Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women
Delores J. GrantAni ManichaikulAnthony J. AlbergElisa V. BanderaJill S. Barnholtz‐SloanMelissa L. BondyMichele L. CotéEllen FunkhouserPatricia G. MoormanLauren C. PeresEdward PetersAnn G. SchwartzPaul TerryXin‐Qun WangTemitope O. KekuCathrine HoyoAndrew BerchuckDale P. SandlerJack A. TaylorKatie M. O’BrienDigna R. Velez EdwardsTodd L. EdwardsAlicia Beeghly‐FadielNicolas WentzensenCeleste Leigh PearceAnna H. WuAlice S. WhittemoreValerie McGuireWeiva SiehJoseph H. RothsteinFrancesmary ModugnoRoberta B. NessKirsten B. MoysichMary Anne RossingJennifer A. DohertyThomas A. SellersJennifer B. PermuthÁlvaro N.A. MonteiroDouglas A. LevineVeronica Wendy SetiawanChristopher A. HaimanLoı̈c Le MarchandLynne R. WilkensBeth Y. KarlanUsha MenonSusan J. RamusSimon A. GaytherAleksandra Gentry‐MaharajKathryn L. TerryDaniel W. CramerEllen L. GoodeMelissa C. LarsonScott H. KaufmannRikki A. CanniotoKunle OdunsiJohn Lewis EtterRuea‐Yea HuangMarcus Q. BernardiniAlicia ToneTaymaa MayMarc T. GoodmanPamela J. ThompsonMichael E. CarneyShelley S. TworogerElizabeth M. PooleDiether LambrechtsIgnace VergoteAdriaan VandersticheleEls Van NieuwenhuysenHoda Anton‐CulverArgyrios ZiogasJames D. BrentonLine BjørgeHelga B. SalvensenLambertus A. KiemeneyLeon F.A.G. MassugerTanja PejovićAmanda BrueglMelissa MoffittLinda S. CookNhu D. LeAngela Brooks‐WilsonLinda E. KelemenPaul D.P. PharoahHonglin SongIan CampbellDiana EcclesAnna deFazioCatherine J. KennedyJoellen M. Schildkraut
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Abstract An association between genetic variants in the vitamin D receptor ( VDR ) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets ( EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5 , CYP2R1 , CYP27B1 , CYP24A1 , CYP11A1 , and GC ). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10 −6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10 −5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10 −5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.Keywords:
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Higher vitamin D exposure is hypothesized to prevent several cancers, possibly through genomic effects modulated by the vitamin D receptor (VDR), and autocrine/paracrine metabolism of the VDR's ligand, 1α,25-(OH) 2 -vitamin D. Herein we review the background and evidence to date on associations between polymorphisms in VDR and selected genes in the vitamin D pathway in relation to colorectal, breast, and prostate cancer. Although most studies to date have examined only a few VDR polymorphisms, more are beginning to comprehensively investigate polymorphisms in the VDR as well as in other vitamin D pathway genes, such as the vitamin D–binding protein gene (Gc) and CYP27B1 and CYP24A1, which code for enzymes that, respectively, synthesize and degrade 1α,25-(OH) 2 -vitamin D. Currently, there is no strong, consistent epidemiologic evidence for substantial influences of single variants in vitamin D pathway genes on risk for colorectal, breast, or prostate cancer, but promising leads are developing.
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A large number of studies have pointed to the relations between blood levels of 25-hydroxy vitamin D with cancer incidence and survival. The phenomenon of the multidirectional activity of vitamin D is possibly due to the presence of VDR in most nonskeletal human cells, including cancer cells. A wide range of the genes regulated by VDR are related with cell proliferation, apoptosis, differentiation, angiogenesis and metastasis. In some preclinical studies, colon, lung and BC have all demonstrated downregulation of VDR expression as compared to normal cells, and well-differentiated tumors have shown more VDR expression when compared to their poorly differentiated counterparts. Generally, higher tumor VDR expression has been noted as correlating with better prognosis in cancer patients. However, vitamin D pathway genetic polymorphisms also may influence cancer risk. VDR polymorphisms have received the most attention, but this influence has also been observed in genes related to vitamin D metabolism or signalling, such as: CYP27B1, CYP24A1, VDBP or RXRA. Even though the associations between most of them and cancers were not significant, some studies show that VDR polymorphisms may be a better or poor prognostic factor to assess the risk of cancer. The aim of this paper was to present the molecular pathways affected by vitamin D, which are included in carcinogenesis. The literature survey comprised of research compiled from mostly the last five years and it proves vitamin D as the most phenomenal among other vitamins.
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Vitamin D3 (D3) can be metabolized by cytochrome P450scc (CYP11A1) into 20S-hydroxyvitamin D3 (20D3) as a major metabolite. This bioactive metabolite has shown strong antiproliferative, antifibrotic, pro-differentiation and anti-inflammatory effects while being non-toxic (non-calcemic) at high concentrations. Since D3 analogs with two symmetric side chains (Gemini analogs) result in potent activation of the vitamin D receptor (VDR), we hypothesized that the chain length and composition of these types of analogs also containing a 20-hydroxyl group would affect their biological activities. In this study, we designed and synthesized a series of Gemini 20D3 analogs. Biological tests showed that some of these analogs are partial VDR activators and can significantly stimulate the expression of mRNA for VDR and VDR-regulated genes including CYP24A1 and transient receptor potential cation channel V6 (TRPV6). These analogs inhibited the proliferation of melanoma cells with potency comparable to that of 1α,25-dihydroxyvitamin D3. Moreover, these analogs reduced the level of interferon γ and up-regulated the expression of leukocyte associated immunoglobulin-like receptor 1 in splenocytes, indicating that they have potent anti-inflammatory activities. There are no clear correlations between the Gemini chain length and their VDR activation or biological activities, consistent with the high flexibility of the ligand-binding pocket of the VDR.
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Purpose: To investigate the effects of 1,25-Vit D3 and 24,25-Vit D3 on corneal fibroblast expression of the vitamin D-associated enzymes CYP27B1 and CYP24A1 and the roles of the vitamin D receptor (VDR) and protein disulfide isomerase, family A, member 3 (Pdia3) in these cells.Methods: CYP24A1, CYP27B1, VDR, and Pdia3 expression in corneas was detected using immunohistochemistry. Western blotting was used to measure protein expression in human and mouse fibroblasts, including VDR KO mouse cells, treated with 1,25-Vit D3 (20 nM) and 24,25-Vit D3 (100 nM). The Pdia3 inhibitor LOC14 was used to explore the role of Pdia3 as a Vit D3 receptor in these cells.Results: CYP24A1, CYP27B1, VDR, and Pdia3 were all expressed in mouse and human corneal fibroblasts. 1,25-Vit D3 significantly increased VDR expression in human and mouse fibroblasts. 1,25-Vit D3 and 24,25-VitD3 significantly increased CYP24A1 and CYP27B1 expression level in human, VDR WT mouse, and VDR KO mouse corneal fibroblasts. CYP24A1 and CYP27B1 expression was unchanged in VDR KO mouse fibroblasts treated with 1,25-Vit D3 or 24,25-Vit D3 plus LOC14. Human fibroblast VDR, CYP24A1, and CYP27B1 expression were unaffected by LOC14.Conclusions: Vitamin D metabolic enzymes, VDR, and Pdia3 are all expressed in mouse and human corneal fibroblasts. 1,25-Vit D3 modulates fibroblast vitamin D enzymes through both the VDR and Pdia3 pathways in a species-dependent manner. 24,25-Vit D3 can increase expression of fibroblast CYP24A1 and CYP27B1 in the absence of VDR and is likely involved in fibroblast regulation independent of 1,25-Vit D3 or VDR.
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Vitamin D deficit is considered an important risk factor for many inflammatory and autoimmune diseases.To investigate the influence of the multiple sclerosis (MS)-associated regulatory variant rs10877013 on the expression of genes involved in vitamin D activation (CYP27B1), vitamin D receptor (VDR), and vitamin D degradation (CYP24A1) under inflammatory environment or vitamin D.We used lipopolysaccharide and interferon-gamma (LPS+IFNγ) activated monocytes from 119 individuals and vitamin D-stimulated lymphoblastoid cell lines (LCLs, n = 109) of 1000 genomes to quantify the mRNA expression of vitamin D genes by quantitative reverse transcription polymerase chain reaction (RT-qPCR).We found that CYP27B1 mRNA expression level was associated with the rs10877013 genotypes (p = 5.0E-6) in LPS+IFNγ treated monocytes, but not in vitamin D-stimulated LCLs. Inversely, rs10877013 genotypes were associated with VDR expression in LCLs (p = 6.0E-4) but not in monocytes. Finally, CYP24A1 was highly induced by the active form of vitamin D and its expression correlated with the expression of VDR in LCLs but neither the MS-associated variant in the region (rs2248359) nor any other variant located in 1 Mb around CYP24A1 was associated with its expression.The MS-associated variant rs10877013 is a genetic determinant that affects the functioning of the vitamin D system linking environmental and genetic factors.
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Vitamin D is a promising anticancer agent for the prevention and treatment of several cancers, including melanoma. Low 25-hydroxyvitamin D levels, a routinely used marker for vitamin D, have been suggested as one of the factors in the development and progression of melanoma. The parent vitamin D needs activation by cytochrome P450 (CYP) enzymes to exert its actions via the vitamin D receptor (VDR). This review discusses the role of vitamin D in melanoma and how CYP-mediated metabolism can potentially affect the actions of vitamin D. Through interacting with the retinoid X receptor, VDR signaling leads to anti-inflammatory, antioxidative, and anticancer actions. Calcitriol, the dihydroxylated form of vitamin D3, is the most active and potent ligand of VDR. CYP27A1, CYP27B1, and CYP2R1 are involved in the activation of vitamin D, whereas CYP24A1 and CYP3A4 are responsible for the degradation of the active vitamin D. CYP24A1, the primary catabolic enzyme of calcitriol, is overexpressed in melanoma tissues and cells. Several drug classes and natural health products can modulate vitamin D-related CYP enzymes and eventually cause lower levels of vitamin D and its active metabolites in tissues. Although the role of vitamin D in the development of melanoma is yet to be fully elucidated, it has been proposed that melanoma prevention may be significantly aided by increased vitamin D signaling. Furthermore, selective targeting of the catabolic enzymes responsible for vitamin D degradation could be a plausible strategy in melanoma therapy. Vitamin D signaling can be improved by utilizing dietary supplements or by modulating CYP metabolism. A positive association exists between the intake of vitamin D supplements and improved prognosis for melanoma patients. Further investigation is required to determine the function of vitamin D supplementation and specific enzyme targeting in the prevention of melanoma.
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