Chronic disruption of the late cholesterol synthesis leads to female-prevalent liver cancer

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

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.

• Language: English
• Keywords: cholesterol biosynthesis, hepatocellular carcinoma, sex dimorphism, lanosterol 14α-demethylase (CYP51)
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 24 str.
• Numbering: Vol. 12, iss. 11, art. 3302
• PID: 20.500.12556/RUL-134459
• UDC: 616-006
• ISSN on article: 2072-6694
• DOI: 10.3390/cancers12113302
• COBISS.SI-ID: 36485123
• Publication date in RUL: 17.01.2022

Record is a part of a journal

• Title: Cancers
• Shortened title: Cancers
• Publisher: MDPI
• ISSN: 2072-6694
• COBISS.SI-ID: 517914137

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 09.11.2020

Secondary language

• Language: Slovenian
• Keywords: biosinteza holesterola, hepatocelularni karcinom, spolni dimorfizem