MMP-2基因3’UTR 119A>C多态性对晚期非小细胞肺癌不同含铂化疗方案白细胞毒性的预测作用及其调控机制研究

项目名称： MMP-2基因3’UTR 119A>C多态性对晚期非小细胞肺癌不同含铂化疗方案白细胞毒性的预测作用及其调控机制研究

项目编号： No.81201829

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 王洵

作者单位： 南京医科大学

项目金额： 23万元

中文摘要： 白细胞减少是含铂化疗的主要毒副作用之一，我们前期研究发现，在使用长春瑞滨联合顺铂方案的患者中，MMP-2 rs7201位点(119A>C)A/A纯合子患者严重白细胞减少的发生率显著低于C/C纯合子患者，rs7201处于MMP2 3'UTR与miR-361/373的结合区，因而rs7201多态性可能通过影响miR-361/373与MMP-2 3'UTR的结合，从而干扰miR-361/373对MMP-2基因转录的调控，进而影响造血干细胞的增殖及凋亡，导致患者化疗后白细胞减少具有个体化差异。本课题首次探讨了rs7201多态性预测化疗白细胞减少的机制，拟通过构建荧光素酶表达系统，检测rs7201多态性对基因转录的调控作用；利用表面等离子共振技术，分析该位点与miR-361/373的结合力；并通过集落形成试验及流式细胞术，检测miR-361/373对造血干细胞增殖及凋亡的调控作用。

中文关键词： 基质金属蛋白酶2；单核苷酸多态性；白细胞减少；含铂化疗；非小细胞肺癌

英文摘要： Platinum (cisplatin or carboplatin), in combination with navelbine, gemcitabine, or paclitaxel, has been widely used as first-line chemotherapy for advanced nonsmall cell lung cancer (NSCLC).These platinum-based regimens bring modest benefits but also adverse effects, which may cause distressing symptoms and prevent further therapies.Matrix metalloproteinase-2 (MMP-2) is well known for its critical role in cell survival and cancer development.It also plays an important role in hematopoietic recovery after chemotherapy-induced myelosuppression. Our recent study provides the first evidence for a predictive role of MMP-2 polymorphisms in the variability of severe chemotherapy-related leukopenia among Chinese patients with platinum-treated, advanced NSCLC.The variant homozygotes of reference MMP-2 3'UTR 119A>C polymorphism (rs7201) exhibited the most significant effect on the risk of leucopenia, This 3'UTR 119A>C variant was predicted to modulate the binding of miR-361 and miR-373. Our hypothesis is that the MMP-2 rs7201 variant modifies leukopenia after first-line, platinum-based chemotherapy in Advanced Non-small Cell Lung Cancer Patients by affecting miRNA-mediated gene regulation. Surface plasmon resonance assay and luciferase assay is planning to analysis RNA binding affinity and transcriptional activity. Proli

英文关键词： Matrix metalloproteinase-2；polymorphisms；leucopenia；platinum-based chemotherapy；non-small cell lung cancer