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A new identified lncBCAS1-4_1 associated with Vitamin D signaling and EMT in ovarian cancer cells

ABSTRACT: Long non-coding RNAs (lncRNAs) has been identified rapidly due to the important role of lncRNAs in many biological processes and human diseases including cancer. Vitamin D compounds are supported to be applied as preventative and therapeutic anticancer agents. However, the expression profile of lncRNAs regulated by 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] in ovarian cancer remains to be clarified. In the present study, we identified 244 differentially expression (DE) lncRNAs and 102 DE mRNAs by our microarray data. GO and KEGG pathway analysis indicated that the DE genes were mainly enriched in TGF-β, MAPK, Ras, PI3K-Akt and Hippo signaling pathways, as well as vitamin D-related pathway. We further assessed the potential lncRNAs linking vitamin D signaling with EMT, and lncBCAS1-4_1 was identified. Moreover, we found the most upregulation lncBCAS1-4_1 has 75% transcripts same to CYP24A1, metabolic enzyme of 1α,25(OH)2D3. Finally, we established lncBCAS1-4_1 gain-of-function cell models and demonstrated that knockdown of lncBCAS1-4_1 inhibited proliferation and migration of ovarian cancer cells by regulating EMT-related mRNAs. Furthermore, our results also indicated that high lncBCAS1-4_1 obviously resisted the anti-tumor effect of 1α,25(OH)2D3 by upregulating ZEB1. These data will provide new evidence that lncRNAs are served as a target for the anti-tumor of 1α,25(OH)2D3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173633 | GEO | 2021/05/01

REPOSITORIES: GEO

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Project description:Fibroblast growth factor 23 (FGF23) is produced and secreted by osteocytes and is essential for maintaining phosphate homeostasis. One of the main regulators of FGF23, 1,25-dihydroxyvitamin D (1,25(OH)2D3), is primarily synthesized in the kidney from 25-hydroxyvitamin D (25(OH)D) by 1α-hydroxylase (encoded by CYP27B1). Hitherto, it is unclear whether osteocytes can convert 25(OH)D and thereby allow for 1,25(OH)2D3 to induce FGF23 production and secretion locally. Here, we differentiated MC3T3-E1 cells towards osteocyte-like cells expressing and secreting FGF23. Treatment with 10-6 M 25(OH)D resulted in conversion of 25(OH)D to 150 pmol/L 1,25(OH)2D3 and increased FGF23 expression and secretion but the converted amount of 1,25(OH)2D3 was insufficient to trigger an FGF23 response, so the effect on FGF23 was most likely directly caused by 25(OH)D. Interestingly, combining phosphate with 25(OH)D resulted in a synergistic increase in FGF23 expression and secretion, likely due to activation of additional signaling pathways by phosphate. Blockage of the vitamin D receptor (VDR) only partially abolished the effects of 25(OH)D or 25(OH)D combined with phosphate on Fgf23, while completely inhibiting the upregulation of cytochrome P450 family 24 subfamily A member 1 (Cyp24a1), encoding for 24-hydroxylase. RNA sequencing and in silico analyses showed that this could potentially be mediated by the nuclear receptors Retinoic Acid Receptor b (RARB) and Estrogen Receptor 2 (ESR2). Taken together, we demonstrate that osteocytes are able to convert 25(OH)D to 1,25(OH)2D3, but this is insufficient for FGF23 activation, implicating a direct effect of 25(OH)D in the regulation of FGF23, which occurs at least partially independent from its cognate vitamin D receptor Moreover, phosphate and 25(OH)D synergistically increase expression and secretion of FGF23, which warrants investigating consequences in patients receiving a combination of vitamin D analogues and phosphate supplements. These observations help us to further understand the complex relations between, phosphate, vitamin D and FGF23.

Project description:The proximal tubule is the sensing site of sodium and phosphorus and the main place for the synthesis and metabolism of 1,25 (OH)2D3. Sodium may share the sensing mechanism with phosphate in proximal tubule epithelial cells; whether sodium cooperates with phosphate or plays an independent role in the regulation of phosphorus homeostasis remains unknown. In this in vitro study, we investigated the effects of high sodium on the synthesis and function of active vitamin D and local phosphorus regulation in proximal tubular epithelial cells. Human proximal tubule epithelial (HK-2) cells were treated with different concentrations of sodium/phosphorus. The expression of 1α-OHase (Cyp27b1) and 24-OHase (Cyp24a1) was determined by RT-PCR and Western Blot. Liquid chromatography/mass spectrometry (LC/MS) and enzyme-linked immunosorbent assay (ELISA) were used to detect the levels of 1,25 (OH)2D3. Intracellular Ca2+ ([Ca2+]i) was detected with the Ca2+ indicator dye Fura-4. Chromatin samples were immunoprecipitated with antibodies against parathyroid receptor 1 (PTH1R) and Klotho. High sodium decreased the expression of 1,25 (OH)2D3 by reducing 1α-OHase and 24-OHase in HK-2 cells, reduced the expression of PTH1R and Klotho, and increased the intracellular calcium concentration. These effects were reversed by sodium phosphorus transporter inhibitor (PFA), sodium hydrogen transporter inhibitor (Caliporide), and a chelator of the extracellular calcium, whereas enhanced by ouabain. Vitamin D receptor agonists significantly increased the recruitment of VDR to the Vitamin D response element (VDRE) of PTH1R and Klotho promoter, thus increasing the expression of PTH1R and Klotho. High extracellular sodium can decrease the synthesis of active vitamin D in the proximal tubules, affect the gene regulation of 1,25 (OH)2D3/VDR, and significantly reduce the expression of PTH1R and Klotho. The data reveal the influence of a high-sodium diet on mineral metabolism and the core role of vitamin D in kidney mineral metabolism.

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A new identified lncBCAS1-4_1 associated with Vitamin D signaling and EMT in ovarian cancer cells

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