微小RNA-34家族抑制EMT逆转肺癌EGFR-TKI获得性耐药的机制研究

项目名称： 微小RNA-34家族抑制EMT逆转肺癌EGFR-TKI获得性耐药的机制研究

项目编号： No.81472193

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 胡雪君

作者单位： 中国医科大学

项目金额： 68万元

中文摘要： EGFR-TKI是治疗EFGR突变型NSCLC患者的首选药物，但几乎所有患者终将发生EGFR-TKI获得性耐药，导致治疗失败。研究表明，肺癌细胞上皮间质转化(EMT)是导致化疗和靶向治疗耐药的新机制。我们在前期研究中，建立了TKI 诱导的耐药细胞,并观察到EMT现象。同时miRNA芯片分析结果显示，与其亲本敏感细胞相比，耐药细胞的miR-34家族表达显著降低。过表达miR-34拟似物，显著提高了TKI的敏感性，同时下调了Notch1、c-Met等EMT的上游调节分子，提示miR-34家族可能通过抑制EMT逆转TKI耐药。本研究旨在进一步明确在TKI获得性耐药细胞中，miR-34家族降低的分子机制，以及miR-34如何抑制耐药细胞发生EMT，并探索以miR-34和Notch1、c-Met为靶点的逆转TKI耐药的新方法。

中文关键词： 非小细胞肺癌；EGFR突变细胞；酪氨酸激酶抑制剂；获得性耐药；微小RNA

英文摘要： Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are clinically effective treatments for non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, in almost NSCLC patients, acquired TKI resistance can develop during treatment with TKI, which can lead to treatment failure. It is reported that epithelial-mesenchymal transition (EMT) is a new mechanism leading to chemotherapy and targeted drugs resistance. In our previous study, TKI resistance cell line was established and EMT phenomenon was observed in the resistance cell line. Next, microarray profile analysis of microRNAs was performed in TKI resistant cells and the parental cells respectively. Our results demonstrated that the miR-34 family expressed much lower in the resistant cells than the parental cells. Treatment of TKI resistance cells with miR-34 mimics significantly increased the sensitivity to TKI and down-regulated the expressions of Notch1 and c-Met, which acts to upstream in EMT pathway. These results suggest that miR-34 might reverse TKI resistance through suppressing EMT in NSCLC. The aim of this study is to clarify how miR-34 family are downregulated in the TKI resistant cells and the mechanisms of miR-34 family members suppressing EMT. Eventually, our study will provide a novel way for reversing the TKI resistance through targeting miR-34, Notch1 and c-Met.

英文关键词： Non-small cell lung cancer;EGFR-mutant cells;Tyrosine kinase inhibitors;Acquired resistance;microRNAs