Abstract
We previously showed a decreased expression of vitamin D receptor (VDR) mRNA/protein in a small group of adrenocortical carcinoma (ACC) tissues, suggesting the loss of a protective role of VDR against malignant cell growth in this cancer type. Downregulation of VDR gene expression may result from epigenetics events, that is, methylation of cytosine nucleotide of CpG islands in VDR gene promoter. We analyzed methylation of CpG sites in the VDR gene promoter in normal adrenals and adrenocortical tumor samples. Methylation of CpG-rich 5′ regions was assessed by bisulfite sequencing PCR using bisulfite-treated DNA from archival microdissected paraffin-embedded adrenocortical tissues. Three normal adrenals and 23 various adrenocortical tumor samples (15 adenomas and 8 carcinomas) were studied. Methylation in the promoter region of VDR gene was found in 3/8 ACCs, while no VDR gene methylation was observed in normal adrenals and adrenocortical adenomas. VDR mRNA and protein levels were lower in ACCs than in benign tumors, and VDR immunostaining was weak or negative in ACCs, including all 3 methylated tissue samples. The association between VDR gene promoter methylation and reduced VDR gene expression is not a rare event in ACC, suggesting that VDR epigenetic inactivation may have a role in adrenocortical carcinogenesis.
Highlights
Besides the classical role in calcium and bone homeostasis, 1α,25-dihydroxycholecalciferol D3 [1α,25(OH)2D3], the active metabolite of vitamin D, has been recognized to have “noncalcemic” effects in a variety of cells after binding to vitamin D receptor (VDR, NR1I1), a member of the nuclear receptor superfamily which includes receptors for steroids, thyroid hormones, and retinoic acid [1]
We showed a decreased expression of VDR mRNA and protein in a small group of human adrenocortical carcinomas (ACCs), suggesting the loss of a protective role of VDR against malignant cell growth, as suggested for other cancer types [9, 10]
Diagnosis of adrenal malignancy was performed according to the histopathological criteria proposed by Weiss et al [16] and the modification proposed by Aubert et al [17]
Summary
Besides the classical role in calcium and bone homeostasis, 1α,25-dihydroxycholecalciferol D3 [1α,25(OH)2D3] (calcitriol), the active metabolite of vitamin D, has been recognized to have “noncalcemic” effects in a variety of cells after binding to vitamin D receptor (VDR, NR1I1), a member of the nuclear receptor superfamily which includes receptors for steroids, thyroid hormones, and retinoic acid [1]. The binding of 1α,25(OH)2D3 with VDR-RXR complex is followed by the attachment of this complex to vitamin D responsive elements, which initiate transcription in the promoter of target genes [2, 3]. The effect of liganded VDR depends on the epigenetic landscape of target gene [4]. There is evidence that 1α,25(OH)2D3 protects against tumor formation by several VDR-mediated mechanisms, including regulation of growth arrest, cell differentiation, migration, invasion, and apoptosis, making it a candidate agent for cancer regulation [5,6,7]. We showed a decreased expression of VDR mRNA and protein in a small group of human adrenocortical carcinomas (ACCs), suggesting the loss of a protective role of VDR against malignant cell growth, as suggested for other cancer types [9, 10]
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