Small extracellular vesicle‐derived miR‐574‐5p regulates PGE2‐biosynthesis via TLR7/8 in lung cancer

Abstract

Intercellular communication plays an essential role in lung cancer (LC). One of the major players in cell‐cell‐communication is small extracellular vesicles (sEV). SEV trigger various biological responses by transporting cellular cargo to target cells. One essential sEV component are microRNAs (miRs), whose transport has recently attracted increasing research interest. We report that prostaglandin E 2 (PGE 2 ), a key inflammatory lipid mediator, specifically induces the sorting of miR‐574‐5p in sEV of A549 and 2106T cells. We found that sEV‐derived miR‐574‐5p activates Toll‐like receptors (TLR) 7/8, thereby decreasing PGE 2 ‐levels. In contrast, intracellular miR‐574‐5p induces PGE 2 ‐biosynthesis. Consequently, the combination of intracellular and sEV‐derived miR‐574‐5p controls PGE 2 ‐levels via a feedback loop. This was only observed in adeno‐ but not in squamous cell carcinoma, indicating a cell‐specific response to sEV‐derived miRs, which might be due to unique tetraspanin compositions. Hence, we describe a novel function of miR‐574‐5p unique to adenocarcinoma. Intracellular miR‐574‐5p induces PGE 2 and thus the secretion of sEV‐derived miR‐574‐5p, which in turn decreases PGE 2 ‐biosynthesis in recipient cells.

Detailed Characterization of Small Extracellular Vesicles from Different Cell Types Based on Tetraspanin Composition by ExoView R100 Platform

“…In recent years, several studies have shown that sEV from different cell types have different combinations and amounts of these proteins on their surface [ 34 , 35 ]. We supported these findings with the characterization of the sEV phenotype from non-small cell lung cancer (NSCLC) cells [ 36 ]. SEV populations of the NSCLC subtypes of adeno- and squamous cell carcinoma exhibit the distinct expression and colocalization of CD9, CD63, and CD81 at a single sEV level.…”

“…SEV populations of the NSCLC subtypes of adeno- and squamous cell carcinoma exhibit the distinct expression and colocalization of CD9, CD63, and CD81 at a single sEV level. We further demonstrated that among themselves, individual sEV populations are highly heterogeneous [ 36 ].…”

Emerging role of RNA sensors in tumor microenvironment and immunotherapy

“…As we mentioned above, single or combined application of RNA sensor agonists is becoming a potential effective treatment of cancers, and more burgeoning agonists have been found and developed. It is reported that even recombinant viruses and cellular noncoding RNAs are expected to be agonists [ 74 , 76 , 106 – 108 ]. Although the primary focus lies on RNA sensor agonists in combination with other conventional treatments or as components of cancer vaccines, systematic treatment strategies based on RNA sensors, novel drug delivery methods and innovative combination with other immunotherapies will continue to promote progress in this field.…”

“…In addition, several noncoding RNAs and even recombinant virus have been identified as RNA senor inducers. MiR-574-5p derived from small extracellular vesicles activated TLR7/8, thereby decreased PGE2-levels in lung cancer [ 106 ]. CircNDUFB2 is reported to be recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the TME in NSCLC [ 107 ].…”

Current and prospective applications of exosomal microRNAs in pulmonary fibrosis (Review)

“…In a previous study involving the analysis of exosomes secreted by different cell lines, some miRNA subgroups, such as miR-150, miR-142-3p and miR-451, were found to preferentially localize into exosomes ( 56 ). For instance, miRNA-574-5p has been shown to be only expressed in lung adenocarcinoma cells, but not in squamous cell carcinoma, suggesting a cell-specific response to exosomal miRNAs, which may be due to the unique composition of tetraspanin which strongly influences EV uptake ( 57 ). Exosomes internalize miRNAs through various mechanisms, and different RNA subpopulations bind to different exosome-targeted RNA-binding proteins (RBPs).…”