Guo Yong, Xia Peng, Zheng Jian-Jian, Sun Xian-Bin, Pan Xiao-Dong, Zhang Xing, Wu Cun-Zao
Transplantation Centre, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325014, China.
Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325014, China.
Biomed Pharmacother. 2015 Jul;73:147-53. doi: 10.1016/j.biopha.2015.06.006. Epub 2015 Jul 9.
The receptor for advanced glycation end products (RAGE) is involved in a variety of biological processes, including tumorigenisis. Previous studies have demonstrated that RAGE regulates the neo-angiogenesis related downstream molecule - vascular endothelial growth factor receptor 2 (VEGFR-2). Here, we investigated the potential relationship between RAGE, VEGFR-2 and angiogenesis in 80 renal cell carcinoma (RCC) patients. Real-time quantitative PCR and ELISA analysis were used to explore the RAGE and VEGFR-2 gene expression levels and the protein of VEGFR-2 expression. Meanwhile, angiogenesis was detected by the semi-quantification of endothelial cell marker CD34 combined with caldesmon, which was detected by microvessel density (MVD) technique and immunohistochemistry. Tumors were classified as low or high RAGE-expressing using the median as the cut-off. Immunofluorescence staining for RAGE protein was performed as well. Additionally, the median gene expression levels of VEGFR-2 in the tumors were significantly lower expressing low levels of RAGE expression, 0.34 (95% CI, 0.28-0.39) compared to the expressing high levels of RAGE expression, 0.45 (95% CI, 0.29-0.61), (P=0.03). The median MVD was significantly lower in the tumors expressing low levels of RAGE, 6.5 (95% CI, 6.21-7.43), compared to the expressing high levels, 7.9 (95% CI, 6.25-8.93), (P<0.01). Further, a positive association was certified with VEGFR-2 protein levels, P=0.07. Besides, RCC with high levels of RAGE expression are associated with high VEGFR-2 mRNA/protein levels and a higher density of microvessels; conversely, Kaplan-Meier survival analysis suggests that a significant correlation of elevated RAGE expression with decreased overall survival and metastasis-free survival. Our results establish that RAGE was identified as a potential prognostic biomarker for disease prognosis of RCC.
晚期糖基化终末产物受体（RAGE）参与多种生物学过程，包括肿瘤发生。先前的研究表明，RAGE调节与新生血管生成相关的下游分子——血管内皮生长因子受体2（VEGFR-2）。在此，我们调查了80例肾细胞癌（RCC）患者中RAGE、VEGFR-2与血管生成之间的潜在关系。采用实时定量PCR和ELISA分析来探究RAGE和VEGFR-2基因表达水平以及VEGFR-2蛋白表达。同时，通过内皮细胞标志物CD34与钙调蛋白的半定量检测血管生成，钙调蛋白通过微血管密度（MVD）技术和免疫组织化学进行检测。以中位数作为临界值，将肿瘤分为RAGE低表达或高表达。还进行了RAGE蛋白的免疫荧光染色。此外，肿瘤中VEGFR-2的中位基因表达水平在RAGE低表达时显著较低，为0.34（95%CI，0.28 - 0.39），而在RAGE高表达时为0.45（95%CI，0.29 - 0.61），（P = 0.03）。RAGE低表达肿瘤的中位MVD显著较低，为6.5（95%CI，6.21 - 7.43），而高表达时为7.9（95%CI，6.25 - 8.93），（P < 0.01）。此外，VEGFR-2蛋白水平呈正相关，P = 0.07。此外，RAGE高表达的RCC与高VEGFR-2 mRNA/蛋白水平及更高的微血管密度相关；相反，Kaplan-Meier生存分析表明，RAGE表达升高与总生存期和无转移生存期降低显著相关。我们的结果表明，RAGE被确定为RCC疾病预后的潜在预后生物标志物。
