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) i...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-11-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/11/3302 |
| _version_ | 1797548490778214400 |
|---|---|
| author | Kaja Blagotinšek Cokan Žiga Urlep Gregor Lorbek Madlen Matz-Soja Cene Skubic Martina Perše Jera Jeruc Peter Juvan Tadeja Režen Damjana Rozman |
| author_facet | Kaja Blagotinšek Cokan Žiga Urlep Gregor Lorbek Madlen Matz-Soja Cene Skubic Martina Perše Jera Jeruc Peter Juvan Tadeja Režen Damjana Rozman |
| author_sort | Kaja Blagotinšek Cokan |
| collection | DOAJ |
| description | 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 LXRα and activated TGF-β 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 PPARα were recognized as important for female hepatocarcinogenesis, while overexpressed <i>Cd36</i>, 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. |
| first_indexed | 2024-03-10T15:00:08Z |
| format | Article |
| id | doaj.art-bcf14ce90e8845ceaf2e95e5a5162b11 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T15:00:08Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-bcf14ce90e8845ceaf2e95e5a5162b112023-11-20T20:16:46ZengMDPI AGCancers2072-66942020-11-011211330210.3390/cancers12113302Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver CancerKaja Blagotinšek Cokan0Žiga Urlep1Gregor Lorbek2Madlen Matz-Soja3Cene Skubic4Martina Perše5Jera Jeruc6Peter Juvan7Tadeja Režen8Damjana Rozman9Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaRudol-Schönheimer-Institute of Biochemistry, Divison of General Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, GermanyCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaMedical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaInstitute of Pathology, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, SloveniaWhile 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 LXRα and activated TGF-β 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 PPARα were recognized as important for female hepatocarcinogenesis, while overexpressed <i>Cd36</i>, 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.https://www.mdpi.com/2072-6694/12/11/3302cholesterol biosynthesishepatocellular carcinomalanosterol 14α-demethylase (CYP51)sex dimorphism |
| spellingShingle | Kaja Blagotinšek Cokan Žiga Urlep Gregor Lorbek Madlen Matz-Soja Cene Skubic Martina Perše Jera Jeruc Peter Juvan Tadeja Režen Damjana Rozman Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer Cancers cholesterol biosynthesis hepatocellular carcinoma lanosterol 14α-demethylase (CYP51) sex dimorphism |
| title | Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer |
| title_full | Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer |
| title_fullStr | Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer |
| title_full_unstemmed | Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer |
| title_short | Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer |
| title_sort | chronic disruption of the late cholesterol synthesis leads to female prevalent liver cancer |
| topic | cholesterol biosynthesis hepatocellular carcinoma lanosterol 14α-demethylase (CYP51) sex dimorphism |
| url | https://www.mdpi.com/2072-6694/12/11/3302 |
| work_keys_str_mv | AT kajablagotinsekcokan chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT zigaurlep chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT gregorlorbek chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT madlenmatzsoja chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT ceneskubic chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT martinaperse chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT jerajeruc chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT peterjuvan chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT tadejarezen chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer AT damjanarozman chronicdisruptionofthelatecholesterolsynthesisleadstofemaleprevalentlivercancer |