Abstract
BackgroundIn this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms.MethodsRepresentative areas of prostate carcinoma (n = 51) and of nodular prostate hyperplasia (n = 20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1α), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray. DNA was isolated from peripheral blood and used to genotype functional polymorphisms at the corresponding genes (HIF1A +1772 C > T, rs11549465; CA9 + 201 A > G; rs2071676; LOX +473 G > A, rs1800449; KDR – 604 T > C, rs2071559).ResultsImmunohistochemistry analyses disclosed predominance of positive CAIX and VEGFR2 expression in epithelial cells of prostate carcinomas compared to nodular prostate hyperplasia (P = 0.043 and P = 0.035, respectively). In addition, the VEGFR2 expression score in prostate epithelial cells was higher in organ-confined and extra prostatic carcinoma compared to nodular prostate hyperplasia (P = 0.031 and P = 0.004, respectively). Notably, for LOX protein the immunoreactivity score was significantly higher in organ-confined carcinomas compared to nodular prostate hyperplasia (P = 0.015). The genotype-phenotype analyses showed higher LOX staining intensity for carriers of the homozygous LOX +473 G-allele (P = 0.011). Still, carriers of the KDR−604 T-allele were more prone to have higher VEGFR2 expression in prostate epithelial cells (P < 0.006).ConclusionsProtein expression of hypoxia markers (VEGFR2, CAIX and LOX) on prostate epithelial cells was different between malignant and benign prostate disease. Two genetic polymorphisms (LOX +473 G > A and KDR−604 T > C) were correlated with protein level, accounting for a potential gene-environment effect in the activation of hypoxia-driven pathways in prostate carcinoma. Further research in larger series is warranted to validate present findings.
Highlights
In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms
Association of hypoxia proteins with prostate cancer and extra-prostatic disease To assess the prevalence of the key hypoxia-associated proteins in prostate carcinomas and nodular prostate hyperplasia, a tissue microarray was constructed for immunohistochemistry analyses
carbonic anhydrase IX (CAIX) immunoreactivity was observed in the cytoplasm of epithelial cells and significant differences were found among disease groups: CAIX expression was predominantly positive in epithelial cells of carcinomas (P = 0.043) (Fig. 2)
Summary
In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms. Prostate carcinoma is the most common cancer and the second cause of death due to malignancy in men [1] It is clinically heterogeneous in aggressiveness, not with standing comparable clinicopathological features. The HIF-1α/HIF-1β complex binds hypoxia response elements in promoters of many downstream target genes, notably vascular endothelial growth factor (VEGF), carbonic anhydrase IX (CAIX), and lysyl oxidase (LOX) promoters. They have been demonstrated to be up-regulated by hypoxia, ensuing aggressive and treatment-resistant tumor phenotypes [3, 5,6,7,8,9]. Further studies at the genetic and protein levels are required to confirm molecules in hypoxia pathway as useful markers in prostate carcinoma
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