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Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.

ABSTRACT: 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.Representative areas of prostate carcinoma (n?=?51) and of nodular prostate hyperplasia (n?=?20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1?), 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).Immunohistochemistry 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??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.

SUBMITTER: Fraga A

PROVIDER: S-EPMC5282787 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.

Fraga Avelino A Ribeiro Ricardo R Coelho André A Vizcaíno José Ramon JR Coutinho Helena H Lopes José Manuel JM Príncipe Paulo P Lobato Carlos C Lopes Carlos C Medeiros Rui R

BMC urology 20170131 1

<h4>Background</h4>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.<h4>Methods</h4>Representative 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) immunohistochemist ...[more]

PMID: 28143503

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Project description:BACKGROUND:The genetic architecture of a quantitative trait influences the phenotypic response to natural or artificial selection. One of the main objectives of genetic mapping studies is to identify the genetic factors underlying complex traits and understand how they contribute to phenotypic expression. Presently, we are good at identifying and locating individual loci with large effects, but there is a void in describing more complex genetic architectures. Although large networks of connected genes have been reported, there is an almost complete lack of information on how polymorphisms in these networks contribute to phenotypic variation and change. To date, most of our understanding comes from theoretical, model-based studies, and it remains difficult to assess how realistic their conclusions are as they lack empirical support. RESULTS:A previous study provided evidence that nearly half of the difference in eight-week body weight between two divergently selected lines of chickens was a result of four loci organized in a 'radial' network (one central locus interacting with three 'radial' loci that, in turn, only interacted with the central locus). Here, we study the relationship between phenotypic change and genetic polymorphism in this empirically detected network. We use a model-free approach to study, through individual-based simulations, the dynamic properties of this polymorphic and epistatic genetic architecture. The study provides new insights to how epistasis can modify the selection response, buffer and reveal effects of major loci leading to a progressive release of genetic variation. We also illustrate the difficulty of predicting genetic architecture from observed selection response, and discuss mechanisms that might lead to misleading conclusions on underlying genetic architectures from quantitative trait locus (QTL) experiments in selected populations. CONCLUSION:Considering both molecular (QTL) and phenotypic (selection response) data, as suggested in this work, provides additional insights into the genetic mechanisms involved in the response to selection. Such dissection of genetic architectures and in-depth studies of their ability to contribute to short- or long-term selection response represents an important step towards a better understanding of the genetic bases of complex traits and, consequently, of the evolutionary properties of populations.

Project description:Dysregulation of transforming growth factor ? (TGF-?) signaling and hypoxic microenvironment have respectively been reported to be involved in disease progression in malignancies of prostate. Emerging evidence indicates that downregulation of TGFBR2, a pivotal regulator of TGF-? signaling, may contribute to carcinogenesis and progression of prostate cancer (PCa). However, the biological function and regulatory mechanism of TGFBR2 in PCa remain poorly understood. In this study, we propose to investigate the crosstalk of hypoxia and TGF-? signaling and provide insight into the molecular mechanism underlying the regulatory pathways in PCa.Prostate cancer cell lines were cultured in hypoxia or normoxia to evaluate the effect of hypoxia on TGFBR2 expression. Methylation specific polymerase chain reaction (MSP) and demethylation agents was used to evaluate the methylation regulation of TGFBR2 promoter. Besides, silencing of EZH2 via specific siRNAs or chemical inhibitor was used to validate the regulatory effect of EZH2 on TGFBR2. Moreover, we conducted PCR, western blot, and luciferase assays which studied the relationship of miR-93 and TGFBR2 in PCa cell lines and specimens. We also detected the impacts of hypoxia on EZH2 and miR-93, and further examined the tumorigenic functions of miR-93 on proliferation and epithelial-mesenchymal transition via a series of experiments.TGFBR2 expression was attenuated under hypoxia. Hypoxia-induced EZH2 promoted H3K27me3 which caused TGFBR2 promoter hypermethylation and contributed to its epigenetic silencing in PCa. Besides, miR-93 was significantly upregulated in PCa tissues and cell lines, and negatively correlated with the expression of TGFBR2. Ectopic expression of miR-93 promoted cell proliferation, migration and invasion in PCa, and its expression could also be induced by hypoxia. In addition, TGFBR2 was identified as a bona fide target of miR-93.Our findings elucidate diverse hypoxia-regulated pathways including EZH2-mediated hypermethylation and miR-93-induced silencing contribute to attenuation of TGFBR2 expression and promote cancer progression in prostate cancer.

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Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.

Publications

Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.

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