Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.
Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.
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关键缺氧调节的下游分子和前列腺癌的表型相关性的遗传多态性。
DOI：
10.1186/s12894-017-0201-y
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发表时间：
2017-01-31
期刊：
影响因子：
2
通讯作者：
Medeiros R
中科院分区：
文献类型：
--
作者：
Fraga A;Ribeiro R;Coelho A;Vizcaíno JR;Coutinho H;Lopes JM;Príncipe P;Lobato C;Lopes C;Medeiros R
在这项研究中，我们寻找，如果在他们寻求处理缺氧，前列腺肿瘤表达目标缺氧相关分子和他们的相关性与推定的功能遗传多态性。采用组织芯片对前列腺癌（n = 51）和结节性前列腺增生（n = 20）的代表性区域进行缺氧诱导因子1 α（HIF-1α）、碳酸酐酶IX（CAIX）、赖氨酰氧化酶（LOX）和血管内皮生长因子（VEGFR 2）免疫组织化学表达分析。从外周血中分离DNA，并用于对相应基因（HIF 1A +1772 C > T，rs 11549465; CA 9 + 201 A > G; rs 2071676; LOX +473 G > A，rs 1800449; KDR - 604 T > C，rs 2071559）的功能多态性进行基因分型。免疫组织化学分析显示，与结节性前列腺增生相比，前列腺癌上皮细胞中CAIX和VEGFR 2阳性表达占主导地位（分别为P = 0.043和P = 0.035）。此外，与结节性前列腺增生相比，前列腺上皮细胞中VEGFR 2表达评分在器官局限性前列腺癌和前列腺癌外较高（分别为P = 0.031和P = 0.004）。值得注意的是，LOX蛋白的免疫反应性评分显着较高的器官局限性癌相比，结节性前列腺增生（P = 0.015）。基因型-表型分析显示，LOX +473 G等位基因纯合子携带者的LOX染色强度更高（P = 0.011）。尽管如此，KDR−604 T等位基因携带者更倾向于在前列腺上皮细胞中具有较高的VEGFR 2表达（P < 0.006）。缺氧标志物VEGFR 2、CAIX和LOX在前列腺上皮细胞上的蛋白表达在良性和恶性前列腺疾病中存在差异。两个基因多态性（LOX +473 G > A和KDR−604 T > C）与蛋白水平相关，解释了前列腺癌中低氧驱动通路激活的潜在基因-环境效应。进一步的研究，在更大的系列是必要的，以验证目前的研究结果。本文的在线版本（doi：10.1186/s12894-017-0201-y）包含补充材料，可供授权用户使用。
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-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). 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 < 0.006). Protein 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. The online version of this article (doi:10.1186/s12894-017-0201-y) contains supplementary material, which is available to authorized users.