Abstract
Paclitaxel treatment has been applied for late-stage nasopharyngeal carcinoma (NPC), but therapy failure usually occurs due to paclitaxel resistance. Besides, microRNAs (miRs) delivered by extracellular vesicles (EVs) have been demonstrated as promising biomarkers affecting cancer development. Our work clarified the role of bioinformatically predicted miR-183-5p, which could be delivered by EVs, in the paclitaxel resistance of NPC. Downstream targets of miR-183-5p were predicted in publicly available databases, followed by GO enrichment analysis. A confirmatory dual-luciferase reporter assay determined the targeting relationship between miR-183-5p and P-glycoprotein (P-gp). The shuttling of extracellular miR-183-5p was identified by immunofluorescence. EVs transferred miR-183-5p from paclitaxel-sensitive NPC cells to paclitaxel-resistant NPC cells. Furthermore, overexpression of miR-183-5p and under-expression of P-gp occurred in clinical samples and cells of NPC. High expression of miR-183-5p corresponded to better survival of paclitaxel-treated patients. The effects of manipulated expression of miR-183-5p on NPC cell activities, tumor growth, and paclitaxel resistance were investigated in vitro and in vivo. Its effect was achieved through negatively regulating drug transporters P-gp. Ectopically expressed miR-183-5p enhanced the cancer-suppressive effects of paclitaxel by targeting P-gp, corresponding to diminished cell viability and tumor growth. Taken together, this work goes to elucidate the mechanical actions of miR-183-5p delivered by EVs and its significant contribution towards paclitaxel sensitivity to NPC.
Graphical Abstract
1. This study provides mechanistic insight into the role of miR-183-5p-containing EVs in NPC.
2. The intercellular transportation of miR-183-5p is mediated by EVs in NPC.
3. Overexpressing miR-183-5p facilitates the anti-tumor effects of paclitaxel in NPC.
4. miR-183-5p suppresses paclitaxel resistance of NPC cells by inhibiting P-gp.
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XGC and YC designed the study. LQZ and XXD collated the data, carried out the data analyses, and produced the initial draft of the manuscript. XXD contributed to the drafting the manuscript. The authors have read and approved the final submitted manuscript.
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10565_2023_9812_MOESM3_ESM.jpg
Supplementary file3 miR-183-5p reduces paclitaxelresistance in NPC patients and overexpressing P-gp reverses this effect inHNE3/Taxol cells. (A). RT-qPCRmeasurement of the miR-183-5p andP-gp expression in HNE3/Taxol cells treated with miR-183-5p, EVs-miR-183-5p or EVs-miR-183-5p + oe-P-gp. (B).MTT assay was used to detect the viability under paclitaxel (10 nM) treatmentin HNE3/Taxol cells treated with miR-183-5p, EVs-miR-183-5p or EVs-miR-183-5p + oe-P-gp. (C). EdU assay was used to detect theproliferation under paclitaxel (10 nM) treatment in HNE3/Taxol cells treatedwith miR-183-5p, EVs-miR-183-5por EVs-miR-183-5p + oe-P-gp. (D). Flowcytometry was used to detect the apoptosis under paclitaxel (10 nM) treatmentin HNE3/Taxol cells treated with miR-183-5p, EVs-miR-183-5p or EVs-miR-183-5p + oe-P-gp. * p < 0.05. Cell experiments wereindependently repeated three times. (JPG 1588 KB)
10565_2023_9812_MOESM4_ESM.jpg
Supplementary file4 Binding of miR-183-5p to P-gp mRNA in HNE3/Taxol cells as validated bydual-luciferase reporter assay. * p< 0.05. Cell experiments were independently repeated three times. (JPG 226 KB)
10565_2023_9812_MOESM5_ESM.jpg
Supplementary file5 miR-183-5p mediated P-gp suppressionpromotes the inhibitory effects of paclitaxel on NPC in HNE3/Taxol cells. (A). RT-qPCR measurement of the miR-183-5p and P-gp expression in HNE3/Taxol cells treated with miR-183-5p, sh-P-gp, oe-P-gp or EVs-miR-183-5p + oe-P-gp.(B). MTT assay was used to detect the viability underpaclitaxel (10 nM) treatment in HNE3/Taxol cells treated with miR-183-5p, sh-P-gp, oe-P-gp or EVs-miR-183-5p + oe-P-gp.(C). EdU assay was used to detect the proliferation under paclitaxel (10 nM)treatment in HNE3/Taxol cells treated with miR-183-5p, sh-P-gp,oe-P-gp orEVs-miR-183-5p + oe-P-gp. (D). Flowcytometry was used to detect the apoptosis under paclitaxel (10 nM) treatmentin HNE3/Taxol cells treated with miR-183-5p, sh-P-gp,oe-P-gp orEVs-miR-183-5p + oe-P-gp. * p< 0.05. Cell experiments were independently repeated three times. (JPG 1619 KB)
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Cui, X., Chen, Y., Zhao, L. et al. Extracellular vesicles derived from paclitaxel-sensitive nasopharyngeal carcinoma cells deliver miR-183-5p and impart paclitaxel sensitivity through a mechanism involving P-gp. Cell Biol Toxicol 39, 2953–2970 (2023). https://doi.org/10.1007/s10565-023-09812-x
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DOI: https://doi.org/10.1007/s10565-023-09812-x