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1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment.

ABSTRACT: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDRhigh) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDRlow and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH)2D3 sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH)2D3 induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH)2D3-mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH)2D3 opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH)2D3 may prevent lung cancer progression in a molecularly defined subset of NSCLC patients.

SUBMITTER: Upadhyay SK

PROVIDER: S-EPMC3875951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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1,25-dihydroxyvitamin D3 treatment delays cellular aging in human mesenchymal stem cells while maintaining their multipotent capacity.

Project description:1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, β-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence- and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to β-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging.

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1,25(OH)2D3 upregulated lncRNA

Project description:Purpose: The goals of this study are to compare lncRNA between Wild Type and VDR KO in HaCat cell line using NET-CAGE.

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Target gene profiles of 1,25(OH)2D3 and 25(OH)D3 in Cyp27b1 knockout mDCT cells.

Project description:Recently, it has been reported that 25(OH)D3 (25D3) has physiological bioactivity in certain tissues derived from the Cyp27b1 knockout mice. To investigate 25D3 function in the kidney as an informational crossroad of various calciotropic substances, we employed CRISPR-Cas9 system to knock out the Cyp27b1 gene in the mouse renal tubular cell line, mDCT cells. Unlike the previously reported mice targeted to the Cyp27b1 gene systemically, Cyp27b1 knockout mDCT cells did not produce any measurable 1a,25(OH)2D3 (1,25D3) after 25D3 administration. As was seen in the treatment with 10-8 M and higher dose of 1,25D3, we found that 10-7 M of 25D3 could translocate VDR into the nucleus and promoted expression of the representative 1,25D3-responsive Cyp24a1 gene in the Cyp27b1 knockout mDCT cells. The exhaustive target gene profiles of 25D3 showed results closely mimicking those of 1,25D3. Subsequently, we confirmed that 25D3 induced the expression of a calcium reabsorption-related gene, Calbindin-D9K gene, in a similar way to 1,25D3. As another example among others, we found that both 1,25D3 and 25D3 induced the expression of Megalin gene. Our ChIP assay identified that two VDRE sites at the upstream region of the Megalin gene contributed to such gene activation. Together, we surmise that the ability to stimulate VDR target genes may provide a novel perspective with 25D3 contribution in certain tissues.

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1,25(OH)2D3 up-regulated lncRNA

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Stimulation of 1,25-dihydroxyvitamin D3 production by 1,25-dihydroxyvitamin D3 in the hypocalcaemic rat.

Project description:Serum 1,25-dihydroxyvitamin D3 concentration and renal 25-hydroxyvitamin D 1 alpha-hydroxylase activity were measured in rats fed various levels of calcium, phosphorus and vitamin D3. Both calcium deprivation and phosphorus deprivation greatly increased circulating levels of 1,25-dihydroxyvitamin D3. The circulating level of 1,25-dihydroxyvitamin D3 in rats on a low-calcium diet increased with increasing doses of vitamin D3, whereas it did not change in rats on a low-phosphorus diet given increasing doses of vitamin D3. In concert with these results, the 25-hydroxyvitamin D 1 alpha-hydroxylase activity was markedly increased by vitamin D3 administration to rats on a low-calcium diet, whereas the same treatment of rats on a low-phosphorus diet had no effect and actually suppressed the 1 alpha-hydroxylase in rats fed an adequate-calcium/adequate-phosphorus diet. The administration of 1,25-dihydroxyvitamin D3 to vitamin D-deficient rats on a low-calcium diet also increased the renal 25-hydroxy-vitamin D 1 alpha-hydroxylase activity. These results demonstrate that the regulatory action of 1,25-dihydroxyvitamin D3 on the renal 25-hydroxyvitamin D3 1 alpha-hydroxylase is complex and not simply a suppressant of this system.

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1,25-Dihydroxyvitamin D3 regulates furin-mediated FGF23 cleavage.

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| S-EPMC10544208 | biostudies-literature

Paracrine interactions between mesenchymal stem cells and macrophages are regulated by 1,25-dihydroxyvitamin D3.

Project description:Mesenchymal stem cells (MSC) modulate the macrophage-mediated inflammatory response through the secretion of soluble factors. In addition to its classical effects on calcium homeostasis, 1,25-dihydroxyvitamin D3 (1,25D3) has emerged as an important regulator of the immune system. The present study investigates whether 1,25D3 modulates the paracrine interactions between MSC and macrophages. 1,25D3 stimulated MSC to produce PGE2 and VEGF and regulated the interplay between macrophages and MSC toward reduced pro-inflammatory cytokine production. Conditioned media (CM) from co-cultures of macrophages and MSC impaired MSC osteogenesis. However, MSC cultured in CM from 1,25D3-treated co-cultures showed increased matrix maturation and mineralization. Co-culturing MSC with macrophages prevented the 1,25D3-induced increase in RANKL levels, which correlated with up-regulation of OPG secretion. MSC seeding in three-dimensional (3D) substrates potentiated their immunomodulatory effects on macrophages. Exposure of 3D co-cultures to 1,25D3 further reduced the levels of soluble factors related to inflammation and chemotaxis. As a consequence of 1,25D3 treatment, the recruitment of monocytes toward CM of 3D co-cultures decreased, while the osteogenic maturation of MSC increased. These data add new insights into the pleiotropic effects of 1,25D3 on the crosstalk between MSC and macrophages and highlight the role of the hormone in bone regeneration.

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Project description:The purpose of this study are to ensure that whether calcitriol upregulates open chromatin in keratinocytes or not.

2021-12-18 | GSE191099 | GEO

1,25(OH)2D3 upregulated lncRNA

Project description:1,25(OH)2D3 upregulated lncRNA

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1,25(OH)2D3 Promotes the Efficacy of CD28 Costimulation Blockade by Abatacept.

Project description:Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell-mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity. Accordingly, cyclosporin A, an inhibitor of T cell stimulation via the TCR, synergized with abatacept to inhibit T cell activation. We also observed that 1,25-dihydroxyvitamin D3 enhanced the inhibition of T cell activation by abatacept, strongly inhibiting T cell activation driven by cross-linked anti-CD3, but with no effect upon anti-CD28 driven stimulation. Thus, like cyclosporin A, 1,25-dihydroxyvitamin D3 inhibits TCR-driven activation, thereby promoting abatacept sensitivity. Vitamin D3 supplementation may therefore be a useful adjunct for the treatment of conditions such as rheumatoid arthritis in combination with abatacept to promote the efficacy of treatment.

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