Abstract
Abstract PURPOSE: Myxovirus (influenza virus) resistance 1 (MX1) is an interferon regulated gene responsible for a specific antiviral state against viral infection. We have previously shown that MX1 is up-regulated by androgens in the normal prostate epithelial cells; however, there is no known role for MX1 in cancer. Meta-analysis of different expression databases e.g. NCBI GEO and Oncomine suggested a strong inverse association between MX1 expression and prostate cancer. To confirm these studies, we performed Immunohistochemistry on normal prostate and prostate cancer tissues. Our data revealed that MX1 expression was indeed decreased in PCa as compared to normal, indicating that MX1 could be transcriptionally down-regulated. Literature studies indicated that MX1 down-regulation could be due to a specific polymorphism in the proximal MX1 promoter. In the promoter region of MX1 at position -88, a single nucleotide polymorphism G>T (rs2071430) is involved in modifying the gene expression. Interestingly, the rs2071430 harbors an interferon-stimulated response element (ISRE) that is required for MX1 expression in response to interferons. The “T” allele restores whereas the “G” allele attenuates ISRE binding resulting in increased or decreased MX1 expression respectively. Based on these observations we hypothesized that decreased expression of MX1 in prostate cancer could be due to the rs2071430 polymorphism. DESIGN METHODS: We investigated MX1 rs2071430 polymorphism in genomic DNA from equal number of disease free and prostate cancer samples (N=305). The sample size required to achieve statistically significant associations were calculated using the power calculator for case control genetic association studies. Polymorphism was detected by sequencing the PCR amplicon through SNPdetector to ensure that the SNP was due to heterozygous allelic variations and not due to sequencing artifacts. RESULTS: The data suggests that the GG genotype (low promoter activity) is higher in PCa (72%) as compared to normal (58.6%). The TT genotype (high activity) was higher in normal (5.7%) compared to PCa (2.4%). No TT genotype was observed in Caucasian normal samples. The results were statistically significant at P<0.05. Our results, for the first time demonstrate that MX1 is down-regulated in prostate cancer possibly at the transcriptional level due to ISRE polymorphism in the promoter region. ACKNOWLEDGEMENTS: This research is supported by NIH/NCMHD grant 1P20MD002285-01. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-282. doi:1538-7445.AM2012-LB-282
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