食管胃结合部腺癌（AEG）患者确诊时多为局部进展期或已存在远处转移，预后极差。申请人前期研究发现，circCPSF6与AEG的恶性表型及不良预后密切相关。生物信息学分析提示circCPSF6的功能发挥与线粒体分裂相关，并且与线粒体分裂关键蛋白CDK1表达水平存在相关性。进一步研究发现miR-490-3p为circCPSF6与CDK1作用的中间桥梁。据此，我们提出如下科学假说：circCPSF6通过靶向结合并抑制miR-490-3p表达，从而促进CDK1表达，进一步磷酸化激活DRP1，加速线粒体分裂，调控AEG细胞的增殖、迁移、侵袭和肿瘤干细胞干性维持等恶性表型。申请人拟采用RNA测序、免疫荧光共聚焦成像、免疫共沉淀和基因干预等技术在临床、动物、细胞和分子水平多层面、多角度展开深入研究，有望阐明circCPSF6在AEG发生发展中的作用及具体分子机制，为AEG的诊治提供新靶点和分子标记。

Adenocarcinoma of the esophagogastric junction (AEG) is mostly diagnosed as locally advanced or distant metastatic disease, and it is less sensitive to radiotherapy and chemotherapy, with extremely dismal prognosis. Thus, it’s very urgent to seek alternate treatments through a better understanding of the cell biology and find some new molecular targets. .In our previous study, RNA-seq and qRT-PCR analysis revealed an evident up-regulation of circCPSF6 mRNA level in AEG tissues. Kaplan-Meier analysis showed that high expression of circCPSF6 conferred a poor prognosis in patients with AEG. Knockdown of circCPSF6 in AEG cells inhibited cell proliferation, invasion and increased cell apoptosis. More importantly, circCPSF6 knockdown significantly attenuated the expression level of CD44, CD133 and SOX2, which were reported to relate to the stemness of cancer stem cells. These data suggested that circCPSF6 may be a key regulator of the malignant phenotype of AEG. Bioinformatics analysis suggested that circCPSF6 was related to mitochondrial fission function. In AEG clinical samples, circCPSF6 was positively correlated with the expression of mitochondrial fission crucial protein CDK1 and pDRP1. Silencing of circCPSF6 in AEG cells led to a significant reduction of protein levels of CDK1 and pDRP1. Further analysis revealed that miR-490-3p was a connector between circCPSF6 and CDK1. Based on the above results, we propose the following hypothesis: circCPSF6 promotes CDK1 expression by specifically binding and inhibiting miR-490-3p expression. CDK1 further phosphorylates and activates DRP1, accelerates mitochondrial fission, and regulates AEG cell proliferation, migration, invasion, and the stemness of AEG stem cells..To verify this hypothesis, RNA sequencing, immunofluorescence confocal imaging, co-immunoprecipitation, and genetic intervention will be used in clinical, animal, cellular and molecular aspects. Through the implementation of this project, we will reveal the role of circCPSF6 in the regulation of malignant phenotype in AEG, as well as the possible underlying mechanisms, providing a theoretic and experimental basis for development of novel targeted therapies in AEG.