circ_0001613通过稳定c-Met促进甲状腺乳头状癌侵袭转移的机制研究

甲状腺乳头状癌（PTC）出现侵袭转移是预后不良的重要因素，但目前机制不明。我们前期通过高通量测序发现circ_0001613在PTC中显著升高并促进PTC侵袭转移。进一步通过RNA-seq分析提示高表达circ_0001613可激活MAPK及PI3K信号通路。RNA Pull-down/质谱实验显示circ_0001613与c-Met及ALKBH5蛋白相结合。circ_0001613通过结合而维持c-Met蛋白稳定性，但去甲基化酶ALKBH5可下调m6A修饰水平诱导circ_0001613降解。因此，我们提出科学假设：ALKBH5介导的m6A修饰影响circ_0001613稳定性进而激活c-Met/MAPK和c-Met/PI3K通路，本项目将揭示PTC侵袭转移的分子机制，并结合临床样本分析circ_0001613与临床病理学特征及预后关系，为PTC侵袭转移的诊治提供新的科学依据。

Papillary thyroid carcinoma (PTC) has a rapidly increasing incidence over the past decade. Metastasis is the major factor for poor prognosis of PTC, although the molecular mechanisms of which remain unclear. Through high-throughput sequencing, we found that circ_0001613 was significantly up-regulated in PTC tissues. The up-regulation of circ_0001613 was confirmed by qRT-PCR in PTC tissues and cell lines. Functionally, we proved that circ-0001613 promoted PTC invasion and metastasis in vivo and in vitro. Furthermore, RNA sequencing indicated that the MAPK/ERK pathway and the PI3K/AKT pathway are potentially activated by circ-0001613. By performing RNA pull-down analysis and mass spectrometry, we observed that circ-0001613 binds to c-Met and ALKBH5. Knockdown of circ_0001613 reduced the stability of c-Met and inhibited the phosphorylation of ERK1/2 and AKT. On the other hand, down-regulated ALKBH5 was related to the reduction of circ_0001613 degradation. Based on these findings, we speculate that circ_0001613 is frequently up-regulated in PTC and contributes to PTC progression by activating c-Met/MAPK and c-Met/PI3K signaling pathway; down-regulated ALKBH5 improves the stability of circ_0001613 through m6A-dependent mechanism. In this project, we will first reveal the role of ALKBH5 mediating m6A modification in regulating circ_0001613 expression and the molecular mechanism of circ_0001613 in the metastasis of PTC, thus providing novel targets for treatment of metastatic PTC.