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Plasma small-extracellular vesicles enriched in miR-122-5p promote disease aggressiveness in pediatric Anaplastic Large Cell Lymphoma

ABSTRACT: Plasma small-extracellular vesicles enriched in miR-122-5p promote disease aggressiveness in pediatric Anaplastic Large Cell Lymphoma

PROVIDER: PRJNA862602 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20661434.fastq.gz	Fastqsanger.gz
	SRR20661435.fastq.gz	Fastqsanger.gz
	SRR20661436.fastq.gz	Fastqsanger.gz
	SRR20661437.fastq.gz	Fastqsanger.gz
	SRR20661438.fastq.gz	Fastqsanger.gz

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Project description:Renal interstitial fibrosis (RIF) is a common pathological feature and final manifestation of chronic progressive kidney disease. Although exosome-mediated intercellular communication is known to play a crucial role in RIF, the mechanism by which injured tubular epithelial cells (TECs) contribute to fibrogenesis remains incompletely understood. In this study, we investigated the role of exosomal miR-122-5p derived from TECs in modulating fibroblast activation and renal fibrosis. Exosomes were isolated from kidneys of unilateral ureteral obstruction (UUO) mice and from TGF-β1-stimulated HK-2 cells. These exosomes were either co-cultured with fibroblasts (NRK-49F cells) or injected into UUO mice via the tail vein. High-throughput miRNA profiling was used to identify differentially expressed miRNAs in exosomes derived from HK-2 cells, and miR-122-5p was selected for further investigation based on expression level and bioinformatic prediction. Functional analyses were performed using miRNA mimics, inhibitors, and target validation assays. The results showed that exosomal miR-122-5p was significantly downregulated in both fibrotic kidneys and TGF-β1-induced HK-2 cells. In vivo and in vitro, restoration of miR-122-5p levels markedly attenuated renal fibrosis, as evidenced by the reduction of fibrotic markers including α-smooth muscle actin, fibronectin, and collagen I. Mechanistically, miR-122-5p was found to directly target hypoxia-inducible factor 1-alpha (HIF-1α), thereby inhibiting activation of the TGF-β1/Smad signaling pathway. These findings suggest that decreased expression of miR-122-5p in TEC-derived exosomes promotes renal fibrosis through the HIF-1α/TGF-β1/Smad axis, while reintroduction of miR-122-5p can effectively reverse these effects. Taken together, our study provides new insights into the intercellular communication between TECs and fibroblasts via exosomal miRNAs, and identifies miR-122-5p as a potential therapeutic target for the treatment of renal interstitial fibrosis.

Project description:Objective: The objective was to study the expression profile of serum exosomal ncRNAs in patients with PBC and to explore their potential molecular mechanisms. Methods: The expression profile of ncRNAs in serum exosomes of PBC patients was analyzed by RNA-sequence. Bioinformatics analysis predicted target genes and related signaling pathways. Spearson correlation analysis and receiver operating characteristic (ROC) curve were used to explore the relationship between ncRNAs and PBC clinical indicators and application value. Primary human intrahepatic biliary epithelial cells (HIBECs) were cultured in vitro and lipopolysaccharide (LPS) induced HIBECs inflammatory injury model. The expression of miR-122-5p is regulated by miR-122-5p mimics and inhibitors. Enzyme linked immunosorbent assay (Elisa) measured levels of inflammatory cytokines. HIBECs cycle and apoptosis were detected by flow cytometry and HIBECs activity was detected by CCK8. The biomarkers of epithelium-mesenchymal transition (EMT), fibrogenesis, and p38 mitogen-activated protein kinase (MAPK) pathway were detected by real time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). Dual luciferase reporter assay to confirm the binding of miR-122-5p. Results: 8531 differential expressed (DE) lncRNAs and 263 DE miRNAs were identified in serum exosomes of PBC patients. RNA-sequence and verification results showed that miR-122-5p was increased in serum exosomes of PBC patients, and was positively correlated with liver injury and cholestasis indexes. Exosomal miR-122-5p combined with gp210 and sp100 could improve the sensitivity of PBC diagnosis. In vitro experiments showed that the high expression of miR-122-5p promoted the proliferation of HIBECs, and inhibited the apoptosis, EMT and fibrosis of HIBEC. TNFRSF19, p38, p-p38, and inflammatory cytokines interleukin (IL)-1β, IL-6, IL-8, IL-12, IL-17, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and interferon (IFN)-γ were down-regulated and the effect was largely reversed after blocking p38 MAPK pathway. In addition, TNFRSF19 has binding site with miR-122-5p, which is the target gene of miR-122-5p, and could regulate the level of apoptosis signal-regulated kinase 1 (ASK1). Then ASK1 further regulate the downstream p38 MAPK signaling pathway. Conclusion: MiR-122-5p regulates ASK1 by targeting TNFRSF19 and plays an important role in EMT and fibrosis of PBC through p38 MAPK signaling pathway. MiR-122-5p may be a new marker for the diagnosis of PBC and a potential therapeutic target.

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Plasma small-extracellular vesicles enriched in miR-122-5p promote disease aggressiveness in pediatric Anaplastic Large Cell Lymphoma

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