Fraga Avelino, Ribeiro Ricardo, Coelho André, Vizcaíno José Ramon, Coutinho Helena, Lopes José Manuel, Príncipe Paulo, Lobato Carlos, Lopes Carlos, Medeiros Rui
Department of Urology, Porto Hospital Centre - St. António Hospital, Largo Prof. Abel Salazar, 4000-001, Porto, Portugal.
Center for Urological Research, Department of Urology, Porto Hospital Centre - St. António Hospital, Porto, Portugal.
BMC Urol. 2017 Jan 31;17(1):12. doi: 10.1186/s12894-017-0201-y.
BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.
背景：在本研究中，我们探究前列腺肿瘤在应对缺氧过程中是否表达缺氧相关靶分子，以及它们与假定的功能性基因多态性之间的相关性。 方法：使用组织芯片对前列腺癌（n = 51）和前列腺结节性增生（n = 20）的代表性区域进行缺氧诱导因子1α（HIF - 1α）、碳酸酐酶IX（CAIX）、赖氨酰氧化酶（LOX）和血管内皮生长因子（VEGFR2）免疫组化表达分析。从外周血中分离DNA，用于对相应基因的功能性多态性进行基因分型（HIF1A +1772 C>T，rs11549465；CA9 +201 A>G；rs2071676；LOX +473 G>A，rs1800449；KDR - 604 T>C，rs2071559）。 结果：免疫组化分析显示，与前列腺结节性增生相比，前列腺癌上皮细胞中CAIX和VEGFR2阳性表达占优势（分别为P = 0.043和P = 0.035）。此外，与前列腺结节性增生相比，器官局限性和前列腺外癌的前列腺上皮细胞中VEGFR2表达评分更高（分别为P = 0.031和P = 0.004）。值得注意的是，与前列腺结节性增生相比，器官局限性癌中LOX蛋白的免疫反应性评分显著更高（P = 0.015）。基因分型 - 表型分析显示，纯合LOX +473 G等位基因携带者的LOX染色强度更高（P = 0.011）。此外，KDR - 604 T等位基因携带者的前列腺上皮细胞中VEGFR2表达更高的倾向更明显（P < 0.006）。 结论：前列腺上皮细胞中缺氧标志物（VEGFR2、CAIX和LOX）的蛋白表达在恶性和良性前列腺疾病之间存在差异。两种基因多态性（LOX +473 G>A和KDR - 604 T>C）与蛋白水平相关，这可能解释了前列腺癌缺氧驱动通路激活中的潜在基因 - 环境效应。有必要进行更大样本量的进一步研究以验证目前的发现。
BMC Pharmacol Toxicol. 2022-4-26
Front Genet. 2022-1-4
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