E2F1调控长链非编码RNA MTX2增强非小细胞肺癌顺铂耐药性的机制研究

项目名称： E2F1调控长链非编码RNA MTX2增强非小细胞肺癌顺铂耐药性的机制研究

项目编号： No.81472198

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： 王朝霞

作者单位： 南京医科大学

项目金额： 80万元

中文摘要： 化疗耐药是非小细胞肺癌(NSCLC)患者治疗失败的主要原因。而lncRNA与肿瘤耐药关系密切，但报道很少。我们通过测序技术发现NSCLC顺铂耐药细胞较亲本细胞lnc-MTX2表达显著上调，并在耐药组织中得到了验证。干扰lnc-MTX2的表达显著增加耐药细胞对顺铂的敏感性，并上调E-cadherin的表达。生物信息学发现lnc-MTX2启动子区含有3个E2F1的结合位点，干扰E2F1后lnc-MTX2的表达下调3倍，RIP证实lnc-MTX2与PRC2复合体中的核心亚基EZH2结合。据此提出假设：E2F1促进lnc-MTX2的表达，并绑定PRC2介导E-cadherin启动子区的甲基化抑制其转录，增强NSCLC的耐药性。本课题组将通过临床样本验证，运用RIP、ChIP等技术证实上述假设，丰富NSCLC顺铂耐药分子机制的认知，为NSCLC临床个体化治疗及逆转耐药的分子靶向治疗提供新依据。

中文关键词： C05_气管；支气管；肺肿瘤；长链非编码RNA；MTX2；E2F1；顺铂耐药

英文摘要： The main reason for treatment failure of non-small cell lung cancer (NSCLC) patients is chemotherapy resistance. Although long non-coding RNA (lncRNA) is closed related with tumor drug resistance, recent studieds cover little about that. We found that lnc-MTX2 expression was significantly upregulated in cisplatin-resistant NSCLC cells when compared with parental cells by sequencing technology and it had been verified in resistant tissues. Inhibition of lnc-MTX2 could significantly enhance cisplatin-resistant cells sensibility to cisplatin, and increase E-cadherin expression. Bioinformatics was shown that lnc-MTX2 promoter region contained three E2F1 binding sites. Lnc-MTX2 was downregulated by 3 folds while inhibition of E2F1, and RIP was confirmed that lnc-MTX2 binded EZH2, the core subunits of PRC2 complex. Accordingly, the hypothesis is proposed: E2F1 promotes lnc-MTX2 expression, and binds PRC2 which represses E-cadherin transcription by promoter methylation to enhance the resistance of NSCLC. We will documente this hypothesis by clinical samples via RIP and ChIP et.al methonds. Moreover, our work will further the understanding about the molecular mechanisms of NSCLC cells cisplatin resistance and provide a new basis for NSCLC clinical individual therapy and molecular targeted therapy to reverse drug resistance.

英文关键词： trachea;bronchi;lung tumor;long non-coding RNA MTX2;E2F1;cisplatin resistance