Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p

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.

IFN-γ induces the upregulation of RFXAP via inhibition of miR-212-3p in pancreatic cancer cells: A novel mechanism for IFN-γ response

“…A previous study demonstrated miR-212-3p involved in the generation of pancreatic cancer-derived exosomes and could suppress RFXAP protein expression in DCs and thus elicit DC immune tolerance (8). Other studies have also demonstrated the key function of miR-212-3p in pancreatic cancer metastasis; Park et al (22) demonstrated that miR-212 expression increased in pancreatic cancer cells and promoted their proliferation by inhibiting Retinoblastoma 1 gene expression in a targeted manner.…”

“…Previous studies have demonstrated that regulatory factor X-associated protein (RFXAP) is a key transcription factor for the synthesis of MHC class II molecules in dendritic cells (DCs) (7). Exosomal microRNA (miRNA/miR)-212-3p secreted by pancreatic cancer cells can inhibit RFXAP expression in DCs, and thus suppress MHC class II expression and promote the immune escape of pancreatic tumors (8). This may explain why MHC class II expression is downregulated in pancreatic cancer, which leads to poor outcomes.…”

Mining Exosomal Genes for Pancreatic Cancer Targets

“…Exosomal microRNA such as miR-212-3p, miR-203, miR-21 have been shown to enhance invasion, modulate immune response and drug resistance (65,66).…”

Exosomes: Navigating a New Route in Pancreatic Cancer

“…Recently, Ding G et al showed that pancreatic cancer-derived exosomal miR-212-3p inhibits the expression of regulatory factor X-associated protein (RFXAP), a key transcription factor for major histocompatibility complex II (MHC II) in DCs. RFXAP inhibition results in decreased MHC II expression and inactivation of CD4 + T-lymphocytes, ultimately inducing immune tolerance [35]. These data describe a novel mechanism of pancreatic cancer immune tolerance, and suggest that eliminating cancer-derived exosomes can act as an immune agonist in pancreatic cancer immunotherapy.…”