EZH2上调Neuropilin 2表达促进鼻咽癌血管生成的机制研究

Because tumor angiogenesis is closely related to metastasis, anti-angiogenesis therapy might improve the clinical result of patients with advanced nasopharyngeal carcinoma (NPC). Neuropilin 2 (NRP2) is also called the neurofilament protein 2, which is highly expressed in many kinds of malignant tumors and plays an important role in tumor angiogenesis. In our previous studies, NRP2 was up-regulated by EZH2 , which was over expressed and promoted angiogenesis in NPC. NRP2 was also highly expressed and related to angiogenesis in NPC. Therefore, we speculated that NRP2 up-regulated by EZH2 promotes angiogenesis in NPC, which was regulated by miRNA. To prove this hypothesis, we will examine the effect of NRP2 on angiogenesis in NPC by in vitro studies. Then the miRNA chips and bioinformatics analysis will be used to get the target miRNA. Finally, we will confirm that NRP2 was the target genes of miRNA by luciferase assay. This study might show that EZH2 promotes angiogenesis through inhibition of miR/NRP2 axis in NPC and provide a novel molecular target for anti-angiogenesis therapy of NPC.

肿瘤血管生成与转移密切相关，抗血管生成治疗或可提高晚期鼻咽癌患者临床疗效。Neuropilin 2(NRP2)又称神经纤毛蛋白2，高表达于多种恶性肿瘤，在肿瘤血管生成中扮演重要角色。前期的研究发现：EZH2在鼻咽癌中高表达并促进鼻咽癌血管生成；NRP2为EZH2所调控的下游血管生成靶基因；NRP2在鼻咽癌细胞和组织中高表达，且与鼻咽癌血管生成相关。我们推测EZH2可通过EZH2-miR-NRP2通路上调NRP2的表达从而促进鼻咽癌血管生成。为证实这一假设，我们拟通过体外功能实验，检测NRP2对鼻咽癌血管生成的影响；应用miRNA基因芯片筛选EZH2调控的下游miRNA，利用生物信息学预测和比对，寻找中间调控miRNA；采用双荧光素酶报告基因实验和细胞功能实验，行靶基因验证；阐明鼻咽癌中EZH2-miR-NRP2促血管生成的信号通路，为鼻咽癌的抗血管治疗提供新的分子靶标。

肿瘤血管生成与转移密切相关，抗血管生成治疗或可提高晚期鼻咽癌患者临床疗效。Neuropilin 2(NRP2)又称神经纤毛蛋白2，高表达于多种恶性肿瘤，在肿瘤血管生成中扮演重要角色。研究发现：EZH2在鼻咽癌中高表达并促进鼻咽癌血管生成；NRP2为EZH2所调控的下游血管生成靶基因；NRP2在鼻咽癌细胞和组织中高表达，促进鼻咽癌细胞增殖、转移、侵袭、成瘤，可促进鼻咽癌血管生成相关；EZH2的下游miRNA表达基因芯片及生物信息学分析显示miR-200b-3p为EZH2-miR-NRP2通路的目标miRNA；通过RT-qPCR检测发现，相对于健康对照组miR-200b-3p在鼻咽癌组织中低表达，且在鼻咽癌细胞中EZH2可以抑制miR-200b-3p的表达；双荧光素酶报告基因实验证实miR-200b-3p可以通过结合NRP2 3’UTR调控NRP2的表达，且只有唯一的结合位点。综上所述，在鼻咽癌中EZH2-miR-200b-3p-NRP2调控轴促进鼻咽癌血管生成，为鼻咽癌的抗血管治疗了提供新的分子靶标。