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 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.
Highlights
3.1 Location of miR-574-5p, microsomal prostaglandin E synthase 1 (mPGES-1) and CUG-RNA binding protein 1 (CUGBP1) in human non-small-cell lung cancer (NSCLC) tissue sections To compare the regulation of prostaglandin E2 (PGE2) biosynthesis in AC and squamous cell carcinoma (SCC), miR-574-5p, mPGES-1, and CUGBP1 were stained in human NSCLC tissue sections
Contrary to AC spheroids, SCC spheroids showed an upregulation of COX-2, but not mPGES-1. These results demonstrate that the PGE2synthesizing proteins mPGES-1 and COX-2 are differently regulated in AC and SCC spheroid cultures
The lower expression levels of miR-574-5p could not be explained by reduced host messenger RNAs (mRNA) levels of nervous system overexpressed protein 20 (NOXP20), which was expected to correlate with the levels of miR-574-5p
Summary
CAFs support tumor progression by secreting growth factors and cytokines such as C-X-C motif chemokine ligand 12 (CXCL12) and fibroblast growth factor-2 (FGF-2) These signals activate signaling in pericytes and endothelial cells supporting the formation of novel blood vessels in the TME [74, 75]. Due to the link between miR-574-5p and PGE2 in NSCLC, this study investigated whether PGE2-mediated inflammation affects the sorting of miR-574-5p into sEV For this purpose, the two main NSCLC subtypes, AC and SCC, were examined and compared in the experiments of this work. AC and SCC tissue samples and 3D tumor models were used to analyze the expression and regulation of PGE2-synthesizing enzymes Afterwards, it was investigated whether PGE2 affects the secretion of miR-574-5p in sEV of AC and SCC cells. Cell-specific miR-574-5p overexpression sEV were generated to perform functional analyses and unravel the physiological role of sEV-derived miR-574-5p in AC and SCC cells
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