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.
BackgroundAltered expression of serum microRNAs (miRNAs) have been reported to correlate with carcinogenesis and progression of pancreatic adenocarcinoma (PC), but descriptions of serum exosomal miRNAs in PC are still lacking. This study was designed to evaluate serum exosomal miRNA levels in PC patients and to investigate their relationships with clinicopathologic features and prognosis.MethodsFour miRNAs (miR-17-5p, miR-21, miR-155 and miR-196a) related to PC were selected for examination in our research. Serum miRNA was examined by RT-PCR in a group of 49 patients, including 22 with PCs, 6 with benign pancreatic tumors, 7 with ampullary carcinomas, 6 with chronic pancreatitis and 8 healthy participants. The clinicopathologic data were also collected, and PC patients were classified according to the presence of metastasis, tumor differentiation and advanced stage.ResultsThere were low expressions of exosomal miR-155 and miR-196a in serum samples of PC patients when U-6 was used as a control. Serum exosomal miR-17-5p was higher in PC patients than in non–PC patients and healthy participants. High levels of miR-17-5p were significantly correlated with metastasis and advanced stage of PC. The serum exosomal miR-21 level in PC was higher than that in the normal and chronic pancreatitis groups, but was not significantly correlated with PC differentiation and tumor stage.ConclusionsThere were high expressions of serum exosomal miR-17-5p and miR-21 in PC patients. Examination of serum exosomal microRNA is a useful serum biomarker for PC diagnosis other than serum-free microRNA. It is postulated that exosomal miR-17-5p participates in the progression of PC.
Background: Pancreatic cancer is a devastating disease with a low five-year survival rate. Dendritic cells (DCs), which are the most potent antigen-presenting cells in the human body, play a pivotal role in the immune response. However, few studies have investigated the role of pancreatic cancer-derived exosomes (PEXs) in DC-meditated immune escape. The expression profiles of long noncoding RNAs (lncRNAs) and mRNAs of PEX-treated dendritic cells are unknown.Methods: We used integrated lncRNA and mRNA microarrays to determine the expression profiles of PEX-treated DCs and normal DCs derived from five healthy donors. Gene Ontology (GO), KEGG, and cancer genomics analyses were performed to identify significant functions, pathways, and the associations of differentially expressed mRNAs. A coexpression network was constructed to identify the correlation between differentially expressed lncRNAs and mRNAs and further validated using real-time quantitative PCR in twenty healthy donors. The AnnoLnc program was used to perform an annotation analysis of lncRNAs.Results: We identified 3,227 and 924 differentially expressed lncRNAs and mRNAs, respectively, in PEX-treated DCs. GO and pathway analysis revealed differentially expressed mRNAs involved in many critical biological processes and molecular functions. Cancer genomics analysis revealed that 36 of the most differentially expressed mRNAs were involved in a pancreatic cancer network and were associated with many critical mutated genes such as TP53, KRAS, SMAD4, and CDKN2A. LncRNAs such as ENST00000560647 and mRNAs such as legumain (lgmn) were differentially expressed in PEX-treated DCs, and the data were validated using RT-qPCR.Conclusions: To our knowledge, this is the first study to detect the differential expression of lncRNAs and mRNAs associated with PEX-treated DCs. LncRNAs such as ENST00000560647 and mRNAs such as lgmn might play a critical role in immune escape of DCs treated with PEX. Further investigation is required to validate the functions and associations of these RNAs.
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