Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p.
Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p.
复制标题
DOI：
10.18632/oncotarget.4924
复制
发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Cao L
中科院分区：
文献类型：
--
作者：
Ding G;Zhou L;Qian Y;Fu M;Chen J;Chen J;Xiang J;Wu Z;Jiang G;Cao L
已有研究表明，肿瘤来源的exosomes可以将miRNAs转移到肿瘤微环境中的受体细胞，促进肿瘤的侵袭和转移。本研究旨在探讨胰腺癌（PC）来源的exosomemiRNAs如何抑制树突状细胞（DC）mRNA表达并诱导免疫耐受。我们的研究表明，与未成熟树突状细胞（iDC）相比，外泌体刺激的树突状细胞（exo-iDC）中有9种PC相关的miRNA增加，208种mRNA被抑制。通过生物信息学数据库分析，对9种miRNAs和208种mRNAs进行靶点预测。从靶点预测中，预测并验证了调节因子X相关蛋白（RFXAP）是MHC II的重要转录因子，它被从PC分泌的exosomes转移的miR-212- 3 p抑制，导致MHC II表达降低。此外，临床研究显示PC组织中miR-212- 3 p和RFXAP之间呈负相关。从这些数据中，我们得出结论，PC相关的miRNA可以通过外泌体转移到树突状细胞，并抑制靶mRNA的表达。更重要的是，PC衍生的外泌体通过miR-212- 3 p抑制RFXAP表达，从而降低MHC II表达并诱导树突状细胞的免疫耐受。RFXAP缺乏在实体瘤中从未报道过。RFXAP在肿瘤中的作用和机制值得进一步探讨。
It has been reported tumor-derived exosomes can transfer miRNAs to recipient cells in the tumor microenvironment, promoting tumor invasion and metastasis. The present research aimed to explore how pancreatic cancer (PC) derived exosomal miRNAs inhibited mRNA expression of dendritic cells and induced immune tolerance. Our study revealed that 9 PC-related miRNAs were increased and 208 mRNAs were inhibited in exosome-stimulated dendritic cells (exo-iDCs) compared to immature dendritic cells (iDCs). A target prediction between the 9 miRNAs and 208 mRNAs was performed by bioinformatics database analysis. From the target prediction, it was predicted and validated that regulatory factor X-associated protein (RFXAP), an important transcription factor for MHC II, was inhibited by miR-212-3p transferred from PC-secreted exosomes, resulting in decreased MHC II expression. Moreover, a clinical study showed a negative correlation between miR-212-3p and RFXAP in PC tissue. From these data, we concluded that PC-related miRNAs can be transferred to dendritic cells via exosome and inhibit target mRNA expression. More importantly, PC-derived exosomes inhibit RFXAP expression via miR-212-3p, which decrease MHC II expression and induce immune tolerance of dendritic cells. RFXAP deficiency has never been reported in solid tumors. The functions and mechanisms of RFXAP in tumors deserve future explorations.