外泌体传递miR-1229在结直肠癌中转运调控机制研究

The exosome is a new mediator of intercellular communication. Exosome-delivering miRNAs could be involved in the occurrence and development of tumor. A previous miRNAs microarray data suggested that exosome-derived miR-1229 was overexpressed in the sera of colorectal cancer (CRC). However, the exact clinical significance of miR-1229 in CRC and its signal transduction mechanism remains unclear. The present study will investigate the expression profile and prognostic value of miR-1229 in CRC by sera samples, and further explore the effect of miR-1229 on LIFR/Hippo-YAP. We will explore the role of hnRNPA2B1 in the process of exosome-delivering miR-1229, and the transport regulated mechanism of hnRNPA2B1-mediated miR-1229/LIFR/Hippo-YAP in CRC. We expect that these studies will contribute to our understanding of transport regulated mechanism of exosome-based delivery of miR-1229 in colorectal cancer. These experimental evidences may improve the study of mechanism of CRC occurrence and development and the study of screening of effective diagnostic and therapeutic measures.

外泌体是细胞间通讯的新兴介体。研究表明外泌体传递的miRNAs在肿瘤的发生发展中起着重要作用，先前miRNAs微阵列芯片提示外泌体中miR-1229在结直肠癌（CRC）血清中高表达，但是其确切的临床意义和信号转导机制尚未明了。本研究将首先利用CRC血清样本评估外泌体miR-1229在CRC中的表达特征，探讨外泌体中miR-1229的表达与CRC预后及LIFR/Hippo-YAP通路的关系；其次，利用细胞和动物实验探讨不均一型核糖核蛋白A2B1（hnRNPA2B1）在外泌体传递miR-1229的作用及其hnRNPA2B1介导的miR-1229/LIFR/Hippo-YAP调控网络在CRC中的转运调控机制；最后，综合分析外泌体传递miR-1229在CRC中的转运调控作用，为阐明CRC发生发展的作用机制和探寻CRC有效诊治措施提供新的实验依据。

外泌体是细胞间通讯的新兴介体。研究表明外泌体传递的miRNAs在肿瘤的发生发展中起着重要作用，虽然先前miRNAs微阵列芯片提示外泌体中miR-1229在结直肠癌（CRC）血清中高表达，但经本课题组大量临床样本验证发现miR-1229-3p在CRC血清及细胞中低表达，并且miR-1229-3p高表达的患者相比于低表达患者预后更好。进一步通过体内及体外实验发现miR-1229-3p可作为抑癌因子抑制CRC细胞的增殖、迁移、侵袭，促进细胞凋亡。机制研究发现，miR-1229-3p可通过SETD7-FOXO3通路影响CRC恶性进展。本研究为阐明CRC发生发展的作用机制和探寻CRC有效诊治措施提供新的实验依据。