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Chronic disruption of the late cholesterol synthesis leads to female-prevalent liver cancer
ID Blagotinšek Cokan, Kaja (Author), ID Urlep, Žiga (Author), ID Lorbek, Gregor (Author), ID Matz-Soja, Madlen (Author), ID Skubic, Cene (Author), ID Perše, Martina (Author), ID Jeruc, Jera (Author), ID Juvan, Peter (Author), ID Režen, Tadeja (Author), ID Rozman, Damjana (Author)

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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 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 (dk_c)
Typology:1.01 - Original Scientific Article
Organization:MF - Faculty of Medicine
Year:2020
Publication status in journal:Published
Article version:Publisher's version of article
Number of pages:24 str.
Numbering:Vol. 12, iss. 11, art. 3302
PID:20.500.12556/RUL-134459 This link opens in a new window
UDC:616-006
ISSN on article:2072-6694
DOI:10.3390/cancers12113302 This link opens in a new window
COBISS.SI-ID:36485123 This link opens in a new window
Publication date in RUL:17.01.2022
Views:238
Downloads:90
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Record is a part of a journal

Title:Cancers
Shortened title:Cancers
Publisher:MDPI
ISSN:2072-6694
COBISS.SI-ID:517914137 This link opens in a new window

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

Projects

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0104
Name:Funkcijska genomika in biotehnologija za zdravje

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0390
Name:Funkcijska genomika in biotehnologija za zdravje

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:J1-9176
Name:HolesteROR pri presnovnih boleznih jeter

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:BI-DE/17-19-8

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Funding programme:Graduate fellowship

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