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 E2 (
PGE2 ), 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
PGE2 -levels. In contrast, intracellular miR-574-5p induces
PGE2 -biosynthesis. Consequently, the combination of intracellular and sEV-derived miR-574-5p controls
PGE2 -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
PGE2 and thus the secretion of sEV-derived miR-574-5p, which in turn decreases
PGE2 -biosynthesis in recipient cells.