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LncRNA H19/miR-141/PD-L1轴介导EGFR突变型非小细胞肺癌免疫逃逸的作用及机制研究

批准号81702809 学科分类肿瘤免疫 ( H1604 )
项目负责人生金 负责人职称医师 依托单位浙江大学
资助金额19.00
万元
项目类别青年科学基金项目 研究期限2018 年 01 月 01 日 至
2020 年 12 月 31 日
中文主题词长链非编码RNA-H19;微小RNA-141;程序性死亡因子配体-1;表皮生长因子受体;免疫逃逸
英文主题词LncRNA H19;miR-141;programmed death ligand-1;epidermal growth ractor receptor;immune escape

摘要

中文摘要 研究发现,在NSCLC中,驱动基因EGFR突变可上调PD-L1表达、促进肿瘤免疫逃逸。近年来研究发现,microRNA可参与肿瘤免疫逃逸,但对PD-L1的调控仍有待进一步研究。课题组前期研究发现miR-141可能在转录后水平调控NSCLC肿瘤细胞PD-L1的表达,而lncRNA H19与PD-L1共享一段miR-141非编码区的结合序列,提示H19可能通过“竞争性内源性RNA”的机制解除miR-141对PD-L1的翻译抑制、促进肿瘤免疫逃逸。课题组拟通过干预H19和miR-141表达水平,通过免疫印迹、RNA免疫共沉淀、荧光素酶报告基因等实验技术,阐明lncRNA-H19/miR-141/PD-L1轴调节EGFR突变型肺癌免疫逃逸的机制,并通过体内实验验证靶向H19、miR-141对抑制肿瘤免疫逃逸的治疗潜力。本课题有望为深入理解和克服EGFR突变型肺癌免疫逃逸提供研究基础。
英文摘要 Programmed death ligand-1(PD-L1)is vital for immune escapes in non-small cell lung cancer(NSCLC) and proved inducible by EGFR mutation. Evidence shows that microRNA is also involved in regulating tumor immune evasion. Nevertheless, whether microRNA influence the expression of PD-L1 on tumor cells remains elusive. In our prophase research, the expression level of miR-141 and PD-L1 were reversely correlated with significant statistical difference. Morever, the expression of PD-L1 may be post-transcriptionally regulated by miR-141. Long non-coding RNA(lncRNA)H19 shares a common binding sequences with PD-L1 on the untranslated region of miR-141,which indicates that H19 may function as a competitive endogenous RNA (ceRNA) and therefore relieve the translational suppression on PD-L1 by miR-141. To validate our hypothesis that lncRNA-H19/miR-141/PD-L1 axis is a novel mechanism regulating tumor immune evasion, we design to moderate the expression level of lncRNA H19 and miR-141 and apply routine techniques including western blot, RNA co-immunoprecipitation and luciferase reporter gene. Moreover, we would investigate the therapeutic potential by targeting H19 and miR-141 with subcutaneously implanted tumor model. The proposed study is innovative as it may illustrate a new regulating mechanism for tumor immune and provide potential target for treatment EGFR mutant NSCLC by blocking tumor immune escape.
结题摘要

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