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

BMC Urology

Research Article

Ricardo Ribeiro¹  Helena Coutinho²  José Manuel Lopes³  José Ramon Vizcaíno⁴  André Coelho⁴  Paulo Príncipe⁵  Avelino Fraga⁶  Carlos Lobato⁷  Carlos Lopes⁸  Rui Medeiros⁹ 

[1] Center for Urological Research, Department of Urology, Porto Hospital Centre – St. António Hospital, Porto, Portugal;Molecular Oncology Group - CI, Portuguese Institute of Oncology, Porto, Portugal;Genetics Laboratory, Faculty of Medicine, University of Lisbon, Lisbon, Portugal;Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal;Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal;Institute of Pathology and Molecular Immunology of University of Porto (IPATIMUP), Porto, Portugal;Department of Pathology, Porto Hospital Centre – St. António Hospital, Porto, Portugal;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;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;ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal;Department of Urology, Porto Military Hospital, Porto, Portugal;ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal;ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal;Molecular Oncology Group - CI, Portuguese Institute of Oncology, Porto, Portugal;

关键词: Genetic polymorphism;    Hypoxia;    Hypoxia-inducible factor 1;    Prostate cancer;   

DOI  :  10.1186/s12894-017-0201-y

 received in 2016-10-06, accepted in 2017-01-10,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017