Once released, sEV are delivered to target cells where they can transfer cellular components such as proteins, lipids or miRs (Penfornis et al., 2016 Thery et al., 2002). The majority of circulating miRs are selectively loaded into sEV, a class of double-membrane vesicles of 50–150 nm in diameter, which are actively secreted into the extracellular environment by all cell types (Mir & Goettsch, 2020 Raposo & Stoorvogel, 2013). They are characterized by a remarkable stability in body fluids and changes in miR levels are associated with various diseases including cancers (Mitchell et al., 2008). MiRs in the blood stream are called circulating miRs. This association between miR-574-5p and PGE 2 may provide an indirect method to evaluate PGE 2 levels in NSCLC and allow the detection of LC patients who will likely benefit from PGE 2 inhibition (Saul et al., 2019). Furthermore, it is strongly overexpressed in human NSCLC where high mPGES-1 expression correlates with a low survival rate (Saul et al., 2019). MiR-574-5p-induced lung tumour growth in a xenograft mouse model was completely blocked with the mPGES-1 inhibitor compound III (CIII) (Leclerc et al., 2013 Saul et al., 2019). But miR-574-5p is more than an interesting biomarker candidate. More and more evidence points towards miR-574-5p as a biomarker for the detection of NSCLC: increased miR-574-5p plasma levels in NSCLC patients are linked to tumour progression (Foss et al., 2011 Han et al., 2020 Peng et al., 2016) and cancer cells actively secrete miR-574-5p in small extracellular vesicles (sEV) (Han et al., 2020). These results in an mPGES-1 3´UTR isoform with a higher translation rate, increased mPGES-1 protein levels and PGE 2 formation and, finally, advanced tumour growth (Saul et al., 2019). By preventing the binding of CUGBP1 to the mPGES-1 3´ untranslated region (UTR), miR-574-5p promotes alternative splicing of mPGES-1. We demonstrated that microRNA (miR)-574-5p acts as a decoy to the RNA-binding protein CUG binding protein 1 (CUGBP1) and thus antagonizes its function as a splicing silencer (Emmerich et al., 2020 Saul et al., 2019). Recently, we identified a novel post-transcriptional regulation mechanism for mPGES-1-mediated PGE 2 biosynthesis in NSCLC (Emmerich et al., 2020 Saul et al., 2019). Therefore, combining standard cancer therapies with PGE 2 inhibition poses a promising anti-tumour treatment strategy. It may also help to reduce programmed cell death protein ligand 1 (PD-L1) expression, alleviate the immune suppression, and stimulate an anti-tumour immune response (Prima et al., 2017). Inhibition of PGE 2 production not only sensitizes cancer cells to chemotherapeutic drugs (Hanaka et al., 2009). The fact that it is capable of inducing inflammation, angiogenesis, immune suppression, and proliferation, makes it an interesting therapeutic target (Nakanishi & Rosenberg, 2013 Wang & Dubois, 2010). Several studies have observed a tumour-promoting role for PGE 2 (Wang & Dubois, 2010). Then, PGH 2 is processed to PGE 2 by the terminal enzyme microsomal prostaglandin E synthase 1 (mPGES-1) (Smith et al., 2011 Yoshimatsu et al., 2001). First, cyclooxygenases COX-1 and COX-2 convert arachidonic acid to prostaglandin H 2 (PGH 2). Most NSCLCs are associated with an overexpression of prostaglandin E 2 (PGE 2), a bioactive lipid mediator formed by two sequential reactions. Non-small cell lung cancer (NSCLC) is the most frequent LC type and accounts for approximately 80% of all cases (Molina et al., 2008). Lung cancer (LC) is the most common cause of cancer related death worldwide (Sung et al., 2021). 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. Hence, we describe a novel function of miR-574-5p unique to adenocarcinoma. 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. Consequently, the combination of intracellular and sEV-derived miR-574-5p controls PGE 2-levels via a feedback loop. In contrast, intracellular miR-574-5p induces PGE 2-biosynthesis. We found that sEV-derived miR-574-5p activates Toll-like receptors (TLR) 7/8, thereby decreasing PGE 2-levels. We report that prostaglandin E 2 (PGE 2), a key inflammatory lipid mediator, specifically induces the sorting of miR-574-5p in sEV of A5T cells. One essential sEV component are microRNAs (miRs), whose transport has recently attracted increasing research interest. SEV trigger various biological responses by transporting cellular cargo to target cells. One of the major players in cell-cell-communication is small extracellular vesicles (sEV). Intercellular communication plays an essential role in lung cancer (LC).
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