title: Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma.
abstract: 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 1α,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=60) and EC (n=157) showed the expected lower VDR expression in EC (P=0.0002). Instead, CYP24A1 expression was lower in EC compared with NE, while CYP27A1 and CYP2R1 expressions were higher (P=0.0002; P=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.
authors.affiliation: Pathology Group, Pathology and Molecular Genetics Department, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida (Lleida Institute for Biomedical Research), Lleida, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Bergadà
authors.affiliation: Pathology Group, Pathology and Molecular Genetics Department, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida (Lleida Institute for Biomedical Research), Lleida, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Pallares
authors.affiliation: Division of Nephrology, Hospital Universitari Arnau de Vilanova, University of Lleida, and Experimental Nephrology Department, IRB-Lleida, Lleida, Spain.
authors.forename: Arcidiacono
authors.initials: A
authors.lastname: Maria Vittoria
authors.affiliation: Division of Nephrology, Hospital Universitari Arnau de Vilanova, University of Lleida, and Experimental Nephrology Department, IRB-Lleida, Lleida, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Cardus
authors.affiliation: Pathology Group, Pathology and Molecular Genetics Department, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida (Lleida Institute for Biomedical Research), Lleida, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.affiliation: Biostatistics Unit, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida, Lleida, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Valls
authors.affiliation: Laboratory of Clinical Biochemistry, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida, Lleida, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Cao
authors.affiliation: Division of Nephrology, Hospital Universitari Arnau de Vilanova, University of Lleida, and Experimental Nephrology Department, IRB-Lleida, Lleida, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Fernàndez
authors.affiliation: Pathology Group, Pathology and Molecular Genetics Department, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida (Lleida Institute for Biomedical Research), Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
authors.affiliation: Division of Nephrology, Hospital Universitari Arnau de Vilanova, University of Lleida, and Experimental Nephrology Department, IRB-Lleida, Lleida, Spain.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Dusso
authors.affiliation: Pathology Group, Pathology and Molecular Genetics Department, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida (Lleida Institute for Biomedical Research), Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology*; D053493:Cholestanetriol 26-Monooxygenase / Q000032:analysis / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D016889:Endometrial Neoplasms / Q000737:chemistry*; D004717:Endometrium / Q000737:chemistry*; D005260:Female; D006801:Humans; D008875:Middle Aged; D018167:Receptors, Calcitriol / Q000032:analysis / Q000378:metabolism*
chemical_list: D018167:Receptors, Calcitriol; D002762:Cholecalciferol; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase
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