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1,25-Dihydroxyvitamin D3 affects gastric cancer progression by repressing BMP3 promoter methylation.

ABSTRACT: Background:Vitamin D3 has been known to have an anticancer effect, but the mechanisms underlying this is poorly explored. The present study aimed to investigate the antitumor role of vitamin D3 on gastric cancer and mechanisms. Methods:The Roche Elecsys platform was applied in retrospective studies to detect the role of 25-hydroxylvitamin D3 in adenocarcinoma and colony formation assay was conducted to verify the effect of 1, 25-dihydroxyvitamin D3 on the proliferation of gastric cancer cells. After the identification of hypermethylation of BMP3 CpG islands by bisulfite genomic sequencing (BGS), we further investigated the relationship of BMP3 expression and gastric carcinogenesis by Western blot analysis and gel electrophoresis mobility shift assay (EMSA). Results:Here we show that low concentration of 1, 25-dihydroxyvitamin D3 links to can-cerization and significantly inhibits proliferation of undifferentiated gastric cancer cell lines SGC-7901 and BGC-823. BMP3 promoter hypermethylation was highly correlated with gastric tumor. Moreover, BMP3 expression was regulated by its promoter methylation in gastric cells. The further exploration of the relationship between 1, 25-dihydroxyvitamin D3 and BMP3 by EMSA results that 1, 25-dihydroxyvitamin D3 stimulates BMP3 expression by the inhibition of BMP3 promoter methylation in gastric tumor cells. Conclusion:In combination with the data from clinical research, bioinformatics analysis and experimental verification, we propose that 1, 25-hydroxylvitamin D3 affects gastric cancer progression by repressing BMP3 promoter methylation.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6445188 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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1,25-Dihydroxyvitamin D<sub>3</sub> affects gastric cancer progression by repressing BMP3 promoter methylation.

Zhao Ye Y Cai Liang-Liang LL Wang Hui-Ling HL Shi Xiao-Juan XJ Ye Hui-Ming HM Song Ping P Huang Bao-Qi BQ Tzeng Chi-Meng CM

OncoTargets and therapy 20190328

<h4>Background</h4>Vitamin D<sub>3</sub> has been known to have an anticancer effect, but the mechanisms underlying this is poorly explored. The present study aimed to investigate the antitumor role of vitamin D<sub>3</sub> on gastric cancer and mechanisms.<h4>Methods</h4>The Roche Elecsys platform was applied in retrospective studies to detect the role of 25-hydroxylvitamin D<sub>3</sub> in adenocarcinoma and colony formation assay was conducted to verify the effect of 1, 25-dihydroxyvitamin D< ...[more]

PMID: 30992671

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Project description:Fibroblast growth factor 23 (FGF23), a hormone, mainly produced by osteocytes, regulates phosphate and vitamin D metabolism. By contrast, 1,25-dihydroxyvitamin D3, the active form of vitamin D, has been shown to enhance FGF23 production. While it is likely that osteocytes are heterogenous in terms of gene expression profiles, specific subpopulations of Fgf23-expressing osteocytes have not been identified. Single-cell RNA sequencing (scRNA-seq) technology can characterize the transcriptome of an individual cell. Recently, scRNA-seq has been used for bone tissue analysis. However, owing to technical difficulties associated with isolation of osteocytes, studies using scRNA-seq analysis to characterize FGF23-producing osteocytes are lacking. In this study, we characterized osteocytes secreting FGF23 from murine femurs in response to calcitriol (1,25-dihydroxyvitamin D3) using scRNA-seq. We first detected Dmp1, Mepe, and Phex expression in murine osteocytes by in situ hybridization and used these as marker genes of osteocytes. After decalcification, enzyme digestion, and removal of CD45+ cells, femoral bone cells were subjected to scRNA-seq. We identified cell clusters containing osteocytes using marker gene expression. While Fgf23 expression was observed in some osteocytes isolated from femurs of calcitriol-injected mice, no Fgf23 expression was detected in untreated mice. In addition, the expression of several genes which are known to be changed after 1,25-dihydroxyvitamin D3 treatment such as Ccnd2, Fn1, Igfbp7, Pdgfa, and Timp1 was also affected by calcitriol treatment in Fgf23-expressing osteocytes, but not in those lacking Fgf23 expression, even after calcitriol administration. Furthermore, box-and-whisker plots indicated that Fgf23 expression was observed in osteocytes with higher expression levels of the Fam20c, Dmp1, and Phex genes, whose inactivating mutations have been shown to cause FGF23-related hypophosphatemic diseases. These results indicate that osteocytes are heterogeneous with respect to their responsiveness to 1,25-dihydroxyvitamin D3, and sensitivity to 1,25-dihydroxyvitamin D3 is one of the characteristics of osteocytes with Fgf23 expression. It is likely that there is a subpopulation of osteocytes expressing several genes, including Fgf23, involved in phosphate metabolism.

Dataset Information

1,25-Dihydroxyvitamin D3 affects gastric cancer progression by repressing BMP3 promoter methylation.

Publications

1,25-Dihydroxyvitamin D<sub>3</sub> affects gastric cancer progression by repressing BMP3 promoter methylation.

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