益气除痰方调控miRNAs介导GRP78干预NSCLC化疗耐药机制研究

项目名称： 益气除痰方调控miRNAs介导GRP78干预NSCLC化疗耐药机制研究

项目编号： No.81503417

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李元滨

作者单位： 河北大学

项目金额： 18万元

中文摘要： 以铂类药物为基础的联合化疗是目前NSCLC干预的一线方案，而肺癌细胞多药耐药性的出现限制了铂类药物的广泛应用，如何提高NSCLC对药物的敏感性是当前研究的热点。细胞自稳机制内质网UPR是肿瘤细胞维持恶性和耐药性的重要机制，GRP78诱导表达是UPR启动的标记蛋白；最近研究发现，失调的miRNA能调控UPR相关分子蛋白影响细胞对化疗药物的反应性，而抑制或干扰内质网UPR逆转肿瘤耐药是当前耐药领域研究的新亮点。前期研究表明，益气除痰方能抑制肺癌耐药细胞UPR、GRP78的表达，并可能通过调控相关miRNA而发挥作用。本项目拟在前期研究的基础上，以人肺癌耐药细胞、裸鼠移植瘤耐药模型为研究平台；以miRNA芯片、荧光素酶报告基因实验、miRNA模拟物及基因沉默等为研究方法；筛选GRP78相关性miRNA；通过体内外实验对比分析，探讨益气除痰方干预肺癌耐药的疗效机制。

中文关键词： 非小细胞肺癌；miRNA；GRP78；化疗耐药；益气除痰方

英文摘要： Platinum-based combination chemotherapy are currently the first-line chemotherapy for NSCLC, however, the emergence of multidrug resistance (MDR) limites the widespread use of platinum drugs, currently, how to improve the sensitivity of NSCLC to drugs is a hot topic. The unfolded protein response (UPR) is a self-stabilization mechanism of the endoplasmic reticulum stress (ERS) in tumor cells, it plays a key role in tumor development and drug-resistance, and GRP78 is considered to be a marker of UPR. Recently, it has been found that the dysregulation of miRNAs modulate UPR related protein, thus influences cell sensitive to chemotherapy drug. And repression or interference of UPR is a hot topic of reversing drug-resistance in tumor cells. Our previous study demonstrated that up-regulationg of UPR and GRP78 in A549/DDP cell, and Yiqi-Chutan Recipe (YQCT) could inhibit xenografts growth in nude mice, which is possibly related to down-regulation the expression of GRP78/Bip and UPR-related proteins, the weakness of UPR protection, then induced apoptosis pathway. Therefore, by using miRNA array, luciferase reporter gene assay, miRNA mimics and gene silencing, this study aims to screen GRP78 related miRNA, and explore YQCT mechanisms in platinum-resistant lung cancer in vitro and in vivo.

英文关键词： NSCLC;miRNA;GRP78;chemoresistance;Yiqi-Chutan Recipe