Abstract
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.
Highlights
Pancreatic cancer (PC) is one of the most malignant cancers, with a 5-year survival rate of less than 5% [1]
There were 12 PC-related miRNAs increased more than 2-fold in exo-immature dendritic cells (iDCs) compared with iDCs (Figure 2A), among which 9 miRNAs were highly expressed in PANC-1-derived exosomes (Figure 2B)
The results showed that a total of 5 097 mRNAs were increased and 4 929 mRNAs were decreased in exo-iDCs compared with iDCs
Summary
Pancreatic cancer (PC) is one of the most malignant cancers, with a 5-year survival rate of less than 5% [1]. In 2014, there were 39 590 patients who died of pancreatic adenocarcinoma in the United States, making it the fourth leading cause of cancer-related death [2]. The prognosis of PC is extremely poor, as more than 80% of patients are diagnosed at an advanced stage and are no longer eligible for surgical resection because of vessel invasion or distant metastasis. Even for patients who have undergone radical surgery, the 5-year survival rate is only 8.47%, and the rate of recurrence within 1 year is up to 54% [3]. Pancreatic cancer is characterized by strong invasion of tissue and metastasis [4, 5], while the mechanism involved has not yet been fully elucidated. A better understanding of the molecular pathogenesis of PC metastasis would be helpful for early detection and the development of new therapeutic strategies against PC
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