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

Marangoni K, Araújo TG, Neves AF, Goulart LR - BMC Cancer (2008)

Bottom Line: NOS3 gene expression levels were affected by the -786T>C polymorphism, and there was a 2-fold increase in NOS3 levels favored by the incorporation of each C allele.NOS3 levels higher than 80% of the constitutive gene expression level (B2M) presented a 4-fold increase in PCa occurrence.The -786T>C polymorphism was the most important promoter alteration of the NOS3 gene that may affect the PCa progression, but not its occurrence, and the incorporation of the C allele is associated with increased levels of NOS3 transcripts.

View Article: PubMed Central - HTML - PubMed

Affiliation: Federal University of Uberlândia, Institute of Genetics and Biochemistry, Molecular Genetics Laboratory, Campus Umuarama, Block 2E, Room 24, 38400-902, Uberlândia, MG, Brazil. kmarangoni@yahoo.com.br

ABSTRACT

Background: There is no biological or epidemiological data on the association between NOS3 promoter polymorphisms and prostate cancer. The polymorphisms in the promoter region of NOS3 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.

Methods: This study aimed evaluating the NOS3 promoter polymorphisms by PCR-SSCP and sequencing, associating genotypes and haplotypes with NOS3 expression levels through semi-quantitative RT-PCR, and with PCA3 mRNA detection, a specific tumor biomarker, in the peripheral blood of pre-surgical samples from 177 patients; 83 PCa and 94 BPH.

Results: Three novel SNPs were identified -764A>G, -714G>T and -649G>A in the NOS3 gene promoter region, which together with the -786T>C generated four haplotypes (N, T, C, A). NOS3 gene expression levels were affected by the -786T>C polymorphism, and there was a 2-fold increase in NOS3 levels favored by the incorporation of each C allele. NOS3 levels higher than 80% of the constitutive gene expression level (B2M) presented a 4-fold increase in PCa occurrence.

Conclusion: The -786T>C polymorphism was the most important promoter alteration of the NOS3 gene that may affect the PCa progression, but not its occurrence, and the incorporation of the C allele is associated with increased levels of NOS3 transcripts. The NOS3 transcript levels presented a bimodal behavior in tumor development and may be used as a biomarker together with the PCA3 marker for molecular staging of the prostate cancer.

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Graphics representations. A) The average NOS3 relative levels of PCa patients classified according to tumor stages and a predicted tendency line. B) Regression analysis for the average NOS3 relative levels in association with the -786T>C polymorphism genotypes for all patients and for the group of patients with positive PCA3 detection.
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Figure 5: Graphics representations. A) The average NOS3 relative levels of PCa patients classified according to tumor stages and a predicted tendency line. B) Regression analysis for the average NOS3 relative levels in association with the -786T>C polymorphism genotypes for all patients and for the group of patients with positive PCA3 detection.

Mentions: Among PCa patients, only the Pearsons' correlation coefficients obtained among the NOS3 gene expression and PCA3 data (p = 0.038) were significant. For BPH patients, the NOS3 levels, serum PSA, patients' age on diagnosis and PCA3 detection were not correlated among each other. However, the average NOS3 levels presented a bimodal behavior in PCa patients classified according to their tumor stages, with higher levels in the pT2 stage (Figure 5A).


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

Marangoni K, Araújo TG, Neves AF, Goulart LR - BMC Cancer (2008)

Graphics representations. A) The average NOS3 relative levels of PCa patients classified according to tumor stages and a predicted tendency line. B) Regression analysis for the average NOS3 relative levels in association with the -786T>C polymorphism genotypes for all patients and for the group of patients with positive PCA3 detection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2571109&req=5

Figure 5: Graphics representations. A) The average NOS3 relative levels of PCa patients classified according to tumor stages and a predicted tendency line. B) Regression analysis for the average NOS3 relative levels in association with the -786T>C polymorphism genotypes for all patients and for the group of patients with positive PCA3 detection.
Mentions: Among PCa patients, only the Pearsons' correlation coefficients obtained among the NOS3 gene expression and PCA3 data (p = 0.038) were significant. For BPH patients, the NOS3 levels, serum PSA, patients' age on diagnosis and PCA3 detection were not correlated among each other. However, the average NOS3 levels presented a bimodal behavior in PCa patients classified according to their tumor stages, with higher levels in the pT2 stage (Figure 5A).

Bottom Line: NOS3 gene expression levels were affected by the -786T>C polymorphism, and there was a 2-fold increase in NOS3 levels favored by the incorporation of each C allele.NOS3 levels higher than 80% of the constitutive gene expression level (B2M) presented a 4-fold increase in PCa occurrence.The -786T>C polymorphism was the most important promoter alteration of the NOS3 gene that may affect the PCa progression, but not its occurrence, and the incorporation of the C allele is associated with increased levels of NOS3 transcripts.

View Article: PubMed Central - HTML - PubMed

Affiliation: Federal University of Uberlândia, Institute of Genetics and Biochemistry, Molecular Genetics Laboratory, Campus Umuarama, Block 2E, Room 24, 38400-902, Uberlândia, MG, Brazil. kmarangoni@yahoo.com.br

ABSTRACT

Background: There is no biological or epidemiological data on the association between NOS3 promoter polymorphisms and prostate cancer. The polymorphisms in the promoter region of NOS3 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.

Methods: This study aimed evaluating the NOS3 promoter polymorphisms by PCR-SSCP and sequencing, associating genotypes and haplotypes with NOS3 expression levels through semi-quantitative RT-PCR, and with PCA3 mRNA detection, a specific tumor biomarker, in the peripheral blood of pre-surgical samples from 177 patients; 83 PCa and 94 BPH.

Results: Three novel SNPs were identified -764A>G, -714G>T and -649G>A in the NOS3 gene promoter region, which together with the -786T>C generated four haplotypes (N, T, C, A). NOS3 gene expression levels were affected by the -786T>C polymorphism, and there was a 2-fold increase in NOS3 levels favored by the incorporation of each C allele. NOS3 levels higher than 80% of the constitutive gene expression level (B2M) presented a 4-fold increase in PCa occurrence.

Conclusion: The -786T>C polymorphism was the most important promoter alteration of the NOS3 gene that may affect the PCa progression, but not its occurrence, and the incorporation of the C allele is associated with increased levels of NOS3 transcripts. The NOS3 transcript levels presented a bimodal behavior in tumor development and may be used as a biomarker together with the PCA3 marker for molecular staging of the prostate cancer.

Show MeSH
Related in: MedlinePlus