Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness

Revilla, Giovanna; Pons, Monica de Pablo; Baila-Rueda, Lucía; García-León, Annabel; Santos, David; Cenarro, Ana; Magalhães, Marcelo; Blanco, R.; Moral, Antonio; Peŕez, José Ignacio Arias; Sabé, Gerard; González, Cintia; Fusté, Victòria; Lerma, Enrique; Faria, Manuel dos Santos; Leiva, Alberto de; Corcoy, Rosa; Escolà‐Gil, Joan Carles; Mato, Eugènia

doi:10.1038/s41598-019-46727-2

Cited by 52 publications

(51 citation statements)

References 61 publications

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“…27HC is also involved in tumor angiogenesis by inducing VEGF activation through ERa signaling or reactive oxygen species-mediated STAT-3 recruiting (269). Consistently, advanced breast cancers upregulate CYP27A1 while decreasing the expression of CYP7B1, thereby promoting 27HC accumulation (31,270). Higher levels of intracellular cholesterol in cancer cells are determined by aberrant HMGCR activity, due to disrupted sterol-controlled feedback regulation or SREBP-mediated overexpression (271)(272)(273).…”

Section: Oncogenic Signaling and Cholesterol Homeostasismentioning

confidence: 96%

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

et al. 2021

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Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.

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Section: Oncogenic Signaling and Cholesterol Homeostasismentioning

confidence: 96%

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

et al. 2021

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“…CYP7B1 expression has been shown to be lower in ERα-positive breast tumors, relative to normal breast tissue [7], and associated with better prognosis [6,7]. Correlates of tumor protein expression of CYP27A1 and CYP7B1 with cancer characteristics, reproductive and lifestyle factors are not well established in cancer [6,10,11], including breast cancer [6,10].…”

Section: Introductionmentioning

confidence: 99%

Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort

et al. 2020

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Background: Experimental and epidemiological studies demonstrate a role for 27-hydroxycholesterol (27HC) in breast cancer development, though results are conflicting. Cholesterol 27-hydroxylase (CYP27A1) and oxysterol 7alpha-hydroxylase (CYP7B1) regulate 27HC concentrations, while differential expression of the liver X receptor (LXR) and estrogen receptor beta (ERβ) may impact the association between 27HC and breast cancer risk. Methods: We evaluated correlates of tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ and the association between circulating prediagnostic 27HC concentrations and breast cancer risk by marker expression in a nested casecontrol study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort including 287 breast cancer cases with tumor tissue available. Tumor protein expression was evaluated using immunohistochemistry, and serum 27HC concentrations quantified using liquid chromatography-mass spectrometry. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: A higher proportion of CYP7B1-positive cases were progesterone receptor (PR)-positive, relative to CYP7B1negative cases, whereas a higher proportion of ERβ-positive cases were Bcl-2 low, relative to ERβ-negative cases. No differences in tumor tissue marker positivity were observed by reproductive and lifestyle factors. We observed limited evidence of heterogeneity in associations between circulating 27HC and breast cancer risk by tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ, with the exception of statistically significant heterogeneity by LXR-β status in the subgroup of women perimenopausal at blood collection (p = 0.02). Conclusion: This exploratory study suggests limited associations between tumor marker status and epidemiologic or breast cancer characteristics. Furthermore, the association between circulating 27HC and breast cancer risk may not vary by tumor expression of CYP27A1, CYP7B1, LXR-β, or ERβ.

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“…Dysregulation of cholesterol synthesis and steroid levels in different tissues are associated with oxidative stress and cell death, which can contribute to age-related diseases and pathological conditions [5,6]. For example, increased levels of oxysterols have been implicated in Alzheimer's disease (AD), atherosclerosis, type 2 diabetes, and cancer [7][8][9]. In addition, in mice and humans blood steroid concentration changes with age, [10][11][12] and longitudinal studies have identified a correlation between age-related decline in steroid hormones and metabolic syndrome (MetS) as well as cardiovascular disease (CVD) [13,14].…”

Section: Introductionmentioning

confidence: 99%

Optimization of mass spectrometry settings for steroidomic analysis in young and old killifish

et al. 2020

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Steroids are essential structural components of cell membranes that organize lipid rafts and modulate membrane fluidity. They can also act as signalling molecules that work through nuclear and G protein-coupled receptors to impact health and disease. Notably, changes in steroid levels have been implicated in metabolic, cardiovascular and neurodegenerative diseases, but how alterations in the steroid pool affect ageing is less well understood. One of the major challenges in steroidomic analysis is the ability to simultaneously detect and distinguish various steroids due to low in vivo concentrations and naturally occurring stereoisomers. Here, we established such a method to study the mass spectrometry behaviour of nine sterols/steroids and related molecules (cholesterol precursors: squalene, lanosterol; sterol metabolites; 7 Dehydrocholesterol, 24, 25 and 27 Hydroxycholesterol; and steroids: progesterone, testosterone, and corticosterone) during ageing in the African turquoise killifish, a new model for studying vertebrate longevity. We find that levels of all tested steroids change significantly with age in multiple tissues, suggesting that specific steroids could be used as biomarkers of ageing. These findings pave the way for use of Nothobranchius furzeri as a novel model organism to unravel the role of sterols/steroids in ageing and age-related diseases.

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Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness

Cited by 52 publications

References 61 publications

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort

Optimization of mass spectrometry settings for steroidomic analysis in young and old killifish

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