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Abstract
VitaminD3 signaling is involved in inhibiting the development and progression of gastric cancer (GC), while the active vitamin D metabolite 1-alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3)-mediated gene regulatory mechanisms in GC remain unclear. We found that miR-145 is induced by 1,25(OH)2D3 in a dose- and vitamin D receptor (VDR)-dependent manner in GC cells. Inhibition of miR-145 reverses the antiproliferative effect of 1,25(OH)2D3. Furthermore, miR-145 expression was lower in tumors compared with matched normal samples and correlated with increased the E2F3 transcription factor protein staining. Overexpression of miR-145 inhibited colony formation, cell viability and induced cell arrest in S-phase in GC cells by targeting E2F3 and CDK6. miR-145 inhibition consistently abrogates the 1,25(OH)2D3-mediated suppression of E2F3, CDK6, CDK2 and CCNA2 genes. Altogether, our results indicate that miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 in GC cells and might hold promise for prognosis and therapeutic strategies for GC treatment.
Highlights
Gastric cancer (GC) is currently the fourth most common malignancy in the world
The most active vitamin D3 metabolite 1alpha,25dihydroxyvitamin D3 (1,25(OH)2D3) affects cancer development and growth through regulating multiple signaling pathways involved in cell proliferation, apoptosis, invasion, and metastasis [3,4,5]. 1,25(OH)2D3 functions by binding to and activating nuclear vitaminD receptor (VDR), which is a ligand-modulated transcription factor that binds to specific sequences (vitamin D response elements (VDRE)) in target genes and increases or decreases their transcription rate through interaction with a vast array of co-activators, co-repressors, chromatin modifier enzymes, and remodeling complexes [6]
In our previous miRNA microarray analysis, we found that miR-145 was reduced in GC tissues compared with normal gastric tissues [20]
Summary
Gastric cancer (GC) is currently the fourth most common malignancy in the world. It can spread throughout the stomach and to other organs, including the esophagus, lungs, lymph nodes or liver. The most active vitamin D3 metabolite 1alpha,25dihydroxyvitamin D3 (1,25(OH)2D3) affects cancer development and growth through regulating multiple signaling pathways involved in cell proliferation, apoptosis, invasion, and metastasis [3,4,5]. Thereby, nearly 3–5% of human genes are regulated by 1,25(OH)2D3 directly or indirectly, these include miRNAs, which play very important roles in cancer development [7,8,9]. Deregulation of certain miRNAs may contribute to human cancer and miRNAs function as tumor suppressors or oncogenes in cancer cells [10]. We aim to confirm and extend our findings through the identification of target miRNAs for 1,25(OH)2D3, and to analyze their biological mechanism in GC
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