4.7 Article

Associations of a Polymorphism in the Ornithine Decarboxylase Gene with Colorectal Cancer Survival

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CLINICAL CANCER RESEARCH
卷 15, 期 19, 页码 6208-6216

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-09-0592

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  1. NIH [K23 CA133142, L30 CA130160, CA72008, CA78134, CA78285, CA95060]

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Purpose: Activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is required for normal growth and is elevated in many cancers, including colorectal cancer. We examined associations of the +316 ODC1 single nucleotide polymorphism (SNP) with colorectal cancer-specific survival among colorectal cancer cases, and then investigated its functional significance in colon cancer cells. Experimental Design: The study included 400 incident stage I-III colorectal cancer cases from the population-based University of California Irvine Gene-Environment Study of Familial Colorectal Cancer (diagnosed from 1994 to 1996 with follow-up through March 2008). The primary outcome was colorectal cancer-specific survival dependent on ODC1 (rs2302615) genotype (GG versus GA/AA). In human colon cancer cell lines, ODC1 allele-specific binding of E-box transcription factors was determined via Western blotting and chromatin immunoprecipitation assays. ODC1 allele-specific promoter activity was determined using promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MAD1. Results: Genotype-specific survival differences were observed among colorectal cancer cases: compared with cases with the ODC1 GG genotype (hazards ratio, 1; reference) the adjusted colorectal cancer-specific survival hazards ratio was 2.02 (95% confidence interval, 1.17-3.50) for ODC1 GA/AA cases (P = 0.012). In colon cancer cells, the ODC1 SNP, flanked by two E-boxes, predicts ODC1 promoter activity. The E-box activator c-MYC and repressors MAD1 and MAD4 preferentially bind to ODC1 minor A-alleles, compared with major G-alleles, in cultured cells. Conclusions: These results have implications for conditional regulation of polyamine homeostasis and suggest a model in which the ODC1 SNIP may be protective for colon adenoma recurrence and detrimental for survival after colon cancer diagnosis. (Clin Cancer Res 2009;15(19):6208-16)

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