The -786T>C promoter polymorphism of the NOS3 gene is associated with prostate cancer progression

Abstract

<p>Abstract</p> <p>Background</p> <p>There is no biological or epidemiological data on the association between <it>NOS3 </it>promoter polymorphisms and prostate cancer. The polymorphisms in the promoter region of <it>NOS3 </it>gene may be responsible for variations in the plasma NO, which may promote cancer progression by providing a selective growth advantage to tumor cells by angiogenic stimulus and by direct DNA damage.</p> <p>Methods</p> <p>This study aimed evaluating the <it>NOS3 </it>promoter polymorphisms by PCR-SSCP and sequencing, associating genotypes and haplotypes with <it>NOS3 </it>expression levels through semi-quantitative RT-PCR, and with <it>PCA</it>3 mRNA detection, a specific tumor biomarker, in the peripheral blood of pre-surgical samples from 177 patients; 83 PCa and 94 BPH.</p> <p>Results</p> <p>Three novel SNPs were identified -764A>G, -714G>T and -649G>A in the <it>NOS3 </it>gene promoter region, which together with the -786T>C generated four haplotypes (N, T, C, A). <it>NOS3 </it>gene expression levels were affected by the -786T>C polymorphism, and there was a 2-fold increase in <it>NOS3 </it>levels favored by the incorporation of each C allele. <it>NOS3 </it>levels higher than 80% of the constitutive gene expression level (<it>B2M</it>) presented a 4-fold increase in PCa occurrence.</p> <p>Conclusion</p> <p>The -786T>C polymorphism was the most important promoter alteration of the <it>NOS3 </it>gene that may affect the PCa progression, but not its occurrence, and the incorporation of the C allele is associated with increased levels of <it>NOS3 </it>transcripts. The <it>NOS3 </it>transcript levels presented a bimodal behavior in tumor development and may be used as a biomarker together with the <it>PCA3 </it>marker for molecular staging of the prostate cancer.</p