20.500.12556/RUL-134459 Chronic disruption of the late cholesterol synthesis leads to female-prevalent liver cancer 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 14α-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, LXRα:RXRα, and importantly, crosstalk between reduced LXRαand activated TGF-βsignalling, 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 PPARα 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. cholesterol biosynthesis hepatocellular carcinoma sex dimorphism lanosterol 14α-demethylase (CYP51) biosinteza holesterola hepatocelularni karcinom spolni dimorfizem true false true Angleški jezik Slovenski jezik Članek v reviji 2022-01-17 08:35:33 2022-01-17 08:35:42 2023-03-20 15:49:06 0000-00-00 00:00:00 2020 0 0 24 str. iss. 11, art. 3302 Vol. 12 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-006 2072-6694 10.3390/cancers12113302 36485123 RAZ_Blagotinsek_Cokan_Kaja_2020.pdf RAZ_Blagotinsek_Cokan_Kaja_2020.pdf 1 B07C6D8925E5A145E45BB91D53936F3A 0a896c3c5be05fb1d8bf283515204ac7dca5528fe2e8fdc835c9befee948925a 2499534d-7768-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=152921 https://www.mdpi.com/2072-6694/12/11/3302 1 e3615f23-7767-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=152920 Medicinska fakulteta 0 0 0