Circ-PTK2/miR-429/TIF1γ轴调控TGF-β诱导的NSCLC细胞EMT的机制

Epithelial-mesenchymal transition (EMT) is an important mechanism, which endows cancer cell with migratory and invasive capabilities. However, the mechanistic role of circular RNAs (circRNA) has not yet been reported in the EMT process of lung cancer cells. We previously revealed a novel mechanism by which transcription intermediary factor 1 gamma (TIF1γ) inhibited TGF-β-induced EMT in non-small cell lung cancer (NSCLC) (Oncogene, 2016). Prior to this proposal, we identified that miR-429 may target and inhibit TIF1γ, and thereby promote TGF-β-induced EMT; Moreover, circRNA PTK2 (Circ-PTK2) was characterized and may target miR-429 in NSCLC cells. Therefore, we raised the hypothesis that Circ-PTK2/miR-429/TIF1γ axis regulates 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 Circ-PTK2, miR-429 and TIF1γ expression in NSCLC tissues. This project will reveal a novel mechanistic role of Circ-PTK2/miR-429/TIF1γ 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。然而，肺癌细胞EMT过程中环状RNA(circRNA)发挥的作用及其调控机制尚无报道。我们前期揭示了非小细胞肺癌(NSCLC)中转录中介因子TIF1γ抑制TGF-β诱导的EMT的机制(Oncogene,2016)。且预实验表明:1)miR-429可靶向抑制TIF1γ并促进TGF-β诱导的EMT；2)环状RNA-PTK2(Circ-PTK2)被鉴定并可以靶向结合miR-429。因此提出假设：NSCLC转移过程中存在Circ-PTK2/miR-429/TIF1γ轴调控TGF-β诱导的EMT的表观机制。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Circ-PTK2、miR-429与TIF1γ表达之间的关系，以期揭示Circ-PTK2/miR-429/TIFγ轴调控在NSCLC侵袭转移作用中的新机制。

癌细胞转移是肺癌患者预后差的重要原因，而上皮-间质转化(EMT)是肺癌细胞获得侵袭与转移能力的重要生物学过程。然而，肺癌细胞EMT过程中环状RNA(circRNA)发挥的作用及其调控机制鲜见报道。本项目研究了环状RNA hsa_circ_0008305(Circ-PTK2)抑制TGF-β诱导的非小细胞肺癌(NSCLC)细胞发生EMT的作用机制，阐明NSCLC侵袭转移过程中Circ-PTK2与TIF1γ之间的相互作用，为NSCLC的诊断和治疗提供新的思路。我们的实验结果表明：TGF-β诱导NSCLC细胞的EMT过程伴随着环状RNA Circ-PTK2和TIF1γ的表达下调。Circ-PTK2能够促进TIF1γ的表达，且抑制TGF-β诱导NSCLC细胞的EMT和迁移侵袭。裸鼠体内转移实验表明Circ-PTK2抑制NSCLC细胞的转移。Circ-PTK2在NSCLC组织中显著低表达且与TIF1γ表达呈正相关，转移组织中Circ-PTK2的表达要显著低于非转移组织。机制上讲，Circ-PTK2具有海绵吸附miR-429/miR-200b-3p的功能，miR-429/miR-200b-3p通过靶向作用TIF1γ进而促进TGF-β诱导NSCLC细胞的EMT和迁移侵袭。结论：Circ-PTK2/miR-429/miR-200b-3p/TIF1γ轴能够抑制TGF-β诱导的NSCLC细胞的EMT和NSCLC的侵袭转移。在该项目的资助下，直接相关的论文发表于Molecular Cancer(IF: 41.444)，且在Seminars in Cancer Biology发表1篇特邀综述(IF: 17.012)，均标注了资助号(81872343)；同时，基金资助培养了5名研究生(3名硕士、2名博士)。