Circ-EIF3I促进Smad2/3向早期内体富集激活TGF-β信号通路介导的胰腺癌MMPs激活的机制研究

环状RNA在现有的胰腺癌研究中的调控机制以ceRNA机制为主，尚未被充分研究发掘。课题组借助基因芯片及临床样本发现并验证了circ-EIF3I在胰腺癌组织中高表达，并与分期及预后密切相关。通过转录组学我们发现circ-EIF3I的可能参与调控MMP及胰腺癌转移；进一步借助TRAP、RNA pull-down等实验技术发现circ-EIF3I能够直接结合Smad2/3并通过促进其向内化的TβRI富集致使其磷酸化。据此，我们提出科学假说：circ-EIF3I直接结合Smad2/3，促使其向内体上的TβRI上富集，进而被磷酸化从而激活TGF-β信号转导，增加MMP1及MMP14的转录表达，进而激活MMPs并促进胰腺癌转移。本项目着力探讨circ-EIF3I发挥功能的独特分子机制，拓宽相关环状RNA的研究思路，并为其作为筛选评估胰腺癌病人预后的生物学指标及开发特异性药物提供崭新的理论依据。

The regulatory mechanism of circular RNA in the current pancreatic cancer research is mainly based on the ceRNA mechanism, which has not been fully studied and discovered. With the help of gene chips and clinical samples, the research group discovered and verified that circ-EIF3I is highly expressed in pancreatic cancer tissues, and is closely related to staging and prognosis. Through transcriptomics, we found that circ-EIF3I may be involved in the regulation of matrix metalloproteinases and metastasis of pancreatic cancer; further using TRAP, RNA pull-down and other experimental techniques, we found that circ-EIF3I can directly bind to Smad2/3 and promote its recruitment to TβRI and resulting in Smad2/3 phosphorylation. Based on this, we put forward a scientific hypothesis: circ-EIF3I directly binds to Smad2/3, and promotes its enrichment to the TβRI internalized on the endosome, which is then phosphorylated to activate the TGF-β signaling transduction, increasing the transcriptional expression of MMP1 and MMP14, and then activating MMPs and promotes pancreatic cancer metastasis. This project focuses on exploring the unique molecular mechanism of circ-EIF3I, broadening the research ideas of related circular RNA, and providing new theoretical basis for screening and evaluating the prognosis of pancreatic cancer patients and developing specific targeted drugs.