Pathogenic role of 25-hydroxycholesterol in cancer development and progression

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References

• 1. Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Caveolae and signalling in cancer. Nat. Rev. Cancer 15(4), 225–237 (2015).
  Medline CASGoogle Scholar
• 2. Mundal L, Sarancic M, Ose L et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992–2010. J. Am. Heart Assoc. 3(6), e001236 (2014).
  MedlineGoogle Scholar
• 3. Jasim SA, Kzar HH, Hamad MH et al. The emerging role of 27-hydroxycholesterol in cancer development and progression: an update. Int. Immunopharmacol. 110, 109074 (2022).
  MedlineGoogle Scholar
• 4. Zusman O, Avni T, Leibovici L et al. Systematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems. Antimicrob. Agents Chemother. 57(10), 5104–5111 (2013).
  Medline CASGoogle Scholar
• 5. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 72, 137–174 (2003).
  Medline CASGoogle Scholar
• 6. Schroepfer GJ Jr. Oxysterols: modulators of cholesterol metabolism and other processes. Physiol. Rev. 80(1), 361–554 (2000).
  Medline CASGoogle Scholar
• 7. Cao Q, Liu Z, Xiong Y, Zhong Z, Ye Q. Multiple roles of 25-hydroxycholesterol in lipid metabolism, antivirus process, inflammatory response, and cell survival. Oxid. Med. Cell. Longev. 2020, 8893305 (2020).
  MedlineGoogle Scholar
• 8. Lund EG, Kerr TA, Sakai J, Li WP, Russell DW. cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism. J. Biol. Chem. 273(51), 34316–34327 (1998).
  Medline CASGoogle Scholar
• 9. Park K, Scott AL. Cholesterol 25-hydroxylase production by dendritic cells and macrophages is regulated by type I interferons. J. Leukoc. Biol. 88(6), 1081–1087 (2010).
  Medline CASGoogle Scholar
• 10. Liu Y, Wei Z, Ma X et al. 25-hydroxycholesterol activates the expression of cholesterol 25-hydroxylase in an LXR-dependent mechanism. J. Lipid Res. 59(3), 439–451 (2018).
  Medline CASGoogle Scholar
• 11. Diczfalusy U. On the formation and possible biological role of 25-hydroxycholesterol. Biochimie 95(3), 455–460 (2013).
  Medline CASGoogle Scholar
• 12. Honda A, Miyazaki T, Ikegami T et al. Cholesterol 25-hydroxylation activity of CYP3A. J. Lipid Res. 52(8), 1509–1516 (2011).
  Medline CASGoogle Scholar
• 13. Diczfalusy U, Björkhem I. Still another activity by the highly promiscuous enzyme CYP3A4: 25-hydroxylation of cholesterol. J. Lipid Res. 52(8), 1447–1449 (2011).
  Medline CASGoogle Scholar
• 14. Bah SY, Dickinson P, Forster T, Kampmann B, Ghazal P. Immune oxysterols: role in mycobacterial infection and inflammation. J. Steroid Biochem. Mol. Biol. 169, 152–163 (2017).
  Medline CASGoogle Scholar
• 15. Perucha E, Melchiotti R, Bibby JA et al. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nat. Commun. 10(1), 498 (2019).
  Medline CASGoogle Scholar
• 16. Bauman DR, Bitmansour AD, McDonald JG, Thompson BM, Liang G, Russell DW. 25-hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production. Proc. Natl Acad. Sci. USA 106(39), 16764–16769 (2009).
  Medline CASGoogle Scholar
• 17. McDonald JG, Russell DW. Editorial: 25-hydroxycholesterol: a new life in immunology. J. Leukoc. Biol. 88(6), 1071–1072 (2010).
  Medline CASGoogle Scholar
• 18. Brown MS, Goldstein JL. Cholesterol feedback: from Schoenheimer's bottle to SCAP's MELADL. J. Lipid Res. 50(Suppl.), S15–S27 (2009).
  MedlineGoogle Scholar
• 19. Johnson KA, Morrow CJ, Knight GD, Scallen TJ. In vivo formation of 25-hydroxycholesterol from endogenous cholesterol after a single meal, dietary cholesterol challenge. J. Lipid Res. 35(12), 2241–2253 (1994).
  Medline CASGoogle Scholar
• 20. Lappano R, Recchia AG, De Francesco EM et al. The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor α-mediated signaling in cancer cells and in cardiomyocytes. PLOS ONE 6(1), e16631 (2011).
  Medline CASGoogle Scholar
• 21. Simigdala N, Gao Q, Pancholi S et al. Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. Breast Cancer Res. 18(1), 58 (2016).
  MedlineGoogle Scholar
• 22. Chen L, Zhang L, Xian G, Lv Y, Lin Y, Wang Y. 25-hydroxycholesterol promotes migration and invasion of lung adenocarcinoma cells. Biochem. Biophys. Res. Commun. 484(4), 857–863 (2017).
  Medline CASGoogle Scholar
• 23. Eibinger G, Fauler G, Bernhart E et al. On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment. Exp. Cell Res. 319(12), 1828–1838 (2013).
  Medline CASGoogle Scholar
• 24. Wang S, Yao Y, Rao C, Zheng G, Chen W. 25-HC decreases the sensitivity of human gastric cancer cells to 5-fluorouracil and promotes cells invasion via the TLR2/NF-κB signaling pathway. Int. J. Oncol. 54(3), 966–980 (2019).
  Medline CASGoogle Scholar
• 25. Kuzu OF, Noory MA, Robertson GP. The role of cholesterol in cancer. Cancer Res. 76(8), 2063–2070 (2016).
  Medline CASGoogle Scholar
• 26. King RJ, Singh PK, Mehla K. The cholesterol pathway: impact on immunity and cancer. Trends Immunol. 43(1), 78–92 (2022).
  Medline CASGoogle Scholar
• 27. Llaverias G, Danilo C, Mercier I et al. Role of cholesterol in the development and progression of breast cancer. Am. J. Pathol. 178(1), 402–412 (2011).
  Medline CASGoogle Scholar
• 28. Allott EH, Howard LE, Cooperberg MR et al. Serum lipid profile and risk of prostate cancer recurrence: results from the SEARCH database. Cancer Epidemiol. Biomarkers Prev. 23(11), 2349–2356 (2014).
  Medline CASGoogle Scholar
• 29. Marwarha G, Raza S, Hammer K, Ghribi O. 27-hydroxycholesterol: a novel player in molecular carcinogenesis of breast and prostate cancer. Chem. Phys. Lipids 207(Pt B), 108–126 (2017).
  Medline CASGoogle Scholar
• 30. Cardwell CR, Hicks BM, Hughes C, Murray LJ. Statin use after colorectal cancer diagnosis and survival: a population-based cohort study. J. Clin. Oncol. 32(28), 3177–3183 (2014).
  MedlineGoogle Scholar
• 31. Jacobs EJ, Newton CC, Thun MJ, Gapstur SM. Long-term use of cholesterol-lowering drugs and cancer incidence in a large United States cohort. Cancer Res. 71(5), 1763–1771 (2011).
  Medline CASGoogle Scholar
• 32. Murtola TJ, Tammela TL, Lahtela J, Auvinen A. Cholesterol-lowering drugs and prostate cancer risk: a population-based case–control study. Cancer Epidemiol. Biomarkers Prev. 16(11), 2226–2232 (2007).
  Medline CASGoogle Scholar
• 33. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N. Engl. J. Med. 367(19), 1792–1802 (2012).
  Medline CASGoogle Scholar
• 34. Bjerre LM, LeLorier J. Do statins cause cancer? A meta-analysis of large randomized clinical trials. Am. J. Med. 110(9), 716–723 (2001).
  Medline CASGoogle Scholar
• 35. Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 275(1), 55–60 (1996).
  Medline CASGoogle Scholar
• 36. Pedersen TR, Wilhelmsen L, Faergeman O et al. Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering. Am. J. Cardiol. 86(3), 257–262 (2000).
  Medline CASGoogle Scholar
• 37. Montero J, Morales A, Llacuna L et al. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res. 68(13), 5246–5256 (2008).
  Medline CASGoogle Scholar
• 38. Vassilev B, Sihto H, Li S et al. Elevated levels of StAR-related lipid transfer protein 3 alter cholesterol balance and adhesiveness of breast cancer cells: potential mechanisms contributing to progression of HER2-positive breast cancers. Am. J. Pathol. 185(4), 987–1000 (2015).
  Medline CASGoogle Scholar
• 39. Freed-Pastor WA, Mizuno H, Zhao X et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148(1–2), 244–258 (2012).
  Medline CASGoogle Scholar
• 40. Sorrentino G, Ruggeri N, Specchia V et al. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat. Cell Biol. 16(4), 357–366 (2014).
  Medline CASGoogle Scholar
• 41. Swinnen JV, Brusselmans K, Verhoeven G. Increased lipogenesis in cancer cells: new players, novel targets. Curr. Opin. Clin. Nutr. Metab. Care 9(4), 358–365 (2006).
  Medline CASGoogle Scholar
• 42. Mirzaei R, Babakhani S, Ajorloo P et al. The emerging role of exosomal miRNAs as a diagnostic and therapeutic biomarker in Mycobacterium tuberculosis infection. Mol. Med. 27(1), 1–31 (2021).
  MedlineGoogle Scholar
• 43. Clendening JW, Pandyra A, Boutros PC et al. Dysregulation of the mevalonate pathway promotes transformation. Proc. Natl Acad. Sci. USA 107(34), 15051–15056 (2010).
  Medline CASGoogle Scholar
• 44. Ginestier C, Monville F, Wicinski J et al. Mevalonate metabolism regulates basal breast cancer stem cells and is a potential therapeutic target. Stem Cells 30(7), 1327–1337 (2012).
  Medline CASGoogle Scholar
• 45. Li HY, Appelbaum FR, Willman CL, Zager RA, Banker DE. Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses. Blood 101(9), 3628–3634 (2003).
  Medline CASGoogle Scholar
• 46. Mo H, Elson CE. Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention. Exp. Biol. Med. (Maywood) 229(7), 567–585 (2004).
  Medline CASGoogle Scholar
• 47. Warburg O. On the origin of cancer cells. Science 123(3191), 309–314 (1956).
  Medline CASGoogle Scholar
• 48. Biswas S, Lunec J, Bartlett K. Non-glucose metabolism in cancer cells – is it all in the fat? Cancer Metastasis Rev. 31(3–4), 689–698 (2012).
  Medline CASGoogle Scholar
• 49. DuSell CD, McDonnell DP. 27-hydroxycholesterol: a potential endogenous regulator of estrogen receptor signaling. Trends Pharmacol. Sci. 29(10), 510–514 (2008).
  Medline CASGoogle Scholar
• 50. Umetani M, Domoto H, Gormley AK et al. 27-hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat. Med. 13(10), 1185–1192 (2007).
  Medline CASGoogle Scholar
• 51. Ørsted DD, Bojesen SE. The link between benign prostatic hyperplasia and prostate cancer. Nat. Rev. Urol. 10(1), 49–54 (2013).
  Medline CASGoogle Scholar
• 52. Crosignani A, Zuin M, Allocca M, Del Puppo M. Oxysterols in bile acid metabolism. Clin. Chim. Acta 412(23–24), 2037–2045 (2011).
  Medline CASGoogle Scholar
• 53. Cyster JG, Dang EV, Reboldi A, Yi T. 25-hydroxycholesterols in innate and adaptive immunity. Nat. Rev. Immunol. 14(11), 731–743 (2014).
  Medline CASGoogle Scholar
• 54. Mutemberezi V, Guillemot-Legris O, Muccioli GG. Oxysterols: from cholesterol metabolites to key mediators. Prog. Lipid Res. 64, 152–169 (2016).
  Medline CASGoogle Scholar
• 55. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 72(1), 137–174 (2003).
  Medline CASGoogle Scholar
• 56. Ma L, Nelson ER. Oxysterols and nuclear receptors. Mol. Cell. Endocrinol. 484, 42–51 (2019).
  Medline CASGoogle Scholar
• 57. Janowski BA, Grogan MJ, Jones SA et al. Structural requirements of ligands for the oxysterol liver X receptors LXRα and LXRβ. Proc. Natl Acad. Sci. USA 96(1), 266–271 (1999).
  Medline CASGoogle Scholar
• 58. Liu Y, Wei Z, Zhang Y et al. Activation of liver X receptor plays a central role in antiviral actions of 25-hydroxycholesterol. J. Lipid Res. 59(12), 2287–2296 (2018).
  Medline CASGoogle Scholar
• 59. Hannedouche S, Zhang J, Yi T et al. Oxysterols direct immune cell migration via EBI2. Nature 475(7357), 524–527 (2011).
  Medline CASGoogle Scholar
• 60. Liu C, Yang XV, Wu J et al. Oxysterols direct B-cell migration through EBI2. Nature 475(7357), 519–523 (2011).
  Medline CASGoogle Scholar
• 61. Endo-Umeda K, Makishima M. Liver X receptors regulate cholesterol metabolism and immunity in hepatic nonparenchymal cells. Int. J. Mol. Sci. 20(20), 5045 (2019).
  Medline CASGoogle Scholar
• 62. Leussink S, Aranda-Pardos I, Noelia A. Lipid metabolism as a mechanism of immunomodulation in macrophages: the role of liver X receptors. Curr. Opin. Pharmacol. 53, 18–26 (2020).
  Medline CASGoogle Scholar
• 63. Dzhagalov I, Zhang N, He YW. The roles of orphan nuclear receptors in the development and function of the immune system. Cell. Mol. Immunol. 1(6), 401–407 (2004).
  Medline CASGoogle Scholar
• 64. Zhao L, Zhou S, Gustafsson J-Å. Nuclear receptors: recent drug discovery for cancer therapies. Endocr. Rev. 40(5), 1207–1249 (2019).
  MedlineGoogle Scholar
• 65. Kumar N, Solt LA, Conkright JJ et al. The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-α/γ inverse agonist. Mol. Pharmacol. 77(2), 228–236 (2010).
  Medline CASGoogle Scholar
• 66. Jin L, Martynowski D, Zheng S, Wada T, Xie W, Li Y. Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORγ. Mol. Endocrinol. 24(5), 923–929 (2010).
  Medline CASGoogle Scholar
• 67. Soroosh P, Wu J, Xue X et al. Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation. Proc. Natl Acad. Sci. USA 111(33), 12163–12168 (2014).
  Medline CASGoogle Scholar
• 68. Daugvilaite V, Arfelt KN, Benned-Jensen T, Sailer AW, Rosenkilde MM. Oxysterol-EBI2 signaling in immune regulation and viral infection. Eur. J. Immunol. 44(7), 1904–1912 (2014).
  Medline CASGoogle Scholar
• 69. Holthuis JC, Menon AK. Lipid landscapes and pipelines in membrane homeostasis. Nature 510(7503), 48–57 (2014).
  Medline CASGoogle Scholar
• 70. Wilkins C, Gale M Jr. Sterol-izing innate immunity. Immunity 38(1), 3–5 (2013).
  Medline CASGoogle Scholar
• 71. Mirzaei R, Zamani F, Hajibaba M et al. The pathogenic, therapeutic and diagnostic role of exosomal microrna in the autoimmune diseases. J. Neuroimmunol. 358, 577640 (2021).
  Medline CASGoogle Scholar
• 72. Brown MS, Goldstein JL. Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol. J. Biol. Chem. 249(22), 7306–7314 (1974).
  Medline CASGoogle Scholar
• 73. Kandutsch AA, Chen HW. Inhibition of sterol synthesis in cultured mouse cells by cholesterol derivatives oxygenated in the side chain. J. Biol. Chem. 249(19), 6057–6061 (1974).
  Medline CASGoogle Scholar
• 74. Björkhem I. Are side-chain oxidized oxysterols regulators also in vivo? J. Lipid Res. 50, S213–S218 (2009).
  MedlineGoogle Scholar
• 75. Diczfalusy U, Olofsson KE, Carlsson AM et al. Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide. J. Lipid Res. 50(11), 2258–2264 (2009).
  Medline CASGoogle Scholar
• 76. Zhao J, Chen J, Li M, Chen M, Sun C. Multifaceted functions of CH25H and 25HC to modulate the lipid metabolism, immune responses, and broadly antiviral activities. Viruses 12(7), 727 (2020).
  Medline CASGoogle Scholar
• 77. Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG. Inflammation. 25-hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345(6197), 679–684 (2014).
  Medline CASGoogle Scholar
• 78. Joseph SB, Bradley MN, Castrillo A et al. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119(2), 299–309 (2004).
  Medline CASGoogle Scholar
• 79. Korf H, Vander Beken S, Romano M et al. Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice. J. Clin. Invest. 119(6), 1626–1637 (2009).
  Medline CASGoogle Scholar
• 80. A-Gonzalez N, Bensinger SJ, Hong C et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31(2), 245–258 (2009).
  Medline CASGoogle Scholar
• 81. Li C, Deng YQ, Wang S et al. 25-hydroxycholesterol protects host against Zika virus infection and its associated microcephaly in a mouse model. Immunity 46(3), 446–456 (2017).
  Medline CASGoogle Scholar
• 82. Dang EV, McDonald JG, Russell DW, Cyster JG. Oxysterol restraint of cholesterol synthesis prevents AIM2 inflammasome activation. Cell 171(5), 1057–1071.e11 (2017).
  Medline CASGoogle Scholar
• 83. Jang J, Park S, Hur HJ et al. 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nat. Commun. 7(1), 1–11 (2016). •• Found that 25-HC promoted robust NLRP3 inflammasome assembly and activation via potassium efflux-, mitochondrial reactive oxygen species (ROS)- and liver X receptor (LXR)-mediated pathways.
  Google Scholar
• 84. Preuss I, Ludwig MG, Baumgarten B et al. Transcriptional regulation and functional characterization of the oxysterol/EBI2 system in primary human macrophages. Biochem. Biophys. Res. Commun. 446(3), 663–668 (2014).
  Medline CASGoogle Scholar
• 85. Chalmin F, Rochemont V, Lippens C et al. Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity. J. Autoimmun. 56, 45–55 (2015).
  Medline CASGoogle Scholar
• 86. Forwell AL, Bernales CQ, Ross JP et al. Analysis of CH25H in multiple sclerosis and neuromyelitis optica. J. Neuroimmunol. 291, 70–72 (2016).
  Medline CASGoogle Scholar
• 87. Doms A, Sanabria T, Hansen JN, Altan-Bonnet N, Holm GH. 25-hydroxycholesterol production by the cholesterol-25-hydroxylase interferon-stimulated gene restricts mammalian reovirus infection. J. Virol. 92(18), e01047-18 (2018).
  MedlineGoogle Scholar
• 88. Shrivastava-Ranjan P, Bergeron É. 25-hydroxycholesterol inhibition of Lassa virus infection through aberrant GP1 glycosylation. mBio 7(6), e01808-16 (2016).
  MedlineGoogle Scholar
• 89. Wang J, Zeng L, Zhang L et al. Cholesterol 25-hydroxylase acts as a host restriction factor on pseudorabies virus replication. J. Gen. Virol. 98(6), 1467–1476 (2017).
  Medline CASGoogle Scholar
• 90. Liu SY, Aliyari R, Chikere K et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38(1), 92–105 (2013).
  MedlineGoogle Scholar
• 91. Ke W, Fang L, Jing H et al. Cholesterol 25-hydroxylase inhibits porcine reproductive and respiratory syndrome virus replication through enzyme activity-dependent and -independent mechanisms. J. Virol. 91(19), (2017).
  Google Scholar
• 92. Song Z, Zhang Q, Liu X et al. Cholesterol 25-hydroxylase is an interferon-inducible factor that protects against porcine reproductive and respiratory syndrome virus infection. Vet. Microbiol. 210, 153–161 (2017).
  Medline CASGoogle Scholar
• 93. Karampoor S, Zahednasab H, Farahmand M et al. A possible pathogenic role of syndecan-1 in the pathogenesis of coronavirus disease 2019 (COVID-19). Int. Immunopharmacol. 97, 107684 (2021).
  Medline CASGoogle Scholar
• 94. Blanc M, Hsieh WY, Robertson KA et al. The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response. Immunity 38(1), 106–118 (2013).
  Medline CASGoogle Scholar
• 95. Rasoul M, Rokhsareh M, Mohammad SM, Sajad K, Ahmadreza M. The human immune system against Staphylococcus epidermidis. Crit. Rev. Immunol. 39(3), (2019).
  MedlineGoogle Scholar
• 96. Pereira JP, Kelly LM, Cyster JG. Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses. Int. Immunol. 22(6), 413–419 (2010).
  Medline CASGoogle Scholar
• 97. Emgård J, Kammoun H, García-Cassani B et al. Oxysterol sensing through the receptor GPR183 promotes the lymphoid-tissue-inducing function of innate lymphoid cells and colonic inflammation. Immunity 48(1), 120–132.e8 (2018).
  MedlineGoogle Scholar
• 98. Schüle R, Siddique T, Deng HX et al. Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. J. Lipid Res. 51(4), 819–823 (2010).
  Medline CASGoogle Scholar
• 99. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13(6), 397–411 (2013).
  Medline CASGoogle Scholar
• 100. Wu T, Ma F, Ma X et al. Regulating innate and adaptive immunity for controlling SIV infection by 25-hydroxycholesterol. Front. Immunol. 9, 2686 (2018).
  MedlineGoogle Scholar
• 101. Smith LL. Cholesterol autoxidation 1981–1986. Chem. Phys. Lipids 44(2–4), 87–125 (1987).
  Medline CASGoogle Scholar
• 102. Malvitte L, Montange T, Joffre C et al. Analogies entre processus athéromateux et dégénérescence maculaire liée à l'âge: rôles présumés des oxystérols. J. Fr. Ophtalmol. 29(5), 570–578 (2006).
  Medline CASGoogle Scholar
• 103. Rodríguez IR, Larrayoz IM. Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration. J. Lipid Res. 51(10), 2847–2862 (2010).
  Medline CASGoogle Scholar
• 104. Dugas B, Charbonnier S, Baarine M et al. Effects of oxysterols on cell viability, inflammatory cytokines, VEGF, and reactive oxygen species production on human retinal cells: cytoprotective effects and prevention of VEGF secretion by resveratrol. Eur. J. Nutr. 49(7), 435–446 (2010).
  Medline CASGoogle Scholar
• 105. Lemaire-Ewing S, Prunet C, Montange T et al. Comparison of the cytotoxic, pro-oxidant and pro-inflammatory characteristics of different oxysterols. Cell Biol. Toxicol. 21(2), 97–114 (2005).
  Medline CASGoogle Scholar
• 106. Rydberg EK, Salomonsson L, Hultén LM et al. Hypoxia increases 25-hydroxycholesterol-induced interleukin-8 protein secretion in human macrophages. Atherosclerosis 170(2), 245–252 (2003).
  Medline CASGoogle Scholar
• 107. Prunet C, Montange T, Véjux A et al. Multiplexed flow cytometric analyses of pro- and anti-inflammatory cytokines in the culture media of oxysterol-treated human monocytic cells and in the sera of atherosclerotic patients. Cytometry A 69(5), 359–373 (2006).
  MedlineGoogle Scholar
• 108. Yoon JH, Canbay AE, Werneburg NW, Lee SP, Gores GJ. Oxysterols induce cyclooxygenase-2 expression in cholangiocytes: implications for biliary tract carcinogenesis. Hepatology 39(3), 732–738 (2004).
  Medline CASGoogle Scholar
• 109. Yoshida T, Klinkspoor JH, Kuver R et al. Effects of bile salts on cholestan-3β,5α,6β-triol-induced apoptosis in dog gallbladder epithelial cells. Biochim. Biophys. Acta 1530(2–3), 199–208 (2001).
  Medline CASGoogle Scholar
• 110. Edwards PA, Kennedy MA, Mak PA. LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis. Vascul. Pharmacol. 38(4), 249–256 (2002).
  Medline CASGoogle Scholar
• 111. Vejux A, Malvitte L, Lizard G. Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis. Braz. J. Med. Biol. Res. 41(7), 545–556 (2008).
  Medline CASGoogle Scholar
• 112. Englund MC, Karlsson AL, Wiklund O, Bondjers G, Ohlsson BG. 25-hydroxycholesterol induces lipopolysaccharide-tolerance and decreases a lipopolysaccharide-induced TNF-alpha secretion in macrophages. Atherosclerosis 158(1), 61–71 (2001).
  Medline CASGoogle Scholar
• 113. Nelson ER, Wardell SE, Jasper JS et al. 27-hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342(6162), 1094–1098 (2013).
  Medline CASGoogle Scholar
• 114. Prunet C, Petit JM, Ecarnot-Laubriet A et al. High circulating levels of 7beta- and 7alpha-hydroxycholesterol and presence of apoptotic and oxidative markers in arterial lesions of normocholesterolemic atherosclerotic patients undergoing endarterectomy. Pathol. Biol. (Paris) 54(1), 22–32 (2006).
  Medline CASGoogle Scholar
• 115. Kloudova A, Guengerich FP, Soucek P. The role of oxysterols in human cancer. Trends Endocrinol. Metab. 28(7), 485–496 (2017).
  Medline CASGoogle Scholar
• 116. Dalenc F, Iuliano L, Filleron T et al. Circulating oxysterol metabolites as potential new surrogate markers in patients with hormone receptor-positive breast cancer: results of the OXYTAM study. J. Steroid Biochem. Mol. Biol. 169, 210–218 (2017).
  Medline CASGoogle Scholar
• 117. Ortiz A, Gui J, Zahedi F et al. An interferon-driven oxysterol-based defense against tumor-derived extracellular vesicles. Cancer Cell 35(1), 33–45.e6 (2019). • Found the importance of CH25H in defense against education of normal cells by tumor-derived extracellular vesicles (TEVs) and argue for the use of reserpine in adjuvant melanoma therapy.
  Medline CASGoogle Scholar
• 118. You JS, Lim H, Kim TH et al. 25-hydroxycholesterol induces death receptor-mediated extrinsic and mitochondria-dependent intrinsic apoptosis in head and neck squamous cell carcinoma cells. Anticancer Res. 40(2), 779–788 (2020).
  Medline CASGoogle Scholar
• 119. Wang S, Yao Y, Rao C, Zheng G, Chen W. 25-HC decreases the sensitivity of human gastric cancer cells to 5-fluorouracil and promotes cells invasion via the TLR2/NF-κB signaling pathway. Int. J. Oncol. 54(3), 966–980 (2019).
  Medline CASGoogle Scholar
• 120. Wang S, Fei R, Xu X et al. 25-hydroxycholesterol regulates migration, invasion and EMT of colorectal cancer through miR-92a-3p/ACAA1/NF-κB pathway (2021).
  Google Scholar
• 121. Tanaka AR, Noguchi K, Fukazawa H, Igarashi Y, Arai H, Uehara Y. p38MAPK and Rho-dependent kinase are involved in anoikis induced by anicequol or 25-hydroxycholesterol in DLD-1 colon cancer cells. Biochem. Biophys. Res. Commun. 430(4), 1240–1245 (2013). •• Found that p38MAPK is involved in anicequol- and 25-HC-induced anoikis in DLD-1 cells and that activation of p38MAPK and ROCK pathways might provide a new therapeutic strategy against cancer and also raised the possibility that tumor metastasis is influenced by 25-HC under physiological conditions.
  Medline CASGoogle Scholar
• 122. Hitsuda A, Dan R, Urakawa A et al. 25-hydroxycholesterol-induced cell death via activation of ROCK/LIMK/cofilin axis in colorectal cancer cell spheroids. J. Steroid Biochem. Mol. Biol. 216, 106037 (2022).
  Medline CASGoogle Scholar
• 123. Kakimoto M, Yamamoto H, Tanaka AR. Spermine synthesis inhibitor blocks 25-hydroxycholesterol-induced-apoptosis via SREBP2 upregulation in DLD-1 cell spheroids. Biochem. Biophys. Rep. 22, 100754 (2020).
  MedlineGoogle Scholar
• 124. Wang C, He H, Fang W. Oncogenic roles of the cholesterol metabolite 25-hydroxycholesterol in bladder cancer. Oncol. Lett. 19(6), 3671–3676 (2020).
  Medline CASGoogle Scholar
• 125. Eibinger G, Fauler G, Bernhart E et al. On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment. Exp. Cell Res. 319(12), 1828–1838 (2013).
  Medline CASGoogle Scholar
• 126. You JS, Lim H, Kim TH et al. 25-hydroxycholesterol induces death receptor-mediated extrinsic and mitochondria-dependent intrinsic apoptosis in head and neck squamous cell carcinoma cells. Anticancer Res. 40(2), 779–788 (2020).
  Medline CASGoogle Scholar
• 127. Villablanca EJ, Raccosta L, Zhou D et al. Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat. Med. 16(1), 98–105 (2010).
  Medline CASGoogle Scholar
• 128. Segala G, de Medina P, Iuliano L et al. 5,6-epoxy-cholesterols contribute to the anticancer pharmacology of tamoxifen in breast cancer cells. Biochem. Pharmacol. 86(1), 175–189 (2013).
  Medline CASGoogle Scholar
• 129. Poirot M, Silvente-Poirot S, Weichselbaum RR. Cholesterol metabolism and resistance to tamoxifen. Curr. Opin. Pharmacol. 12(6), 683–689 (2012).
  Medline CASGoogle Scholar
• 130. Silvente-Poirot S, Poirot M. Cholesterol epoxide hydrolase and cancer. Curr. Opin. Pharmacol. 12(6), 696–703 (2012).
  Medline CASGoogle Scholar
• 131. Poirot M, Silvente-Poirot S. Cholesterol-5,6-epoxides: chemistry, biochemistry, metabolic fate and cancer. Biochimie 95(3), 622–631 (2013).
  Medline CASGoogle Scholar
• 132. Lappano R, Recchia AG, De Francesco EM et al. The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor α-mediated signaling in cancer cells and in cardiomyocytes. PLOS ONE 6(1), e16631 (2011). •• Showed that estrogen action exerted by 25-hydroxycholesterol (25-HC) can be considered an additional factor involved in the progression of breast and ovarian tumors and that the estrogen-like activity of 25-HC elicited in the cardiovascular system can play a role in hypoxic environments.
  Medline CASGoogle Scholar
• 133. Dzeletovic S, Breuer O, Lund E, Diczfalusy U. Determination of cholesterol oxidation products in human plasma by isotope dilution–mass spectrometry. Anal. Biochem. 225(1), 73–80 (1995).
  Medline CASGoogle Scholar
• 134. Sharma I, Dhaliwal LK, Saha SC, Sangwan S, Dhawan V. Role of 8-iso-prostaglandin F2alpha and 25-hydroxycholesterol in the pathophysiology of endometriosis. Fertil. Steril. 94(1), 63–70 (2010).
  Medline CASGoogle Scholar
• 135. Chen JJ, Lukyanenko Y, Hutson JC. 25-hydroxycholesterol is produced by testicular macrophages during the early postnatal period and influences differentiation of Leydig cells in vitro. Biol. Reprod. 66(5), 1336–1341 (2002).
  Medline CASGoogle Scholar
• 136. Hanley K, Ng DC, He SS et al. Oxysterols induce differentiation in human keratinocytes and increase Ap-1-dependent involucrin transcription. J. Invest. Dermatol. 114(3), 545–553 (2000).
  Medline CASGoogle Scholar
• 137. Yokoyama S, Nozawa F, Mugita N, Ogawa M. Suppression of rat liver tumorigenesis by 25-hydroxycholesterol and all-trans retinoic acid: differentiation therapy for hepatocellular carcinoma. Int. J. Oncol. 15(3), 565–569 (1999).
  Medline CASGoogle Scholar
• 138. Ma Y, Xu L, Rodriguez-Agudo D et al. 25-hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway. Am. J. Physiol. Endocrinol. Metab. 295(6), e1369–e1379 (2008).
  Medline CASGoogle Scholar
• 139. Flötotto T, Djahansouzi S, Gläser M et al. Hormones and hormone antagonists: mechanisms of action in carcinogenesis of endometrial and breast cancer. Horm. Metab. Res. 33(8), 451–457 (2001).
  Medline CASGoogle Scholar
• 140. O'Donnell AJ, Macleod KG, Burns DJ, Smyth JF, Langdon SP. Estrogen receptor-alpha mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen. Endocr. Relat. Cancer 12(4), 851–866 (2005).
  MedlineGoogle Scholar
• 141. Simigdala N, Gao Q, Pancholi S et al. Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. Breast Cancer Res. 18(1), 58 (2016).
  MedlineGoogle Scholar
• 142. Mittempergher L, Saghatchian M, Wolf DM et al. A gene signature for late distant metastasis in breast cancer identifies a potential mechanism of late recurrences. Mol. Oncol. 7(5), 987–999 (2013).
  Medline CASGoogle Scholar
• 143. Madenspacher JH, Morrell ED, Gowdy KM et al. Cholesterol 25-hydroxylase promotes efferocytosis and resolution of lung inflammation. JCI Insight 5(11), e137189 (2020).
  MedlineGoogle Scholar
• 144. Sugiura H, Koarai A, Ichikawa T et al. Increased 25-hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology 17(3), 533–540 (2012).
  MedlineGoogle Scholar
• 145. Hosseinpour F, Wikvall K. Porcine microsomal vitamin D3 25-hydroxylase (CYP2D25): catalytic properties, tissue distribution, and comparison with human CYP2D6. J. Biol. Chem. 275(44), 34650–34655 (2000).
  Medline CASGoogle Scholar
• 146. Blanc M, Hsieh WY, Robertson KA et al. The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response. Immunity 38(1), 106–118 (2013).
  Medline CASGoogle Scholar
• 147. Adams CM, Reitz J, De Brabander JK et al. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and INSIGs. J. Biol. Chem. 279(50), 52772–52780 (2004).
  Medline CASGoogle Scholar
• 148. Gold ES, Diercks AH, Podolsky I et al. 25-hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc. Natl Acad. Sci. USA 111(29), 10666–10671 (2014).
  Medline CASGoogle Scholar
• 149. Pereira JP, Kelly LM, Cyster JG. Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses. Int. Immunol. 22(6), 413–419 (2010).
  Medline CASGoogle Scholar
• 150. Yi T, Wang X, Kelly LM et al. Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses. Immunity 37(3), 535–548 (2012).
  Medline CASGoogle Scholar
• 151. Ecker J, Liebisch G, Englmaier M, Grandl M, Robenek H, Schmitz G. Induction of fatty acid synthesis is a key requirement for phagocytic differentiation of human monocytes. Proc. Natl Acad. Sci. USA 107(17), 7817–7822 (2010).
  Medline CASGoogle Scholar
• 152. Ichikawa T, Sugiura H, Koarai A et al. 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Exp. Cell Res. 319(8), 1176–1186 (2013).
  Medline CASGoogle Scholar
• 153. Rosklint T, Ohlsson B, Wiklund O, Noren K, Hulten L. Oxysterols induce interleukin-1β production in human macrophages. Eur. J. Clin. Invest. 32(1), 35–42 (2002).
  Medline CASGoogle Scholar
• 154. Fu H, Spieler F, Großmann J et al. Interleukin-1 potently contributes to 25-hydroxycholesterol-induced synergistic cytokine production in smooth muscle cell–monocyte interactions. Atherosclerosis 237(2), 443–452 (2014).
  Medline CASGoogle Scholar
• 155. Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG. 25-hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345(6197), 679–684 (2014).
  Medline CASGoogle Scholar
• 156. Nelson ER, Wardell SE, Jasper JS et al. 27-hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342(6162), 1094–1098 (2013).
  Medline CASGoogle Scholar
• 157. Pencheva N, Buss CG, Posada J, Merghoub T, Tavazoie SF. Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell 156(5), 986–1001 (2014).
  Medline CASGoogle Scholar
• 158. Gao C, Zhuang J, Zhou C et al. Prognostic value of aberrantly expressed methylation gene profiles in lung squamous cell carcinoma: a study based on The Cancer Genome Atlas. J. Cell. Physiol. 234(5), 6519–6528 (2019).
  Medline CASGoogle Scholar
• 159. Hardy MP, Zirkin BR, Ewing LL. Kinetic studies on the development of the adult population of Leydig cells in testes of the pubertal rat. Endocrinology 124(2), 762–770 (1989).
  Medline CASGoogle Scholar
• 160. Ariyaratne HB, Mendis-Handagama SC. Changes in the testis interstitium of Sprague Dawley rats from birth to sexual maturity. Biol. Reprod. 62(3), 680–690 (2000).
  Medline CASGoogle Scholar
• 161. Hutson JC. Development of cytoplasmic digitations between Leydig cells and testicular macrophages of the rat. Cell Tissue Res. 267(2), 385–389 (1992).
  Medline CASGoogle Scholar
• 162. Yee JB, Hutson JC. Effects of testicular macrophage-conditioned medium on Leydig cells in culture. Endocrinology 116(6), 2682–2684 (1985).
  Medline CASGoogle Scholar
• 163. Lukyanenko YO, Carpenter AM, Brigham DE, Stocco DM, Hutson JC. Regulation of Leydig cells through a steroidogenic acute regulatory protein-independent pathway by a lipophilic factor from macrophages. J. Endocrinol. 158(2), 267–275 (1998).
  Medline CASGoogle Scholar
• 164. Hutson JC, Garner CW, Doris PA. Purification and characterization of a lipophilic factor from testicular macrophages that stimulates testosterone production by Leydig cells. J. Androl. 17(5), 502–508 (1996).
  Medline CASGoogle Scholar
• 165. Nes WD, Lukyanenko YO, Jia ZH et al. Identification of the lipophilic factor produced by macrophages that stimulates steroidogenesis. Endocrinology 141(3), 953–958 (2000).
  Medline CASGoogle Scholar
• 166. Bergh A, Damber JE, van Rooijen N. Liposome-mediated macrophage depletion: an experimental approach to study the role of testicular macrophages in the rat. J. Endocrinol. 136(3), 407–413 (1993).
  Medline CASGoogle Scholar
• 167. Cohen PE, Hardy MP, Pollard JW. Colony-stimulating factor-1 plays a major role in the development of reproductive function in male mice. Mol. Endocrinol. 11(11), 1636–1650 (1997).
  Medline CASGoogle Scholar
• 168. Lukyanenko YO, Carpenter AM, Boone MM, Baker CR, McGunegle DE, Hutson JC. Specificity of a new lipid mediator produced by testicular and peritoneal macrophages on steroidogenesis. Int. J. Androl. 23(5), 258–265 (2000).
  Medline CASGoogle Scholar
• 169. Lukyanenko Y, Chen JJ, Hutson JC. Testosterone regulates 25-hydroxycholesterol production in testicular macrophages. Biol. Reprod. 67(5), 1435–1438 (2002).
  Medline CASGoogle Scholar
• 170. Mirzaei R, Afaghi A, Babakhani S et al. Role of microbiota-derived short-chain fatty acids in cancer development and prevention. Biomed. Pharmacother. 139, 111619 (2021).
  Medline CASGoogle Scholar
• 171. Mirzaei R, Mirzaei H, Alikhani MY et al. Bacterial biofilm in colorectal cancer: what is the real mechanism of action? Microb. Pathog. 142, 104052 (2020).
  Medline CASGoogle Scholar
• 172. Zeljkovic A, Vekic J, Mihajlovic M et al. Revealing the role of high-density lipoprotein in colorectal cancer. Int. J. Mol. Sci. 22(7), 3352 (2021).
  Medline CASGoogle Scholar
• 173. Jusakul A, Yongvanit P, Loilome W, Namwat N, Kuver R. Mechanisms of oxysterol-induced carcinogenesis. Lipids Health Dis. 10(1), 44 (2011).
  Medline CASGoogle Scholar
• 174. Leonarduzzi G, Scavazza A, Biasi F et al. The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis. FASEB J. 11(11), 851–857 (1997).
  Medline CASGoogle Scholar
• 175. Biasi F, Tessitore L, Zanetti D et al. Associated changes of lipid peroxidation and transforming growth factor beta1 levels in human colon cancer during tumour progression. Gut 50(3), 361–367 (2002).
  Medline CASGoogle Scholar
• 176. Kitahara CM, de González AB, Freedman ND et al. Total cholesterol and cancer risk in a large prospective study in Korea. J. Clin. Oncol. 29(12), 1592–1598 (2011).
  Medline CASGoogle Scholar
• 177. Rodriguez-Broadbent H, Law PJ. Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer. Int. J. Cancer 140(12), 2701–2708 (2017).
  Medline CASGoogle Scholar
• 178. Ito H, Matsuo K, Hosono S et al. Association between CYP7A1 and the risk of proximal colon cancer in Japanese. Int. J. Mol. Epidemiol. Genet. 1(1), 35–46 (2010).
  Medline CASGoogle Scholar
• 179. Hagiwara T, Kono S, Yin G et al. Genetic polymorphism in cytochrome P450 7A1 and risk of colorectal cancer: the Fukuoka Colorectal Cancer Study. Cancer Res. 65(7), 2979–2982 (2005).
  Medline CASGoogle Scholar
• 180. Aune D, Chan DS, Lau R et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose–response meta-analysis of prospective studies. BMJ 343, d6617 (2011).
  MedlineGoogle Scholar
• 181. Zhu Y, Soroka D, Sang S. Oxyphytosterols as active ingredients in wheat bran suppress human colon cancer cell growth: identification, chemical synthesis, and biological evaluation. J. Agric. Food Chem. 63(8), 2264–2276 (2015).
  Medline CASGoogle Scholar
• 182. Biasi F, Mascia C, Astegiano M et al. Pro-oxidant and proapoptotic effects of cholesterol oxidation products on human colonic epithelial cells: a potential mechanism of inflammatory bowel disease progression. Free Radic. Biol. Med. 47(12), 1731–1741 (2009).
  Medline CASGoogle Scholar
• 183. Warns J, Marwarha G, Freking N, Ghribi O. 27-hydroxycholesterol decreases cell proliferation in colon cancer cell lines. Biochimie 153, 171–180 (2018).
  Medline CASGoogle Scholar
• 184. Biasi F, Chiarpotto E, Sottero B et al. Evidence of cell damage induced by major components of a diet-compatible mixture of oxysterols in human colon cancer Caco-2 cell line. Biochimie 95(3), 632–640 (2013).
  Medline CASGoogle Scholar
• 185. Roussi S, Winter A, Gosse F et al. Different apoptotic mechanisms are involved in the antiproliferative effects of 7beta-hydroxysitosterol and 7beta-hydroxycholesterol in human colon cancer cells. Cell Death Differ. 12(2), 128–135 (2005).
  Medline CASGoogle Scholar
• 186. Maier G, Bing G, Falken U, Wagner E, Unger C. Antitumor activity and induction of apoptosis by water-soluble derivatives of 7 beta-hydroxycholesterol in human colon carcinoma cell lines. Anticancer Res. 19(5B), 4251–4256 (1999).
  Medline CASGoogle Scholar
• 187. Chalubinski M, Wojdan K, Gorzelak P, Borowiec M, Broncel M. The effect of oxidized cholesterol on barrier functions and IL-10 mRNA expression in human intestinal epithelium co-cultured with dendritic cells in the transwell system. Food Chem. Toxicol. 69, 289–293 (2014).
  Medline CASGoogle Scholar
• 188. Lee WH, Lee CS, Kwon K et al. 7-ketocholesterol induces endoplasmic reticulum stress in HT-29 cells. Z. Naturforsch. C J. Biosci. 64(3–4), 307–310 (2009).
  Medline CASGoogle Scholar
• 189. Alemany L, Laparra JM, Barberá R, Alegría A. Evaluation of the cytotoxic effect of 7keto-stigmasterol and 7keto-cholesterol in human intestinal (Caco-2) cells. Food Chem. Toxicol. 50(9), 3106–3113 (2012).
  Medline CASGoogle Scholar
• 190. Vedin LL, Gustafsson J, Steffensen KR. The oxysterol receptors LXRα and LXRβ suppress proliferation in the colon. Mol. Carcinog. 52(11), 835–844 (2013).
  Medline CASGoogle Scholar
• 191. Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18(5), 309–324 (2018).
  Medline CASGoogle Scholar
• 192. Englund MC, Karlsson ALK, Wiklund O, Bondjers G, Ohlsson BG. 25-hydroxycholesterol induces lipopolysaccharide-tolerance and decreases a lipopolysaccharide-induced TNF-α secretion in macrophages. Atherosclerosis 158(1), 61–71 (2001).
  Medline CASGoogle Scholar
• 193. Wong MY, Lewis M, Doherty J et al. 25-Hydroxycholesterol amplifies microglial IL-1beta production in an APOE isoform-dependent manner. Alzheimers Dement. 16, e043097 (2020).
  Google Scholar
• 194. Russo L, Muir L, Geletka L et al. Cholesterol 25-hydroxylase (CH25H) as a promoter of adipose tissue inflammation in obesity and diabetes. Mol. Metab. 39, 100983 (2020). • Found a critical role for CH25H/25-HC in the progression of meta-inflammation and insulin resistance in obese humans and mouse models of obesity.
  Medline CASGoogle Scholar
• 195. Derangère V, Chevriaux A, Courtaut F et al. Liver X receptor β activation induces pyroptosis of human and murine colon cancer cells. Cell Death Differ. 21(12), 1914–1924 (2014). • Demonstrated that LXR-β, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis.
  Medline CASGoogle Scholar
• 196. Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim. Biophys. Acta 1833(12), 3481–3498 (2013).
  Medline CASGoogle Scholar
• 197. Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on cholesterol homeostasis: the central role of SCAP. Annu. Rev. Biochem. 87, 783–807 (2018).
  Medline CASGoogle Scholar
• 198. Lembo D, Cagno V, Civra A, Poli G. Oxysterols: an emerging class of broad spectrum antiviral effectors. Mol. Aspects Med. 49, 23–30 (2016).
  Medline CASGoogle Scholar
• 199. Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology-divergent pathophysiology. Nat. Rev. Endocrinol. 13(12), 710–730 (2017).
  Medline CASGoogle Scholar
• 200. Cheng X, Li J, Guo D. SCAP/SREBPs are central players in lipid metabolism and novel metabolic targets in cancer therapy. Curr. Top. Med. Chem. 18(6), 484–493 (2018).
  Medline CASGoogle Scholar
• 201. Oguro H. The roles of cholesterol and its metabolites in normal and malignant hematopoiesis. Front. Endocrinol. (Lausanne) 10, 204 (2019).
  MedlineGoogle Scholar
• 202. Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell Biol. 9(2), 125–138 (2008).
  Medline CASGoogle Scholar
• 203. Zou T, Garifulin O, Berland R, Boyartchuk VL. Listeria monocytogenes infection induces prosurvival metabolic signaling in macrophages. Infect. Immun. 79(4), 1526–1535 (2011).
  Medline CASGoogle Scholar
• 204. Liu SY, Aliyari R, Chikere K et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38(1), 92–105 (2013).
  MedlineGoogle Scholar
• 205. Gold ES, Ramsey SA, Sartain MJ et al. ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation. J. Exp. Med. 209(4), 807–817 (2012).
  Medline CASGoogle Scholar
• 206. Gatto D, Paus D, Basten A, Mackay CR, Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31(2), 259–269 (2009).
  Medline CASGoogle Scholar
• 207. Pereira JP, Kelly LM, Xu Y, Cyster JG. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460(7259), 1122–1126 (2009).
  Medline CASGoogle Scholar
• 208. Gatto D, Wood K, Caminschi I et al. The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells. Nat. Immunol. 14(5), 446–453 (2013).
  Medline CASGoogle Scholar
• 209. Li J, Lu E, Yi T, Cyster JG. EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells. Nature 533(7601), 110–114 (2016).
  Medline CASGoogle Scholar
• 210. Nevius E, Pinho F, Dhodapkar M et al. Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis. J. Exp. Med. 212(11), 1931–1946 (2015).
  Medline CASGoogle Scholar
• 211. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of the myelodysplastic syndromes. Br. J. Haematol. 51(2), 189–199 (1982).
  Medline CASGoogle Scholar
• 212. Tsujioka T, Yokoi A, Itano Y et al. Five-aza-2′-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells. Sci. Rep. 5, 16709 (2015). •• Raises the possibility that DNA methyltransferase (DNMT) inhibitors activate the CH25H–oxysterol pathway via their hypomethylating mechanism and induce leukemia cell death.
  Medline CASGoogle Scholar
• 213. Cazzola M, Malcovati L. Myelodysplastic syndromes – coping with ineffective hematopoiesis. N. Engl. J. Med. 352(6), 536–538 (2005).
  Medline CASGoogle Scholar
• 214. Issa JP, Kantarjian HM. Targeting DNA methylation. Clin. Cancer Res. 15(12), 3938–3946 (2009).
  Medline CASGoogle Scholar
• 215. Quintás-Cardama A, Santos FP, Garcia-Manero G. Therapy with azanucleosides for myelodysplastic syndromes. Nat. Rev. Clin. Oncol. 7(8), 433–444 (2010).
  Medline CASGoogle Scholar
• 216. Silverman LR, Demakos EP, Peterson BL et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol. 20(10), 2429–2440 (2002).
  Medline CASGoogle Scholar
• 217. Kornblith AB, Herndon JE 2nd, Silverman LR et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a cancer and leukemia group B study. J. Clin. Oncol. 20(10), 2441–2452 (2002).
  Medline CASGoogle Scholar
• 218. Kantarjian H, Issa JP, Rosenfeld CS et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106(8), 1794–1803 (2006).
  Medline CASGoogle Scholar
• 219. Lübbert M, Suciu S, Baila L et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J. Clin. Oncol. 29(15), 1987–1996 (2011).
  Medline CASGoogle Scholar
• 220. Flotho C, Claus R, Batz C et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia 23(6), 1019–1028 (2009).
  Medline CASGoogle Scholar
• 221. Hollenbach PW, Nguyen AN, Brady H et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLOS ONE 5(2), e9001 (2010).
  MedlineGoogle Scholar
• 222. Qin T, Youssef EM, Jelinek J et al. Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin. Cancer Res. 13(14), 4225–4232 (2007).
  Medline CASGoogle Scholar
• 223. Tsujioka T, Yokoi A, Uesugi M et al. Effects of DNA methyltransferase inhibitors (DNMTIs) on MDS-derived cell lines. Exp. Hematol. 41(2), 189–197 (2013).
  Medline CASGoogle Scholar
• 224. Wang JH, Tuohimaa P. Regulation of cholesterol 25-hydroxylase expression by vitamin D₃ metabolites in human prostate stromal cells. Biochem. Biophys. Res. Commun. 345(2), 720–725 (2006).
  Medline CASGoogle Scholar
• 225. Larsson O, Zetterberg A. Existence of a commitment program for mitosis in early G₁ in tumour cells. Cell Prolif. 28(1), 33–43 (1995).
  Medline CASGoogle Scholar
• 226. Zhou RH, Yao M, Lee TS, Zhu Y, Martins-Green M, Shyy JY. Vascular endothelial growth factor activation of sterol regulatory element binding protein: a potential role in angiogenesis. Circ. Res. 95(5), 471–478 (2004).
  Medline CASGoogle Scholar
• 227. Ayala-Torres S, Zhou F, Thompson EB. Apoptosis induced by oxysterol in CEM cells is associated with negative regulation of c-myc. Exp. Cell Res. 246(1), 193–202 (1999).
  Medline CASGoogle Scholar
• 228. Banker DE, Mayer SJ, Li HY, Willman CL, Appelbaum FR, Zager RA. Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells. Blood 104(6), 1816–1824 (2004).
  Medline CASGoogle Scholar
• 229. Zhang F, Dai X, Wang Y. 5-aza-2′-deoxycytidine induced growth inhibition of leukemia cells through modulating endogenous cholesterol biosynthesis. Mol. Cell. Proteomics 11(7), M111.016915 (2012).
  MedlineGoogle Scholar
• 230. Hu J, La Vecchia C, de Groh M, Negri E, Morrison H, Mery L. Dietary cholesterol intake and cancer. Ann. Oncol. 23(2), 491–500 (2012).
  Medline CASGoogle Scholar
• 231. Mouritsen OG, Bagatolli LA. Lipid domains in model membranes: a brief historical perspective. Essays Biochem. 57, 1–19 (2015).
  MedlineGoogle Scholar
• 232. Chichili GR, Rodgers W. Cytoskeleton–membrane interactions in membrane raft structure. Cell. Mol. Life Sci. 66(14), 2319–2328 (2009).
  Medline CASGoogle Scholar
• 233. George KS, Wu S. Lipid raft: a floating island of death or survival. Toxicol. Appl. Pharmacol. 259(3), 311–319 (2012).
  Medline CASGoogle Scholar
• 234. Hamm R, Chen YR, Seo EJ et al. Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells. Biochem. Pharmacol. 91(1), 18–30 (2014).
  Medline CASGoogle Scholar
• 235. Lu DL, Sookthai D, Le Cornet C et al. Reproducibility of serum oxysterols and lanosterol among postmenopausal women: results from EPIC–Heidelberg. Clin. Biochem. 52, 117–122 (2018).
  Medline CASGoogle Scholar
• 236. Wang C, He H, Fang W. Oncogenic roles of the cholesterol metabolite 25-hydroxycholesterol in bladder cancer. Oncol. Lett. 19(6), 3671–3676 (2020).
  Medline CASGoogle Scholar
• 237. Stupp R, Hegi ME, van den Bent MJ et al. Changing paradigms – an update on the multidisciplinary management of malignant glioma. Oncologist 11(2), 165–180 (2006).
  Medline CASGoogle Scholar
• 238. Bouzari B, Mohammadi S, Bokov DO et al. Angioregulatory role of miRNAs and exosomal miRNAs in glioblastoma pathogenesis. Biomed. Pharmacother. 148, 112760 (2022).
  Medline CASGoogle Scholar
• 239. Makoukji J, Shackleford G, Meffre D et al. Interplay between LXR and Wnt/β-catenin signaling in the negative regulation of peripheral myelin genes by oxysterols. J. Neurosci. 31(26), 9620–9629 (2011). • Reveals new endogenous mechanisms for the negative regulation of myelin gene expression, highlights the importance of oxysterols and LXR in peripheral nerve myelination and opens new perspectives for treating demyelinating diseases with LXR agonists.
  Medline CASGoogle Scholar
• 240. Guo D, Hildebrandt IJ, Prins RM et al. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc. Natl Acad. Sci. USA 106(31), 12932–12937 (2009).
  Medline CASGoogle Scholar
• 241. Guo D, Reinitz F, Youssef M et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 1(5), 442–456 (2011).
  Medline CASGoogle Scholar
• 242. Liu Y, Hultén LM, Wiklund O. Macrophages isolated from human atherosclerotic plaques produce IL-8, and oxysterols may have a regulatory function for IL-8 production. Arterioscler. Thromb. Vasc. Biol. 17(2), 317–323 (1997).
  Medline CASGoogle Scholar
• 243. Nachtergaele S, Mydock LK, Krishnan K et al. Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat. Chem. Biol. 8(2), 211–220 (2012).
  Medline CASGoogle Scholar
• 244. Corcoran RB, Scott MP. Oxysterols stimulate Sonic Hedgehog signal transduction and proliferation of medulloblastoma cells. Proc. Natl Acad. Sci. USA 103(22), 8408–8413 (2006).
  Medline CASGoogle Scholar
• 245. Xu L, Shen S, Ma Y et al. 25-hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages. Am. J. Physiol. Endocrinol. Metab. 302(7), e788–e799 (2012). • Concluded that 25-HC-3-sulfate acts in macrophages as a PPAR-γ ligand and suppresses inflammatory responses via the PPAR-γ/IκB/NF-κB signaling pathway.
  Medline CASGoogle Scholar
• 246. Russo V. Metabolism, LXR/LXR ligands, and tumor immune escape. J. Leukoc. Biol. 90(4), 673–679 (2011).
  Medline CASGoogle Scholar
• 247. Marcuzzi A, Tricarico PM, Piscianz E, Kleiner G, Vecchi Brumatti L, Crovella S. Lovastatin induces apoptosis through the mitochondrial pathway in an undifferentiated SH-SY5Y neuroblastoma cell line. Cell Death Dis. 4(4), e585 (2013).
  Medline CASGoogle Scholar
• 248. Tricarico PM, Crovella S, Celsi F. Mevalonate pathway blockade, mitochondrial dysfunction and autophagy: a possible link. Int. J. Mol. Sci. 16(7), 16067–16084 (2015).
  Medline CASGoogle Scholar
• 249. Tricarico PM, Gratton R, Braga L, Celsi F, Crovella S. 25-hydroxycholesterol and inflammation in lovastatin-deregulated mevalonate pathway. Int. J. Biochem. Cell Biol. 92, 26–33 (2017).
  Medline CASGoogle Scholar
• 250. Mirzaei R, Bouzari B, Hosseini-Fard SR et al. Role of microbiota-derived short-chain fatty acids in nervous system disorders. Biomed. Pharmacother. 139, 111661 (2021).
  Medline CASGoogle Scholar
• 251. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J. Clin. 65(2), 87–108 (2015).
  MedlineGoogle Scholar
• 252. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol. Biomarkers Prev. 23(5), 700–713 (2014).
  MedlineGoogle Scholar
• 253. Kitayama J, Hatano K, Kaisaki S, Suzuki H, Fujii S, Nagawa H. Hyperlipidaemia is positively correlated with lymph node metastasis in men with early gastric cancer. Br. J. Surg. 91(2), 191–198 (2004).
  Medline CASGoogle Scholar
• 254. Guo E, Chen L, Xie Q, Chen J, Tang Z, Wu Y. Serum HDL-C as a potential biomarker for nodal stages in gastric cancer. Ann. Surg. Oncol. 14(9), 2528–2534 (2007).
  MedlineGoogle Scholar
• 255. Chen G, Feng W, Zhang S et al. Metformin inhibits gastric cancer via the inhibition of HIF1α/PKM2 signaling. Am. J. Cancer Res. 5(4), 1423–1434 (2015).
  MedlineGoogle Scholar
• 256. Valaee S, Yaghoobi MM, Shamsara M. Metformin inhibits gastric cancer cells metastatic traits through suppression of epithelial–mesenchymal transition in a glucose-independent manner. PLOS ONE 12(3), e0174486 (2017).
  MedlineGoogle Scholar
• 257. Singh PP, Singh S. Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis. Ann. Oncol. 24(7), 1721–1730 (2013).
  Medline CASGoogle Scholar
• 258. Burkard I, von Eckardstein A, Waeber G, Vollenweider P, Rentsch KM. Lipoprotein distribution and biological variation of 24S- and 27-hydroxycholesterol in healthy volunteers. Atherosclerosis 194(1), 71–78 (2007).
  MedlineGoogle Scholar
• 259. Yang P, Zhou Y, Chen B et al. Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur. J. Cancer 45(16), 2867–2873 (2009).
  MedlineGoogle Scholar
• 260. Guo F, Hong W, Yang M et al. Upregulation of 24(R/S),25-epoxycholesterol and 27-hydroxycholesterol suppresses the proliferation and migration of gastric cancer cells. Biochem. Biophys. Res. Commun. 504(4), 892–898 (2018).
  Medline CASGoogle Scholar
• 261. Bonneterre J, Thürlimann B, Robertson JF et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J. Clin. Oncol. 18(22), 3748–3757 (2000).
  Medline CASGoogle Scholar
• 262. Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 9(1), 45–53 (2008).
  MedlineGoogle Scholar
• 263. Markopoulos CJ. Minimizing early relapse and maximizing treatment outcomes in hormone-sensitive postmenopausal breast cancer: efficacy review of AI trials. Cancer Metastasis Rev. 29(4), 581–594 (2010).
  Medline CASGoogle Scholar
• 264. Arpino G, Green SJ, Allred DC et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. Clin. Cancer Res. 10(17), 5670–5676 (2004).
  Medline CASGoogle Scholar
• 265. Martin LA, Farmer I, Johnston SR, Ali S, Dowsett M. Elevated ERK1/ERK2/estrogen receptor cross-talk enhances estrogen-mediated signaling during long-term estrogen deprivation. Endocr. Relat. Cancer 12(Suppl. 1), S75–S84 (2005).
  Medline CASGoogle Scholar
• 266. Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat. Rev. Cancer 15(5), 261–275 (2015).
  Medline CASGoogle Scholar
• 267. Ellis MJ, Ding L, Shen D et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486(7403), 353–360 (2012).
  Medline CASGoogle Scholar
• 268. Gao Q, Patani N, Dunbier AK et al. Effect of aromatase inhibition on functional gene modules in estrogen receptor-positive breast cancer and their relationship with antiproliferative response. Clin. Cancer Res. 20(9), 2485–2494 (2014).
  Medline CASGoogle Scholar
• 269. Peck B, Schulze A. Cholesteryl esters: fueling the fury of prostate cancer. Cell Metab. 19(3), 350–352 (2014).
  Medline CASGoogle Scholar
• 270. Kovač U, Skubic C, Bohinc L, Rozman D, Režen T. Oxysterols and gastrointestinal cancers around the clock. Front. Endocrinol. (Lausanne) 10, 483 (2019).
  MedlineGoogle Scholar
• 271. Zhong S, Zhang X, Chen L, Ma T, Tang J, Zhao J. Statin use and mortality in cancer patients: systematic review and meta-analysis of observational studies. Cancer Treat. Rev. 41(6), 554–567 (2015).
  Medline CASGoogle Scholar
• 272. Liu Y, Tang W, Wang J et al. Association between statin use and colorectal cancer risk: a meta-analysis of 42 studies. Cancer Causes Control 25(2), 237–249 (2014).
  Medline CASGoogle Scholar
• 273. Zhou YY, Zhu GQ, Wang Y et al. Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. Oncotarget 7(16), 21753–21762 (2016).
  MedlineGoogle Scholar
• 274. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144(2), 323–332 (2013).
  Medline CASGoogle Scholar
• 275. Shi M, Zheng H, Nie B, Gong W, Cui X. Statin use and risk of liver cancer: an update meta-analysis. BMJ Open 4(9), e005399 (2014).
  MedlineGoogle Scholar
• 276. Tsan YT, Lee CH, Ho WC, Lin MH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J. Clin. Oncol. 31(12), 1514–1521 (2013).
  MedlineGoogle Scholar
• 277. Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J. Clin. Oncol. 30(6), 623–630 (2012).
  MedlineGoogle Scholar
• 278. Hsiang JC, Wong GL, Tse YK, Wong VW, Yip TC, Chan HL. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: a propensity score landmark analysis. J. Hepatol. 63(5), 1190–1197 (2015).
  Medline CASGoogle Scholar
• 279. Chen CI, Kuan CF, Fang YA et al. Cancer risk in HBV patients with statin and metformin use: a population-based cohort study. Medicine (Baltimore) 94(6), e462 (2015).
  Medline CASGoogle Scholar
• 280. Janicko M, Drazilova S, Pella D, Fedacko J, Jarcuska P. Pleiotropic effects of statins in the diseases of the liver. World J. Gastroenterol. 22(27), 6201–6213 (2016).
  Medline CASGoogle Scholar
• 281. Nishio T, Taura K, Nakamura N et al. Impact of statin use on the prognosis of patients with hepatocellular carcinoma undergoing liver resection: a subgroup analysis of patients without chronic hepatitis viral infection. Surgery 163(2), 264–269 (2018).
  MedlineGoogle Scholar
• 282. Kawaguchi Y, Sakamoto Y, Ito D et al. Statin use is associated with a reduced risk of hepatocellular carcinoma recurrence after initial liver resection. Biosci. Trends 11(5), 574–580 (2017).
  Medline CASGoogle Scholar
• 283. Archibugi L, Arcidiacono PG, Capurso G. Statin use is associated to a reduced risk of pancreatic cancer: a meta-analysis. Dig. Liver Dis. 51(1), 28–37 (2019).
  Medline CASGoogle Scholar
• 284. Hamada T, Khalaf N, Yuan C et al. Statin use and pancreatic cancer risk in two prospective cohort studies. J. Gastroenterol. 53(8), 959–966 (2018).
  Medline CASGoogle Scholar
• 285. Singh S, Singh PP, Roberts LR, Sanchez W. Chemopreventive strategies in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 11(1), 45–54 (2014).
  Medline CASGoogle Scholar
• 286. Lipkin SM, Chao EC, Moreno V et al. Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer Prev. Res. (Phila.) 3(5), 597–603 (2010).
  Medline CASGoogle Scholar
• 287. Amin S, Boffetta P, Lucas AL. The role of common pharmaceutical agents on the prevention and treatment of pancreatic cancer. Gut Liver 10(5), 665–671 (2016).
  Medline CASGoogle Scholar
• 288. Li N, Zhou ZS, Shen Y et al. Inhibition of the sterol regulatory element-binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice. Hepatology 65(6), 1936–1947 (2017).
  Medline CASGoogle Scholar
• 289. Kim YS, Lee YM, Oh TI et al. Emodin sensitizes hepatocellular carcinoma cells to the anti-cancer effect of sorafenib through suppression of cholesterol metabolism. Int. J. Mol. Sci. 19(10), (2018).
  Google Scholar
• 290. Gabitova L, Gorin A, Astsaturov I. Molecular pathways: sterols and receptor signaling in cancer. Clin. Cancer Res. 20(1), 28–34 (2014).
  Medline CASGoogle Scholar
• 291. Chuu CP. Modulation of liver X receptor signaling as a prevention and therapy for colon cancer. Med. Hypotheses 76(5), 697–699 (2011).
  Medline CASGoogle Scholar
• 292. Bellomo C, Caja L, Fabregat I. Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma. Cell Death Differ. 25(5), 885–903 (2018).
  Medline CASGoogle Scholar
• 293. Pattanayak SP, Bose P, Sunita P, Siddique MUM, Lapenna A. Bergapten inhibits liver carcinogenesis by modulating LXR/PI3K/Akt and IDOL/LDLR pathways. Biomed. Pharmacother. 108, 297–308 (2018).
  Medline CASGoogle Scholar
• 294. Lo Sasso G, Bovenga F, Murzilli S et al. Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. Gastroenterology 144(7), 1497–1507, 1507; e1–13 (2013).
  MedlineGoogle Scholar
• 295. De Boussac H, Alioui A, Viennois E et al. Oxysterol receptors and their therapeutic applications in cancer conditions. Expert Opin. Ther. Targets 17(9), 1029–1038 (2013).
  MedlineGoogle Scholar
• 296. Peng Z, Chen J, Drachenberg CB, Raufman JP, Xie G. Farnesoid X receptor represses matrix metalloproteinase 7 expression, revealing this regulatory axis as a promising therapeutic target in colon cancer. J. Biol. Chem. 294(21), 8529–8542 (2019).
  Medline CASGoogle Scholar
• 297. Alawad AS, Levy C. FXR agonists: from bench to bedside, a guide for clinicians. Dig. Dis. Sci. 61(12), 3395–3404 (2016).
  MedlineGoogle Scholar
• 298. Kowdley KV, Luketic V, Chapman R et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 67(5), 1890–1902 (2018).
  Medline CASGoogle Scholar
• 299. Fu T, Coulter S, Yoshihara E et al. FXR regulates intestinal cancer stem cell proliferation. Cell 176(5), 1098–1112.e18 (2019).
  Medline CASGoogle Scholar
• 300. Ortiz A, Gui J, Zahedi F et al. An interferon-driven oxysterol-based defense against tumor-derived extracellular vesicles. Cancer Cell 35(1), 33–45.e6 (2019).
  Medline CASGoogle Scholar