Role of Endocrine Gland-Derived Vascular Endothelial Growth Factor (EG-VEGF) and Its Receptors in Adrenocortical Tumors.
Role of Endocrine Gland-Derived Vascular Endothelial Growth Factor (EG-VEGF) and Its Receptors in Adrenocortical Tumors.
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DOI：
10.1007/s12672-015-0236-z
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发表时间：
2015-12
影响因子：
3
通讯作者：
Sbiera S
中科院分区：
文献类型：
--
作者：
Heck D;Wortmann S;Kraus L;Ronchi CL;Sinnott RO;Fassnacht M;Sbiera S
血管生成对于肿瘤的生长和转移是必不可少的。内分泌腺源性血管内皮生长因子（EG-VEGF）是一种血管生成因子，主要在类固醇生成器官如肾上腺、卵巢、睾丸和胎盘中表达。EG-VEGF具有抗凋亡、促有丝分裂和化学吸引特性，其通过两种G蛋白偶联受体前动力蛋白受体1（PKR 1）和前动力蛋白受体2（PKR 2）介导。我们采用实时荧光定量PCR技术，研究了EG-VEGF及其受体在大量正常肾上腺（NAG）、肾上腺皮质腺瘤（ACA）和肾上腺癌（ACC）中的表达。（NAG，n = 12; ACA，n = 24;和ACC，n = 30）和免疫组织化学（NAG，n = 9; ACA，n = 23;和ACC，n = 163），并评估其对患者生存的影响。EG-VEGF、PKR 1和PKR 2 mRNA和蛋白质在NAG和绝大多数ACA和ACC样品中表达。ACC中EG-VEGF mRNA的平均表达（606.5 ± 77.1拷贝）显著低于NAG（4，043 ± 1，111）和皮质醇腺瘤（CPA）（4，433 ± 2，378）（分别为p < 0.01和p < 0.05）。然而，ACC中细胞质和细胞核EG-VEGF蛋白表达显著更高或相似（H评分2.4 ± 0.05，p < 0.05和1.7 ± 0.08，n.s.，NAG分别为1.8 ± 0.14和1.7 ± 0.2。EG-VEGF或PKR 1或两者的核蛋白表达与无核表达的患者相比预测更高的死亡率（风险比（HR）= 5.15; 95%置信区间（CI）= 1.24-21.36，n = 100，p = 0.02，与年龄、性别和肿瘤分期无关）。这些发现表明EG-VEGF及其受体PKR 1可能在肾上腺皮质肿瘤的发病机制中发挥作用，并可作为这种罕见恶性疾病的预后标志物。本文的在线版本（doi：10.1007/s12672-015-0236-z）包含补充材料，可供授权用户使用。
Angiogenesis is essential for tumor growth and metastasis. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor predominantly expressed in steroidogenic organs like the adrenal gland, ovary, testes, and placenta. EG-VEGF has antiapoptotic, mitogenic, and chemoattractive properties mediated via the two G protein-coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). We investigated the expression of EG-VEGF and its receptors in a large number of normal adrenal glands (NAG), adrenocortical adenomas (ACA), and carcinomas (ACC) using real-time PCR (NAG, n = 12; ACA, n = 24; and ACC, n = 30) and immunohistochemistry (NAG, n = 9; ACA, n = 23; and ACC, n = 163) and evaluated its impact on patients’ survival. EG-VEGF, PKR1, and PKR2 mRNA and protein are expressed in NAG and the vast majority of ACA and ACC samples. The mean EG-VEGF mRNA expression was significantly lower in ACC (606.5 ± 77.1 copies) compared to NAG (4,043 ± 1,111) and cortisol-producing adenomas (CPA) (4,433 ± 2,378) (p < 0.01 and p < 0.05, respectively). However, cytoplasmic and nuclear EG-VEGF protein expression was either significantly higher or similar in ACC (H score 2.4 ± 0.05, p < 0.05 and 1.7 ± 0.08, n.s., respectively) compared to NAG (1.8 ± 0.14 and 1.7 ± 0.2). Nuclear protein expression of either EG-VEGF or PKR1 or both is predictive for a higher mortality compared to patients without nuclear expression (hazard ratio (HR) = 5.15; 95 % confidence interval (CI) = 1.24–21.36, n = 100, p = 0.02 independent of age, sex, and tumor stage). These findings suggest that EG-VEGF and its receptor PKR1 might play a role in the pathogenesis of adrenocortical tumors and could serve as prognostic markers for this rare malignant disease. The online version of this article (doi:10.1007/s12672-015-0236-z) contains supplementary material, which is available to authorized users.