Expression and Regulation Mechanism of Vitamin D Receptor in Colorectal Cancer / 胃肠病学

ABSTRACT

Background:Vitamin D receptor( VDR)is a member of the steroid hormone receptor superfamily,which plays roles in various biological processes including cell proliferation,differentiation,apoptosis and immune responses,and is low expressed in many malignant tumors. Aims:To evaluate the expression and regulation mechanism of VDR in colorectal cancer. Methods:A total of 30 patients with colorectal cancer admitted from February 2010 to December 2012 at Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University were enrolled. Expression of VDR in cancerous tissue and para-cancer noncancerous tissue was determined by immunohistochemistry. Clinical data of 224 patients with colorectal cancer were collected from Gene Expression Omnibus( GEO)for analyzing the correlation between VDR expression in cancerous tissue and clinicopathological characteristics as well as survival time. Expression of VDR in human colon cancer cell lines HCT116 and SW620 transfected with enhancer of zeste homolog 2( EZH2 )-siRNA or treated with 5-azacytidine (5-AZA)was determined by real-time PCR,and methylation level of VDR promoter was determined by methylation-specific PCR( MSP). Results:Positivity rate of VDR was significantly lower in colorectal cancer tissue than that in para-cancer noncancerous tissue( 26. 7% vs. 70. 0%,P < 0. 001 ). Expression of VDR was negatively correlated with histological staging,distant metastasis,vascular metastasis and lymph node metastasis of colorectal cancer(P<0. 05). Survival time was significantly longer in patients with high expression of VDR than patients with low expression of VDR (P=0. 032). Compared with cells transfected with control-siRNA,expression of EZH2 mRNA and methylation level of VDR promoter in HCT116 and SW620 cells transfected with EZH2-siRNA were significantly decreased(P<0. 05),and expression of VDR mRNA was significantly increased(P<0. 05). Compared with negative control group,methylation level of VDR promoter in HCT116 and SW620 cells treated with 5-AZA was significantly decreased(P<0. 05),and expression of VDR mRNA was significantly increased(P<0. 05). Conclusions:Expression of VDR in colorectal cancer is down-regulated and positively correlated with a favourable prognosis. Transcriptional repression of VDR in colorectal cancer is co-regulated by histone methylation and DNA methylation.