Kaja Blagotinšek Cokan (Author), Žiga Urlep (Author), Gregor Lorbek (Author), Madlen Matz-Soja (Author), Cene Skubic (Author), Martina Perše (Author), Jera Jeruc (Author), Peter Juvan (Author), Tadeja Režen (Author), Damjana Rozman (Author)

Abstract

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.

Keywords

biosinteza holesterola;hepatocelularni karcinom;spolni dimorfizem;cholesterol biosynthesis;hepatocellular carcinoma;sex dimorphism;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL MF - Faculty of Medicine
UDC: 616-006
COBISS: 36485123 Link will open in a new window
ISSN: 2072-6694
Views: 268
Downloads: 93
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Other data

Secondary language: Slovenian
Secondary keywords: biosinteza holesterola;hepatocelularni karcinom;spolni dimorfizem;
Type (COBISS): Article
Pages: str. 1-24
Volume: ǂVol. ǂ12
Issue: ǂiss. ǂ11
Chronology: 2020
DOI: 10.3390/cancers12113302
ID: 14305970