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Exosomal miR-1305 in the oncogenic activity of hypoxic multiple myeloma cells: a biomarker for predicting prognosis.

ABSTRACT: Background: Exosomes have emerged as important mediators of tumor progression, and a prognostic role for serum exosomal miRNAs has been suggested in multiple myeloma (MM). Given the association of hypoxia with tumor aggressiveness, including cancer stem cell-like phenotypes, we explored exosomal miRNAs from MM cells under hypoxic conditions and analyzed their diverse roles both in promoting oncogenic activity and in predicting prognosis. Methods: The human MM cell line, RPMI 8226, was cultured under hypoxic conditions and their exosome production and exosomal miRNA profiles were compared with those of normoxic parental cells. The survival outcome of myeloma patients was compared using serum levels of exosomal miRNAs, and the effects of exosomal miRNAs on the target genes of MM cells and adjacent immune cells were analyzed. Results: Increased expression of stem cell markers and exosome production were observed in hypoxic MM cells. Exosome miRNA analysis identified a higher expression of miR-1305 in exosomes isolated from hypoxic MM cells than in those of normoxic parental cells. The overall survival of patients with high exosomal miR-1305 was poorer than it was in patients with low exosomal miR-1305. In hypoxic MM cells, an increase of exosomal miR-1305 led to a decrease of cellular miR-1305 and increased expression of the miR-1305 target genes, MDM2, IGF1 and FGF2 resulted in the promotion of oncogenic activity of MM. Exosomal miR-1305 was also transferred from MM cells to macrophages, and miR-1305-transferred macrophages showed tumor-promoting, M2-macrophage phenotypes. Conclusions: Exosome-mediated secretion of miR-1305 in MM cells promoted oncogenic activity of hypoxic MM cells and high serum levels of exosomal miR-1305.

SUBMITTER: Lee JY

PROVIDER: S-EPMC8040895 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The natural course of multiple myeloma (MM) varies greatly between patients. The Revised MM International Staging System (R-ISS) identifies high-risk patients, but it is unsuitable for assessing minimal residual disease (MRD). Furthermore, the focal location of myeloma cells and clonal evolution often produce false negative results in flow cytometry. Extracellular microRNA (miRNA/miR) expression levels are stable in bodily fluids, and are retrievable and measurable from fresh or archived serum or plasma samples. Therefore, the present study aimed to investigate the clinical utility of circulating miRNA levels in patients with MM, particularly miR-451a, which is commonly downregulated in MM, and whether it could predict the prognosis and relapse of patients with MM. In total, 66 patients with MM, stratified using the R-ISS criteria, were recruited, while 10 healthy subjects (transplantation donors) were enrolled as controls. Reverse transcription-quantitative PCR was used to evaluate miR-451a expression in bone marrow (BM) and in the circulation. IL-6 levels were measured using ELISA, while western blotting was conducted to analyze the protein expression levels of the IL-6 receptor (IL-6R). During follow-up, MRD was assessed via multiparameter flow cytometry (MFC). miR-451a was identified to target IL-6R using a dual-luciferase reporter assay. Circulating miR-451a levels were low in patients with MM, and was found to be 0.39 times that of the control group (U=4.00; P<0.001). Among the 66 patients with MM, the median level of miR-451a was 0.73 and 0.41 times that of the control group in R-ISS stage I MM (15 patients) and R-ISS stage II stage (17 patients), respectively; patients with R-ISS stage III MM (34 patients) had the lowest level, at 0.24 times the value of the control group. Circulating miR-451a levels had a strong positive correlation with miR-451a levels in BM, but negatively correlated with IL-6 and IL-6R levels. After two courses of consolidation chemotherapy, 19 patients achieved complete remission, 10 of whom presented steady circulating miR-451a levels during follow-up; the other nine patients had an abrupt decrease in circulating miR-451a levels. The turning points in the trend appeared 4–8 weeks before positive results were obtained via MFC, and 4–16 weeks before clinical relapse. Moreover, miR-451a overexpression notably downregulated the expression of the IL-6R mRNA and protein. Collectively, circulating miR-451a levels potentially represent a novel biomarker to monitor MRD and predict relapse.

Project description:BackgroundMultiple myeloma (MM) is a highly malignant hematological tumor with a poor overall survival (OS). Due to the high heterogeneity of MM, it is necessary to explore novel markers for the prognosis prediction for MM patients. Ferroptosis is a form of regulated cell death, playing a critical role in tumorigenesis and cancer progression. However, the predictive role of ferroptosis-related genes (FRGs) in MM prognosis remains unknown.MethodsThis study collected 107 FRGs previously reported and utilized the least absolute shrinkage and selection operator (LASSO) cox regression model to construct a multi-genes risk signature model upon FRGs. The ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA) were carried out to evaluate immune infiltration level. Drug sensitivity was assessed based on the Genomics of Drug Sensitivity in Cancer database (GDSC). Then the synergy effect was determined with Cell counting kit-8 (CCK-8) assay and SynergyFinder software.ResultsA 6-gene prognostic risk signature model was constructed, and MM patients were divided into high and low risk groups. Kaplan-Meier survival curves showed that patients in the high risk group had significantly reduced OS compared with patients in the low risk group. Besides, the risk score was an independent predictor for OS. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of the risk signature. Combination of risk score and ISS stage had better prediction performance. Enrichment analysis revealed immune response, MYC, mTOR, proteasome and oxidative phosphorylation were enriched in high risk MM patients. We found high risk MM patients had lower immune scores and immune infiltration levels. Moreover, further analysis found that MM patients in high risk group were sensitive to bortezomib and lenalidomide. At last, the results of the in vitro experiment showed that ferroptosis inducers (RSL3 and ML162) may synergistically enhance the cytotoxicity of bortezomib and lenalidomide against MM cell line RPMI-8226.ConclusionThis study provides novel insights into roles of ferroptosis in MM prognosis prediction, immune levels and drug sensitivity, which complements and improves current grading systems.

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Exosomal miR-1305 in the oncogenic activity of hypoxic multiple myeloma cells: a biomarker for predicting prognosis.

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