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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12894-017-0201-y) contains supplementary material, which is available to authorized users.

Epigenome-wide DNA methylation profiling of periprostatic adipose tissue in prostate cancer patients with excess adiposity—a pilot study

“…The clinical and pathological characteristics of participants are presented in Table 1 . The ten subjects were selected from a larger group of patients undergoing prostate surgery ( n = 51) [ 4 , 17 ] that fitted the strict inclusion and exclusion criteria, in order to control for variables that might influence adipose tissue gene expression or methylation (e.g., anti-diabetic or anti-dyslipidemia drugs, stage of disease and PSA, concomitant diseases such as diabetes, other neoplasia or metabolic syndrome). Subjects were matched for age at diagnosis, PSA value, Gleason grade, and stage of disease, which differed in body mass index (BMI).…”

Association of Carbonic Anhydrase 9 Polymorphism and the Epithelial Growth Factor Receptor Mutations in Lung Adenocarcinoma Patients

“…Served as the mediator of intracellular pH that seldom present in the normal human cells, this zinc-containing enzyme may maintain the tumor proliferation in a hypoxic microenvironment and contribute to the tumor invasiveness as well as therapeutic resistance according to previous studies [19,[33][34][35]. Concerning the specific cancer that is associated with the existence of CA9, the expression of CA9 was more common in prostate cancer than in nodular prostate hyperplasia [36], and the higher expression of CA9 was correlated to poor survival in certain types of breast cancers [37]. In addition to the CA9 itself, the SNP of CA9 also influence the disease course of malignancy to a large extends [26,28,29].…”

Qianlie Xiaozheng Decoction Induces Autophagy in Human Prostate Cancer Cells via Inhibition of the Akt/mTOR Pathway

“…This largely explains the effectiveness of mTOR inhibitors, such as rapamycin, as anticancer agents. However, rapamycin only inhibits mTORC1, whereas its upstream regulators are still activated ( Yori et al, 2014 ; Fraga et al, 2017 ). This limits its antineoplastic effects.…”