 12, no. 11, 3302, 2020. Volume 12 Issue 11 |
| ISSN: | 2072-6694 |
| Popis: | While the role of cholesterol in liver carcinogenesis remains controversial, hepatocellular carcinoma generally prevails in males. Herein, we uncover pathways of female-prevalent progression to hepatocellular carcinoma due to chronic repression of cholesterogenic lanosterol 14&alpha demethylase (CYP51) in hepatocytes. Tumors develop in knock-out mice after year one, with 2:1 prevalence in females. Metabolic and transcription factor networks were deduced from the liver transcriptome data, combined by sterol metabolite and blood parameter analyses, and interpreted with relevance to humans. Female knock-outs show increased plasma cholesterol and HDL, dampened lipid-related transcription factors FXR, LXR&alpha RXR&alpha and importantly, crosstalk between reduced LXR&alpha and activated TGF-&beta signalling, indicating a higher susceptibility to HCC in aging females. PI3K/Akt signalling and ECM-receptor interaction are common pathways that are disturbed by sex-specific altered genes. Additionally, transcription factors (SOX9)2 and PPAR&alpha were recognized as important for female hepatocarcinogenesis, while overexpressed Cd36, a target of nuclear receptor RORC, is a new male-related regulator of ECM-receptor signalling in hepatocarcinogenesis. In conclusion, we uncover the sex-dependent metabolic reprogramming of cholesterol-related pathways that predispose for hepatocarcinogenesis in aging females. This is important in light of increased incidence of liver cancers in post-menopausal women. |
| Databáze: | OpenAIRE |
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