miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 by directly targeting E2F3 in gastric cancer cells
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Su’e Chang1, Ling Gao1,2, Yang Yang1, Dongdong Tong1, Bo Guo1, Liying Liu1, Zongfang Li3, Tusheng Song1, Chen Huang1
1Department of Genetics and Molecular Biology/Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
2Department of Oral Maxillofacial Surgery, Stomatology Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, P. R. China
3Department of General Surgery, the Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
Chen Huang, e-mail: [email protected]
Keywords: 1,25(OH)2D3, miR-145, gastric cancer, E2F3, proliferation
Received: October 20, 2014 Accepted: January 06, 2015 Published: February 18, 2015
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.
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