Expression of VDR and CYP24A1 mRNA in human tumors

Anderson, Mark G.; Nakane, Masaki; Ruan, Xiaoan; Kroeger, Paul E.; Wu-Wong, J. Ruth

doi:10.1007/s00280-005-0059-7

Cited by 213 publications

(194 citation statements)

References 20 publications

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“…2001). In advanced CRC stages VDR expression decreases (Larriba and Mun˜oz., 2005;Matusiak et al, 2005;Anderson et al, 2006), and blocks the anti-cancer action of 1, 25(OH) 2 D (Pereira et al, 2012). Both 25 (OH) D and 1, 25(OH) 2 D have localized effect in colon tissue mediated by reducing cell proliferation and inducing cell differentiation (Seifert et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

Atoum¹,

Tchoporyan²

2014

Asian Pacific Journal of Cancer Prevention

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Section: Discussionmentioning

confidence: 99%

Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

Atoum¹,

Tchoporyan²

2014

Asian Pacific Journal of Cancer Prevention

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“…VDR mRNA was downregulated, while CYP24 mRNA was up-regulated in lung and colon tumors (30). CYP24 maps to chromosome 20q13.2 region and is proposed to be a candidate oncogene in human breast cancer (31) and esophageal cancer (32).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Silencing of CYP24 in Tumor-derived Endothelial Cells Contributes to Selective Growth Inhibition by Calcitriol

Chung

Karpf

Muindi

et al. 2007

Journal of Biological Chemistry

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Calcitriol (1,25-dihydroxycholecalciferol), the most active form of vitamin D, has selective anti-proliferative effects on tumor-derived endothelial cells (TDEC) compared with Matrigel-derived endothelial cells (MDEC). Although both cell types have an intact vitamin D receptor-signaling axis, this study demonstrates that upon treatment with calcitriol, 24-hydroxylase (CYP24) mRNA, protein and enzymatic activity were markedly induced in MDEC in a time-dependent manner but not in TDEC. Furthermore, treatment of MDEC with a CYP24 small interfering RNA restored sensitivity to calcitriol. To investigate the lack of CYP24 induction in TDEC, we examined methylation patterns in the promoter regions of the CYP24 gene in these two cell types. We identified two putative CpG island regions located at the 5 end. Using methylation-specific PCR and bisulfite sequencing, we determined that these CpG islands were hypermethylated in TDEC but not in MDEC. These data may explain the recruitment of vitamin D receptor to the promoter region in MDEC but not TDEC, as revealed by chromatin immunoprecipitation analyses. Treatment of TDEC with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine restored calcitriol-mediated induction of CYP24, which led to loss of sensitivity to calcitriol growth inhibitory effects. CYP24 promoter hypermethylation was also observed in endothelial cells isolated from other tumors but not in endothelial cells isolated from normal mouse tissues. These observations indicate that the methylation status of the CYP24 promoter differs in endothelial cells isolated from different microenvironments (tumor versus normal) and that methylation silencing of CYP24 contributes to selective calcitriol-mediated growth inhibition in endothelial cells.Although 1,25-dihydroxycholecalciferol (calcitriol), the most active metabolite of vitamin D 3 , is well known for its function in regulating calcium homeostasis and bone mineralization, it also plays a major role in modulating cellular proliferation and differentiation in a variety of cell types, including tumor cells (1). Calcitriol is growth inhibitory in several tumor models in vitro and in vivo including prostate, breast, and colon cancer and promotes cell differentiation, apoptosis, and cell cycle arrest (2-6).The effect of calcitriol in these tumors depends on the expression of the vitamin D receptor (VDR), 3 which upon binding to its ligand, acts as a transcription factor to regulate gene expression. In addition, the expression of the key enzyme of vitamin D catabolism, CYP24, also allows for a tight control of the effects of vitamin D in target tissues (7). Ligand-activated VDR induces expression of CYP24, which initiates inactivation and degradation of calcitriol by hydroxylation at C-24 (7). Overexpression of CYP24 has been documented in prostate, colon, and breast cancer during tumor progression (8), suggesting a mechanism of resistance of these tumor types to calcitriol treatment.Other than tumor cells, the effect of calcitriol on other cell types in the tumor...

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“…These include: (a) reductions in VDR and CYP27B1 expression; (b) the appearance of CYP27B1 splicing variants, 25 and (c) increases in CYP24A1, the enzyme that degrades both 1,25D and its precursor 25(OH)D. [26][27][28] Indeed, the VDR-null mice has higher propensity for premalignant lesions in the descending colon than heterozygous VDR þ / À or wild-type mice. 29 Also, increases in CYP24A1 were associated to poor prognosis in high-grade colonic, 30 pulmonary, ovarian, 31 and breast tumors. 32 A novel mechanism may also link VD deficiency with higher cancer risk: defective local VD activation to 25(OH)D in cells expressing CYP27A1 or CYP2R1, as breast and prostate cells, 12 because locally produced 25(OH)D can activate the VDR directly, 33,34 and also enhance 1,25D/VDR growth inhibition, as in prostate cancer cell lines.…”

mentioning

confidence: 99%

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

Bergadà

Pallarés

Arcidiacono

et al. 2014

Laboratory Investigation

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Vitamin D (VD) deficiency has been suggested as a risk factor for cancer. One recognized mechanism is that the low-serum 25-hydroxyvitamin D (25(OH)D) of VD deficiency reduces intratumoral 25(OH)D conversion to 1a,25-dihydroxyvitamin D (1,25D, the hormonal form of VD), compromising 1,25D-VD receptor (VDR) antitumoral actions. Reduced tumoral VDR and increased CYP24A1, the enzyme that degrades 1,25D and 25(OH)D, further worsen cancer progression. Importantly, in cells expressing CYP27A1 and/or CYP2R1, which convert inert VD into 25(OH)D, low-serum VD may reduce intratumoral 25(OH)D synthesis thereby compromising VDR antitumoral actions because 25(OH)D can activate the VDR directly and enhance 1,25D-VDR action. Therefore, this study examined whether abnormal endometrial expression of CYP27A1 and/or CYP2R1 may impair VDR-antiproliferative properties in endometrial carcinoma (EC). Immunohistochemical analysis of tissue microarrays of normal human endometrium (NE; n ¼ 60) and EC (n ¼ 157) showed the expected lower VDR expression in EC (P ¼ 0.0002). Instead, CYP24A1 expression was lower in EC compared with NE, while CYP27A1 and CYP2R1 expressions were higher (P ¼ 0.0002; P ¼ 0.03). Furthermore, in NE and EC, CYP2R1 and CYP27A1 expression correlated directly with nuclear VDR levels, an indicator of ligand-induced VDR activation, and inversely with the proliferation marker Ki67. Accordingly, in the endometrioid carcinoma cell lines IK, RL95/2 and HEC1-A, which express VDR, CYP27A1, and CYP2R1, VD efficaciously reduced cell viability and colony number, with a time course that paralleled actual increases in both intracellular 25(OH)D and nuclear VDR levels. Thus, VD may protect from EC progression in part through increased intratumoral 25(OH)D production by CYP27A1 and CYP2R1 for autocrine/paracrine enhancement of 1,25D-VDR-antiproliferative actions. Endometrial carcinoma (EC) results from neoplastic transformation of normal endometrium (NE) 1 leading to two main clinicopathological variants: endometrioid carcinoma (EEC) and non-endometrioid carcinomas (NEEC). EECs are estrogen-related tumors, frequently well differentiated, and developing mostly in peri-and postmenopausal women. Low grades (1 and 2) tumors are usually confined to the uterus (stage I) while grade 3 EECs are less frequent, with a higher tendency for extrauterine spread. NEEC, either serous or clear cell (CC) carcinomas, occur in older women, are estrogenunrelated tumors, with aggressive behavior and frequent extrauterine spread to the peritoneum or lymph nodes. 2,3 One risk factor for human cancer that can be safely modified is vitamin D (VD) deficiency/insufficiency.

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Expression of VDR and CYP24A1 mRNA in human tumors

Cited by 213 publications

References 20 publications

Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

Epigenetic Silencing of CYP24 in Tumor-derived Endothelial Cells Contributes to Selective Growth Inhibition by Calcitriol

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

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