长链非编码RNA RP11-1100L3.8对非小细胞肺癌厄洛替尼耐药的机制研究

项目名称： 长链非编码RNA RP11-1100L3.8对非小细胞肺癌厄洛替尼耐药的机制研究

项目编号： No.81502678

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： 潘旋

作者单位： 南京医科大学

项目金额： 18万元

中文摘要： 非小细胞肺癌（NSCLC）EGFR-TKI获得性耐药极大地困扰临床治疗，lncRNA与NSCLC获得性耐药的研究甚少。我们前期研究证实：miR-451在NSCLC组织中显著低表达，运用lncRNA 芯片技术发现在厄洛替尼获得性耐药的NSCLC组织中，lnc- RP11-1100L3.8表达水平显著高于敏感组织11.7 倍，敲低lnc-RP11-1100L3.8诱导耐厄洛替尼肺癌细胞的凋亡，同时荧光素酶实验证实lnc-RP11-1100L3.8与miR-451种子序列特异性结合。据此提出假设： lnc-RP11-1100L3.8通过竞争性结合miR-451，解除miR-451对靶基因RAB14的抑制，进而激活相关信号通路，导致厄洛替尼耐药。本课题以NSCLC为研究对象，拟采用荧光素酶、RIP等实验在细胞、动物及临床标本水平验证此假说，为NSCLC厄洛替尼获得性耐药的生物治疗提供新靶标及依据。

中文关键词： 非小细胞肺癌；EGFR-TKI获得性耐药；长链非编码RNA；RP11-1100L3.8；miR-451；RAB14

英文摘要： Aquired resistance to EGFR-TKI in non small cell lung carcinoma (NSCLC) greatly troubled the clinical therapy. The roles of lncRNAs in the acquired resistance of NSCLC, however, are far from being fully elucidated. Our previous work has shown that miR-451 was significantly downregulated in NSCLC tissues compared with corresponding non-tumor lung tissues. Using lncRNA chip high throughput analytical technique, we found that lnc- RP11-1100L3.8 was upregulated more than 11 times in erlotinib-acquired resistant NSCLC tissues than erlotinib-sensitive NSCLC tissues. Downregulation of lnc- RP11-1100L3.8 induced apoptosis enhancement in erlotinib-resistant NSCLC cells. Moreover, according to the competing endogenous RNA(ceRNA) hypothesis, lncRNAs may act as endogenous sponges for miRNAs for sharing miRNAs responses elements(MREs), inhibiting normal miRNA targeting activity on mRNA., thereby affecting tumor development and progression.Here, the results of luciferase reporting experiments showed that lnc- RP11-1100L3.8 could directly bind to miR-451 seed sequence. Therefore, we hypothesized that lnc- RP11-1100L3.8 could play the ceRNA activity to competitively bind to miR-451, relieving the inhibition of RAB14, thus leading to erlotinib resistance in NSCLC. We will verify the aboved hypothesis by use of clinical samples, RNA immunoprecipitation, luciferase reporter, a nude mouse model of lung erlotinib resistance and other techniques. This study will enrich the molecular mechanism of the acquired resistance of NSCLC, and provide a novel molecular target for overcoming the acquired resistance in NSCLC.

英文关键词： non small cell lung cancer;acquired resistance to EGFR-TKI;lnc- RP11-1100L3.8;miR-451;RAB14