lncRNA XIST/miR-367/ZEB2轴促进TGF-β诱导非小细胞肺癌EMT的表观调控机制

Epithelial-mesenchymal transition (EMT) is an important mechanism, which endows cancer cell with migratory and invasive capabilities. We previously explored the EMT process induced by TGF-β in non-small cell lung cancer (NSCLC) (Oncogene, 2016; Lung Cancer, 2015). However, the mechanisms underlying the interplay between long non-coding RNA (lncRNA) and microRNA (miRNA) have poorly been elucidated in the TGF-β-induced EMT process. Prior to this proposal, we identified that miR-367 may regulate the expression of ZEB2 (one of downstream transcriptional factors of TGF-β signaling pathway) and inhibit EMT; Moreover, lncRNA XIST can affect the expression of miR-367 and ZEB2. Therefore, we raised the hypothesis that lncRNA XIST/miR-367/ZEB2 axis can enhance TGF-β-induced EMT in NSCLC metastasis. In the present proposal, we will perform several experiments in vitro and in vivo to test the hypothesis, and expect to establish the relationship between XIST, miR-367 and ZEB2 expression in NSCLC tissues. This project will reveal a novel mechanistic role of lncRNA XIST/miR-367/ZEB2 axis in NSCLC metastasis.

上皮-间质转化(EMT)是癌细胞获得迁移和侵袭能力的重要机制。我们前期探究了非小细胞肺癌(NSCLC)中TGF-β诱导的EMT过程 (Oncogene, 2016; Lung Cancer, 2015)。但此过程中，长链非编码RNA(lncRNA)与微小RNA(miRNA)之间的相互作用鲜见阐明。且预实验表明miR-367可靶向调控TGF-β通路下游的转录因子ZEB2并抑制EMT；lncRNA XIST可影响miR-367和ZEB2的表达。因此提出假设：NSCLC转移过程中存在lncRNA XIST/miR-367/ZEB2轴促进TGF-β诱导EMT的表观调控机制。项目拟从组织、细胞及实验动物等多层面验证此假设，同时明确NSCLC组织样本中XIST、miR-367与ZEB2表达之间的关系，以期揭示lncRNA XIST/miR-367/ZEB2轴调控在非小细胞肺癌侵袭转移作用中的新机制。

癌细胞转移是肺癌患者预后差不良的重要原因。而上皮-间质转化(EMT)是肺癌细胞获得转移侵袭能力的重要生物学过程。但此过程中，长链非编码RNA(lncRNA)与微小RNA(miRNA)之间的相互作用机制鲜见阐明。越来越多的证据表明，lncRNA XIST发挥着促进肿瘤进程的功能。本项目旨在探讨lncRNA XIST促进TGF-β诱导的非小细胞肺癌(NSCLC)细胞EMT过程的作用机制，阐明lncRNA XIST与miRNA的相互作用在NSCLC侵袭转移过程中的重要作用，为NSCLC的诊断和治疗提供新的思路。我们的实验结果表明:lncRNA XIST和ZEB2 mRNA表达在淋巴结转移的NSCLC组织中表达显著升高。敲弱lncRNA XIST表达能够显著抑制ZEB2的表达，且抑制TGF-β诱导的NSCLC细胞EMT和迁移侵袭。小鼠体内实验证实敲低lncRNA XIST可以抑制NSCLC细胞的肺部转移。敲弱ZEB2抑制TGF-β诱导的NSCLC细胞EMT和迁移侵袭。机制上讲，miR-367和miR-141都能够靶向结合lncRNA XIST和ZEB2。敲弱lncRNA XIST可以上调miR-367和miR-141的表达。结论：lncRNA XIST能够通过调控miR-367/miR-141-ZEB2轴促进NSCLC细胞中TGF-β诱导的EMT过程以及NSCLC的侵袭和转移。在该项目的资助下，直接相关的论文发表于国际知名期刊 Cancer Letters，并第一标注了资助号(81672277)。同时，基金资助培养了3名研究生(1名硕士、2名博士)。