Modulation of microRNA by Vitamin D in Cancer Studies

  • Emma L. BeckettEmail author
  • Martin Veysey
  • Zoe Yates
  • Mark Lucock
Reference work entry


Vitamin D, a steroid hormone, is well known for its influence in regulating gene expression via the action of the vitamin D receptor, in addition to its classical roles in maintaining calcium homeostasis and bone health. Recently, vitamin D status has been linked to a number of additional nonskeletal diseases, including cancers. Aberrant miRNA profiles have been demonstrated in malignant tissues and in the serum and plasma of cancer patients, leading to investigations into the potential that vitamin D-dependent modulation of miRNA profiles is involved in determining the risk and progression of malignancy. A number of studies, mostly in cell culture models, have demonstrated the modulation of a number of miRNA in a number of cancers; however, results vary depending on the cell line, stimulation concentration, and time of treatment. Additional studies are needed to assess similar relationships in other diseases where risk is linked to vitamin D status. While few studies have been conducted in humans, differences in serum profiles relative to vitamin D levels have been demonstrated. miRNA may provide a link between vitamin D status and disease risk, and this may offer a potential therapeutic avenue. Evidence exists to show that vitamin D can modulate miRNA levels by altering expression of the enzymes involved in miRNA biogenesis and direct and indirect induction of miRNA transcription. However, additional studies are needed to fully elucidate the genetic pathways resulting in modulation of miRNA and to understand the complex interactions between miRNA and vitamin D-related targets.


Vitamin D miRNA Calcitriol Cancer Vitamin D receptor VDR VDRE 

List of Abbreviations








Acute myeloid leukemia


Colorectal cancer




Messenger RNA




Precursor microRNA


Primary microRNA


RNA-induced silencing complex


Retinoic acid receptor


Vitamin D receptor


Vitamin D response element


  1. Adorini L, Penna G (2008) Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 4:404–412PubMedGoogle Scholar
  2. Alvarez-Díaz S et al (2012) MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells. Hum Mol Genet 21(10):2157–2165PubMedGoogle Scholar
  3. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297PubMedPubMedCentralGoogle Scholar
  4. Bartoszewski R et al (2011) The unfolded protein response (UPR)-activated transcription factor X-box-binding protein 1 (XBP1) induces microRNA-346 expression that targets the human antigen peptide transporter 1 (TAP1) mRNA and governs immune regulatory genes. J Biol Chem 286(48):41862–41870PubMedPubMedCentralGoogle Scholar
  5. Beckett EL et al (2014) The role of vitamins and minerals in modulating the expression of microRNA. Nutr Res Rev 27(1):94–106PubMedGoogle Scholar
  6. Biasiolo M et al (2011) Impact of host genes and strand selection on miRNA and miRNA* expression. PLoS One 6(8):e23854PubMedPubMedCentralGoogle Scholar
  7. Borkowski R et al (2015) Genetic mutation of p53 and suppression of the miR-17 approximately 92 cluster are synthetic lethal in non-small cell lung cancer due to upregulation of vitamin D signaling. Cancer Res 75(4):666–675PubMedGoogle Scholar
  8. Carlberg C, Campbell MJ (2013) Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor. Steroids 78(2):127–136PubMedGoogle Scholar
  9. Carmeliet G et al (2015) Vitamin D signaling in calcium and bone homeostasis: a delicate balance. Best Pract Res Clin Endocrinol Metab 29(4):621–631PubMedGoogle Scholar
  10. Chang S et al (2015) miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 by directly targeting E2F3 in gastric cancer cells. Oncotarget 6(10):7675–7685PubMedPubMedCentralGoogle Scholar
  11. Cheloufi S et al (2010) A dicer-independent miRNA biogenesis pathway that requires ago catalysis. Nature 465:584–589PubMedPubMedCentralGoogle Scholar
  12. Chen Y et al (2013) 1,25-Dihydroxyvitamin D promotes negative feedback regulation of TLR signaling via targeting microRNA-155-SOCS1 in macrophages. J Immunol 190(7):3687–3695PubMedPubMedCentralGoogle Scholar
  13. Chen Y et al (2014) MicroRNA-346 mediates tumor necrosis factor alpha-induced downregulation of gut epithelial vitamin D receptor in inflammatory bowel diseases. Inflamm Bowel Dis 20(11):1910–1918PubMedPubMedCentralGoogle Scholar
  14. Chiosea S et al (2006) Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma. Am J Pathol 169(5):1812–1820PubMedPubMedCentralGoogle Scholar
  15. de Zhuo X et al (2010) Vitamin D3 up-regulated protein 1(VDUP1) is regulated by FOXO3A and miR-17-5p at the transcriptional and post-transcriptional levels, respectively, in senescent fibroblasts. J Biol Chem 285(41):31491–31501PubMedCentralGoogle Scholar
  16. Disanto G et al (2012) Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum Mol Genet 21(16):3575–3586PubMedPubMedCentralGoogle Scholar
  17. Enquobahrie D et al (2011) Global maternal early pregnancy peripheral blood mRNA and miRNA expression profiles according to plasma 25-hydroxyvitamin D concentrations. J Matern Fetal Neonatal Med 24(8):1002–1012PubMedPubMedCentralGoogle Scholar
  18. Fang F et al (2011) Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One 6(4):e18625PubMedPubMedCentralGoogle Scholar
  19. Fetahu IS et al (2014) Vitamin D and the epigenome. Front Physiol 5:164PubMedPubMedCentralGoogle Scholar
  20. Fontemaggi G et al (2015) Identification of post-transcriptional regulatory networks during myeloblast-to-monocyte differentiation transition. RNA Biol 12(7):690–700PubMedPubMedCentralGoogle Scholar
  21. Friedman RC et al (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19(1):92–105PubMedPubMedCentralGoogle Scholar
  22. Gandini S et al (2011) Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer 128(6):1414–1424PubMedGoogle Scholar
  23. Garzon R et al (2006) MicroRNA expression and function in cancer. Trends Mol Med 12(12):580–587PubMedGoogle Scholar
  24. Giangreco AA, Nonn L (2013) The sum of many small changes: microRNAs are specifically and potentially globally altered by vitamin D3 metabolites. J Steroid Biochem Mol Biol 136:86–93PubMedPubMedCentralGoogle Scholar
  25. Giangreco A et al (2013) Tumor suppressor microRNAs, miR-100 and -125b, are regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in patient tissue. Cancer Prev Res (Phila) 6(5):483–494Google Scholar
  26. Giovannucci E (2005) The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 16(2):83–95PubMedGoogle Scholar
  27. Gocek E et al (2011) MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res 71(19):6230–6239PubMedPubMedCentralGoogle Scholar
  28. Gonzalez-Duarte RJ et al (2015) Calcitriol increases Dicer expression and modifies the microRNAs signature in SiHa cervical cancer cells. Biochem Cell Biol 93(4):376–384PubMedGoogle Scholar
  29. Griffin MD et al (2001) Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci U S A 98(12):6800–6805PubMedPubMedCentralGoogle Scholar
  30. Guan H et al (2013) 1,25-Dihydroxyvitamin D3 up-regulates expression of hsa-let-7a-2 through the interaction of VDR/VDRE in human lung cancer A549 cells. Gene 522(2):142–146PubMedGoogle Scholar
  31. He L et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435(7043):828–833PubMedPubMedCentralGoogle Scholar
  32. Heikkinen S et al (2011) Nuclear hormone 1alpha,25-dihydroxyvitamin D3 elicits a genome-wide shift in the locations of VDR chromatin occupancy. Nucleic Acids Res 39(21):9181–9193PubMedPubMedCentralGoogle Scholar
  33. Hsu JY et al (2001) Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res 61(7):2852–2856PubMedGoogle Scholar
  34. Iosue I et al (2013) Argonaute 2 sustains the gene expression program driving human monocytic differentiation of acute myeloid leukemia cells. Cell Death Dis 4:e926PubMedPubMedCentralGoogle Scholar
  35. Jacobs ET et al (2016) Vitamin D and colorectal, breast, and prostate cancers: a review of the epidemiological evidence. J Cancer 7(3):232–240PubMedPubMedCentralGoogle Scholar
  36. Jiao L et al (2014) miR-663 induces castration-resistant prostate cancer transformation and predicts clinical recurrence. J Cell Physiol 229(7):834–844PubMedGoogle Scholar
  37. Jorde R et al (2012) Plasma profile of microRNA after supplementation with high doses of vitamin D3 for 12 months. BMC Res Notes 5(1):245PubMedPubMedCentralGoogle Scholar
  38. Kim Y, Kim V (2012) MicroRNA factory: RISC assembly from precursor MicroRNAs. Mol Cell 46(4):384–386PubMedGoogle Scholar
  39. Kinjyo I et al (2002) SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17(5):583–591PubMedGoogle Scholar
  40. Komagata S et al (2009) Human CYP24 catalyzing the inactivation of calcitriol is post-transcriptionally regulated by miR-125b. Mol Pharmacol 76(4):702–709PubMedGoogle Scholar
  41. Lamprecht S, Lipkin M (2003) Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3:601–614PubMedGoogle Scholar
  42. Lappe J et al (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial1,2. Am J Clin Nutr 85(6):1586–1591PubMedGoogle Scholar
  43. Lee Y et al (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21(17):4663–4670PubMedPubMedCentralGoogle Scholar
  44. Lee J et al (2013) Hypermethylation and post-transcriptional regulation of DNA methyltransferases in the ovarian carcinomas of the laying hen. PLoS One 8(4):e61658PubMedPubMedCentralGoogle Scholar
  45. Lee HJ et al (2014) Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult acute myeloid leukemia. Cancer 120(4):521–529PubMedGoogle Scholar
  46. Li YC et al (2014) MicroRNA-mediated mechanism of vitamin D regulation of innate immune response. J Steroid Biochem Mol Biol 144(Pt A):81–86PubMedGoogle Scholar
  47. Li F et al (2015) 1alpha,25-Dihydroxyvitamin D3 prevents the differentiation of human lung fibroblasts via microRNA-27b targeting the vitamin D receptor. Int J Mol Med 36(4):967–974PubMedPubMedCentralGoogle Scholar
  48. Liu PT et al (2012) MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy. Nat Med 18(2):267–273PubMedPubMedCentralGoogle Scholar
  49. Ma Y et al (2015) 1alpha,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer cells. J Steroid Biochem Mol Biol 148:166–171PubMedGoogle Scholar
  50. Min D et al (2013) Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity. Br J Cancer 109(3):723–730PubMedPubMedCentralGoogle Scholar
  51. Miyaura C et al (1981) 1 alpha,25-Dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells. Biochem Biophys Res Commun 102(3):937–943PubMedGoogle Scholar
  52. Mohamadkhani A et al (2015) Negative association of plasma levels of vitamin D and miR-378 with viral load in patients with chronic hepatitis B infection. Hepat Mon 15(6):e28315PubMedPubMedCentralGoogle Scholar
  53. Mohr SB et al (2011) Ultraviolet B and incidence rates of leukemia worldwide. Am J Prev Med 41(1):68–74PubMedGoogle Scholar
  54. Mohri T et al (2009) MicroRNA regulates human vitamin D receptor. Int J Cancer 125(6):1328–1333PubMedGoogle Scholar
  55. Munker R et al (1986) Vitamin D compounds. Effect on clonal proliferation and differentiation of human myeloid cells. J Clin Invest 78(2):424–430PubMedPubMedCentralGoogle Scholar
  56. Newmark HL et al (2009) Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer. Carcinogenesis 30(1):88–92PubMedGoogle Scholar
  57. Padi S et al (2013) MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice. Gastroenterology 145(2):437–446PubMedPubMedCentralGoogle Scholar
  58. Pedersen AW et al (2009) Phenotypic and functional markers for 1alpha,25-dihydroxyvitamin D(3)-modified regulatory dendritic cells. Clin Exp Immunol 157(1):48–59PubMedPubMedCentralGoogle Scholar
  59. Peng X et al (2010) Protection against cellular stress by 25-hydroxyvitamin D3 in breast epithelial cells. J Cell Biochem 110(6):1324–1333PubMedGoogle Scholar
  60. Pobezinsky LA et al (2015) Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Nat Immunol 16(5):517–524PubMedPubMedCentralGoogle Scholar
  61. Prosser DE, Jones G (2004) Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci 29(12):664–673PubMedGoogle Scholar
  62. Ramagopalan SV et al (2010) A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res 20(10):1352–1360PubMedPubMedCentralGoogle Scholar
  63. Sakaki T et al (2005) Metabolism of vitamin D3 by cytochromes P450. Front Biosci 10:119–134PubMedGoogle Scholar
  64. Salvatori B et al (2011) Critical role of c-Myc in acute myeloid leukemia involving direct regulation of miR-26a and histone methyltransferase EZH2. Genes Cancer 2(5):585–592PubMedPubMedCentralGoogle Scholar
  65. Salvatori B et al (2012) The microRNA-26a target E2F7 sustains cell proliferation and inhibits monocytic differentiation of acute myeloid leukemia cells. Cell Death Dis 3:e413PubMedPubMedCentralGoogle Scholar
  66. Schotte D et al (2012) MicroRNAs in acute leukemia: from biological players to clinical contributors. Leukemia 26(1):1–12PubMedGoogle Scholar
  67. Singh PK et al (2015) VDR regulation of microRNA differs across prostate cell models suggesting extremely flexible control of transcription. Epigenetics 10(1):40–49PubMedPubMedCentralGoogle Scholar
  68. Sonkoly E et al (2012) MicroRNA-203 functions as a tumor suppressor in basal cell carcinoma. Oncogene 1:e3Google Scholar
  69. Tangpricha V et al (2005) Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c mice. J Nutr 135(10):2350–2354PubMedGoogle Scholar
  70. Thorne JL et al (2011) Epigenetic control of a VDR-governed feed-forward loop that regulates p21(waf1/cip1) expression and function in non-malignant prostate cells. Nucleic Acids Res 39(6):2045–2056PubMedGoogle Scholar
  71. Ting H et al (2013) Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by vitamin D. J Biol Chem 288(1):1–9PubMedGoogle Scholar
  72. Townsend K et al (2005) Autocrine metabolism of vitamin D in normal and malignant breast tissue. Clin Cancer Res 11(9):3579–3586PubMedGoogle Scholar
  73. Trump DL et al (2009) Vitamin D deficiency and insufficiency among patients with prostate cancer. BJU Int 104(7):909–914PubMedPubMedCentralGoogle Scholar
  74. Volinia S et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 103(7):2257–2261PubMedPubMedCentralGoogle Scholar
  75. Wang T et al (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117:503–511PubMedGoogle Scholar
  76. Wang X et al (2009) MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3. Cell Cycle 8(5):736–741PubMedPubMedCentralGoogle Scholar
  77. Wang WL et al (2011) Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer 10:58PubMedPubMedCentralGoogle Scholar
  78. Wang Y et al (2012) Where is the vitamin D receptor? Arch Biochem Biophys 523(1):123–133PubMedGoogle Scholar
  79. Wickramasinghe NS et al (2009) Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids Res 37(8):2584–2595PubMedPubMedCentralGoogle Scholar
  80. Yang X et al (2012) miR-125b regulation of androgen receptor signaling via modulation of the receptor complex co-repressor NCOR2. Biores Open Access 1(2):55–62PubMedPubMedCentralGoogle Scholar
  81. Ye EA, Steinle JJ (2016) miR-146a attenuates inflammatory pathways mediated by TLR4/NF-kappaB and TNFalpha to protect primary human retinal microvascular endothelial cells grown in high glucose. Mediat Inflamm 2016:3958453Google Scholar
  82. Yi R et al (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17(24):3011–3016PubMedPubMedCentralGoogle Scholar
  83. Zhang J et al (2010) microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 103(8):1215–1220PubMedPubMedCentralGoogle Scholar
  84. Zhang J et al (2011) DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nat Struct Mol Biol 18(5):556–563PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Emma L. Beckett
    • 1
    Email author
  • Martin Veysey
    • 2
  • Zoe Yates
    • 3
  • Mark Lucock
    • 4
  1. 1.School of Medicine and Public HealthThe University of NewcastleOurimbahAustralia
  2. 2.School of Medicine and Public HealthThe University of Newcastle, Gosford HospitalGosfordAustralia
  3. 3.School of Biomedical Sciences and PharmacyThe University of NewcastleOurimbahAustralia
  4. 4.School of Environmental and Life SciencesThe University of NewcastleOurimbahAustralia

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