1,25-Dihydroxyvitamin D3 Prevents Epithelial-Mesenchymal Transition of HMrSV5 Human Peritoneal Mesothelial Cells by Inhibiting Histone Deacetylase 3 (HDAC3) and Increasing Vitamin D Receptor (VDR) Expression Through the Wnt/β-Catenin Signaling Pathway

Abstract

Background Peritoneal dialysis is the most common treatment for end-stage renal disease. However, peritoneal fibrosis resulting from long-term peritoneal dialysis restricts peritoneal ultrafiltration. Previous studies have shown a role for 1,25-dihydroxyvitamin D3 (1,25[OH] 2 D3) in preventing fibrosis, but the potential mechanisms remain unknown. This study aimed to investigate the role of 1,25(OH) 2 D3 in epithelial-mesenchymal transition (EMT) and the downstream signaling pathway in HMrSV5 human peritoneal mesothelial cells in vitro . Material/Methods An in vitro cell model of peritoneal fibrosis was established using the HMrSV5 human peritoneal mesothelial cell line. High glucose and lipopolysaccharide (LPS) culture conditions, with or without 1,25(OH) 2 D3, were used. Wnt agonist 1, a Wnt signaling pathway activator, was applied. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure the vitamin D receptor (VDR) and histone deacetylase 3 (HDAC3) gene and protein expression levels, β-catenin, and EMT-associated biomarkers. Results High glucose plus LPS culture medium inhibited cell proliferation, induced cell apoptosis and promoted EMT in HMrSV5 cells, which was reversed by 1,25(OH) 2 D3 by down-regulation of HDAC3 and upregulation of VDR. HDAC3 inhibited VDR gene expression. The expression of EMT-associated biomarkers was increased by Wnt agonist 1 and inhibited by 1,25(OH) 2 D3. Conclusions In HMrSV5 human peritoneal mesothelial cells, 1,25(OH) 2 D3 reversed EMT by inhibiting the expression of HDAC3 and upregulating VDR gene expression via the Wnt/β-catenin signaling pathway.

Vitamin D receptor knockdown attenuates the antiproliferative, pro‑apoptotic and anti‑invasive effect of vitamin D by activating the Wnt/β‑catenin signaling pathway in papillary thyroid cancer

“…The present study analyzed Vdr expression in human PTc and normal thyroid follicular cells, and revealed that Vdr mrna and protein expression levels were increased in PTc cells compared with thyroid follicular cells, which was consistent with previous studies (20,31). Previous studies had revealed that Vdr has the potential to regulate cancer cellular activities and influence tumor progression and metabolism by binding to vitamin d (15,20,32,33). For example, in vitamin d-treated breast cancer cells, silencing of Vdr promotes cancer cell motility and invasiveness by increasing the expression of proteins involved in cell adhesion, proliferation, cytoskeletal organization (33).…”

“…Previous studies had revealed that VDR has the potential to regulate cancer cellular activities and influence tumor progression and metabolism by binding to vitamin D ( 15 , 20 , 32 , 33 ). For example, in vitamin D-treated breast cancer cells, silencing of VDR promotes cancer cell motility and invasiveness by increasing the expression of proteins involved in cell adhesion, proliferation, cytoskeletal organization ( 33 ).…”

“…The present study revealed that Kd-Vdr may attenuate the effect of vitamin d on the oncogenic Wnt/β-catenin signaling pathway in PTc and inhibit cell proliferation and invasion but promote cell proliferation. a previous study revealed that cell proliferation, apoptosis and epithelial-mesenchymal transition are mediated by Vdr-activated vitamin d and the Wnt/β-catenin signaling pathway in renal cancer (32). Furthermore, in uterine fibroid cells, vitamin d reduced the expression levels of Wnt4 and β-catenin, whereas Vdr silencing promoted the expression levels of Wnt4 and β-catenin, further promoting cell proliferation and extracellular matrix production (17).…”

Calcitriol Inhibits Viability and Proliferation in Human Malignant Pleural Mesothelioma Cells

“…VDR is present mainly in metabolic tissues, but also in almost all human cell types ( 10 ); furthermore, VDR expression is low in normal cells, increases in malignant cells and is reduced with tumor growth ( 5 , 11 ). VDR is also expressed in human and rodent peritoneal mesothelial cells and human bronchial epithelial cells ( 12 – 15 ); however, the presence of VDR in pleural mesothelial cells has yet to be demonstrated. Studies have recently indicated that calcitriol reduces fibrosis and prevents epithelial-mesenchymal transition in human peritoneal mesothelial cells in vitro ( 12 , 14 ), while vitamin D analogs reduce peritoneal fibrosis in vivo ( 15 ) through antinflammatory mechanisms.…”

“…VDR is also expressed in human and rodent peritoneal mesothelial cells and human bronchial epithelial cells ( 12 – 15 ); however, the presence of VDR in pleural mesothelial cells has yet to be demonstrated. Studies have recently indicated that calcitriol reduces fibrosis and prevents epithelial-mesenchymal transition in human peritoneal mesothelial cells in vitro ( 12 , 14 ), while vitamin D analogs reduce peritoneal fibrosis in vivo ( 15 ) through antinflammatory mechanisms. In addition to its nuclear localization, VDR has been recently localized in mitochondria and calcitriol was found to suppress mitochondrial respiration in cancer cell lines, keratinocytes and adipocytes, affecting both cell growth and differentiation, as well as lipid metabolism ( 16 – 19 ).…”