Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

Cokan, Kaja Blagotinšek; Urlep, Žiga; Lorbek, Gregor; Matz‐Soja, Madlen; Skubic, Cene; Perše, Martina; Jeruc, Jera; Juvan, Peter; Režen, Tadeja; Rozman, Damjana

doi:10.3390/cancers12113302

Cited by 10 publications

(10 citation statements)

References 81 publications

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“…In addition to the different frequencies of liver diseases, males and females also differ with respect to the metabolism of endobiotics and xenobiotics, including drugs. Reasons for these differences include the sex-specific expression of genes from hepatic signaling pathways and the downstream metabolic genes (Cokan et al 2020 ), like the genes of the cytochrome P450 ( Cyp ) superfamily that are, directly or indirectly, regulated by GH or sex hormones (Shapiro et al 1995 ).…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent dynamics of metabolism in primary mouse hepatocytes

et al. 2021

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The liver is one of the most sexually dimorphic organs. The hepatic metabolic pathways that are subject to sexual dimorphism include xenobiotic, amino acid and lipid metabolism. Non-alcoholic fatty liver disease and hepatocellular carcinoma are among diseases with sex-dependent prevalence, progression and outcome. Although male and female livers differ in their abilities to metabolize foreign compounds, including drugs, sex-dependent treatment and pharmacological dynamics are rarely applied in all relevant cases. Therefore, it is important to consider hepatic sexual dimorphism when developing new treatment strategies and to understand the underlying mechanisms in model systems. We isolated primary hepatocytes from male and female C57BL6/N mice and examined the sex-dependent transcriptome, proteome and extracellular metabolome parameters in the course of culturing them for 96 h. The sex-specific gene expression of the general xenobiotic pathway altered and the female-specific expression of Cyp2b13 and Cyp2b9 was significantly reduced during culture. Sex-dependent differences of several signaling pathways increased, including genes related to serotonin and melatonin degradation. Furthermore, the ratios of male and female gene expression were inversed for other pathways, such as amino acid degradation, beta-oxidation, androgen signaling and hepatic steatosis. Because the primary hepatocytes were cultivated without the influence of known regulators of sexual dimorphism, these results suggest currently unknown modulatory mechanisms of sexual dimorphism in vitro. The large sex-dependent differences in the regulation and dynamics of drug metabolism observed during cultivation can have an immense influence on the evaluation of pharmacodynamic processes when conducting initial preclinical trials to investigate potential new drugs.

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Section: Introductionmentioning

confidence: 99%

Sex-dependent dynamics of metabolism in primary mouse hepatocytes

et al. 2021

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“…In mouse models, the whole body Cyp51 deletion was embryonically lethal (75). Deletion only in the liver resulted in lanosterol and 24,25-dihydrolansterol accumulation, which led to tumour growth and hepatocellular carcinoma-like symptoms (22, 76). Much of our findings in HepG2 CYP51 KO cells where especially 24,25-dihydrolansterol concentration are high, align with results in the mouse models (22), where signalling pathways such as NFKB, PI3K/Akt, and the cell cycle are altered.…”

Section: Discussionmentioning

confidence: 99%

HepG2 cells with knockouts ofCYP51A1,DHCR24orSC5Dfrom cholesterol synthesis accumulate sterols influencing distinct regulatory pathways

Skubic,

Trček,

Nassib

et al. 2023

Preprint

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Sterol intermediates of cholesterol synthesis are largely dedicated to cholesterol. Here we assess how they influence downstream gene regulatory pathways by developing knockouts (KOs) for consecutive enzymes of cholesterol synthesis. Depletion of CYP51, DHCR24 and SC5D resulted in accumulation of specific sterols. The overlap of deregulated genes was only 9% in terms of steroid metabolism and proliferation control, with majority of pathways changed in just one KO. The CYP51 KO with highly elevated 24,25-dihydrolanosterol showed significantly higher proportion of cells in the G2+M phase, in line with enriched cancer and cell cycle pathways, and elevated LEF1 by activation of WNT/NFKB/SMAD signalling. In contrast, SC5D and DHCR24 KOs (with elevated lathosterol or desmosterol) slowed cell proliferation and promoted apoptosis with downregulated E2F, mitosis, cell cycle transition, and enriched HNF1A tumor suppressor. These findings demonstrate that sterols from cholesterol synthesis control distinct gene regulatory pathways, and only early sterols promote cell proliferation.

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“…Additionally, pathway enrichment analysis shed a light on other perturbed pathways implicating the involvement of hsa_circ_0062682 in steroid metabolism, GPCR ligand binding, RNA splicing, and unfolded protein response. The implication of aberrant splicing [ 68 , 69 ], downregulated steroid metabolism [ 70 ], and upregulated unfolded protein response and ER stress [ 71 , 72 ] were previously associated with HCC. Moreover, enriched transcription factors in a knockdown cell model were already previously linked to the HCC pathology and can partially explain the observed phenotype.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA hsa_circ_0062682 Binds to YBX1 and Promotes Oncogenesis in Hepatocellular Carcinoma

Razpotnik

Vidmar

Fonović

et al. 2022

Cancers

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Circular RNAs (circRNAs) have been shown to play an important role in the pathogenesis of hepatocellular carcinoma (HCC). By implementing available transcriptomic analyses of HCC patients, we identified an upregulated circRNA hsa_circ_0062682. Stable perturbations of hsa_circ_0062682 in Huh-7 and SNU-449 cell lines influenced colony formation, migration, cell proliferation, sorafenib sensitivity, and additionally induced morphological changes in cell lines, indicating an important role of hsa_circ_0062682 in oncogenesis. Pathway enrichment analysis and gene set enrichment analysis of the transcriptome data from hsa_circ_0062682 knockdown explained the observed phenotypes and exposed transcription factors E2F1, Sp1, HIF-1α, and NFκB1 as potential downstream targets. Biotinylated oligonucleotide pulldown combined with proteomic analyses identified protein interaction partners of which YBX1, a known oncogene, was confirmed by RNA immunoprecipitation. Furthermore, we discovered a complex cell-type-specific phenotype in response to the oncogenic potential of hsa_circ_0062682. This finding is in line with different classes of HCC tumours, and more studies are needed to shed a light on the molecular complexity of liver cancer.

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Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

Cited by 10 publications

References 81 publications

Sex-dependent dynamics of metabolism in primary mouse hepatocytes

Sex-dependent dynamics of metabolism in primary mouse hepatocytes

HepG2 cells with knockouts ofCYP51A1,DHCR24orSC5Dfrom cholesterol synthesis accumulate sterols influencing distinct regulatory pathways

Circular RNA hsa_circ_0062682 Binds to YBX1 and Promotes Oncogenesis in Hepatocellular Carcinoma

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