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The Role of Exosomal microRNA in Cancer Drug Resistance.

ABSTRACT: Exosomes affect the initiation and progression of cancers. In the tumor microenvironment, not only cancer cells, but also fibroblasts and immunocytes secrete exosomes. Exosomes act as a communicator between cells by transferring different cargos and microRNAs (miRNAs). Drug resistance is one of the critical factors affecting therapeutic effect in the course of cancer treatment. The currently known mechanisms of drug resistance include drug efflux, alterations in drug metabolism, DNA damage repair, alterations of energy programming, cancer stem cells and epigenetic changes. Many studies have shown that miRNA carried by exosomes is closely associated with the development of drug resistance mediated by the above-mentioned mechanisms. This review article will discuss how exosomal miRNAs regulate the drug resistance.

SUBMITTER: Guo QR

PROVIDER: S-EPMC7154138 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Role of Exosomal microRNA in Cancer Drug Resistance.

Guo Qiao-Ru QR Wang Hui H Yan Ying-da YD Liu Yun Y Su Chao-Yue CY Chen Hu-Biao HB Yan Yan-Yan YY Adhikari Rameshwar R Wu Qiang Q Zhang Jian-Ye JY

Frontiers in oncology 20200407

Exosomes affect the initiation and progression of cancers. In the tumor microenvironment, not only cancer cells, but also fibroblasts and immunocytes secrete exosomes. Exosomes act as a communicator between cells by transferring different cargos and microRNAs (miRNAs). Drug resistance is one of the critical factors affecting therapeutic effect in the course of cancer treatment. The currently known mechanisms of drug resistance include drug efflux, alterations in drug metabolism, DNA damage repai ...[more]

PMID: 32318350

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Project description:BackgroundRNA cargo in exosomes, especially microRNAs (miRNAs), play an important role in the chemotherapy drug resistance of human cancers. However, the role and mechanism of exosomal miR-107 on multidrug resistance of gastric cancer cells was still not clear. In this study, we sought to explore whether exosomal miR-107 could reverse the resistance of gastric cancer cells to the chemotherapy drugs.MethodsWe extracted exosomes from sensitive (SGC-7901, MGC-803) and resistant (SGC-7901/5-FU) gastric cancer cells by ultracentrifugation and the isolated exosomes were identified using transmission electron microscopy (TEM) and dynamic light scattering analysis (DLS). The expression of miR-107 and high mobility group A2 (HMGA2) were detected by real-time quantitative PCR (RT-qPCR). MTT assay was used to investigate the effect of exosomes on gastric cancer cells growth in vitro. The uptake of exosomes by recipient cells were observed using a fluorescence microscope. The predicted target relationship between miR-107 and HMGA2 was verified by gauss-luciferase reporter assay. The expression of HMGA2, p-mTOR/mTOR, P-gp and other exosomal indicated marker proteins was detected by western blot.ResultsOur results indicated that the isolated exosomes were typically cup-like lipid bilayer membranes structure. SGC-7901/5-FU cells were cross-resistant to chemotherapy drug cisplatin (CDDP), and the sensitive cells-secreted exosomes drastically reversed the resistance of the resistant GC cells to the chemotherapeutic drugs, which was verified by exosomal inhibitor GW4896. Mechanistically, the reversal effect was mainly mediated by exosome-secreted miR-107 through downregulating the expression of target molecular HMGA2 and inhibiting HMGA2/mTOR/P-gp pathway, which were supported by results from luciferase reporter assay and rescue assay.ConclusionsThese findings demonstrated that exosome-transmitted miR-107 significantly enhanced the sensitivity of resistant gastric cancer cells to chemotherapeutic agents by mediating the HMGA2/mTOR/P-gp axis and exosomal miR-107 may be a novel target in gastric cancers treatment.

Project description:MicroRNAs (miRNAs) serve important roles in drug‑resistance; however, exosomal miRNAs associated with drug‑resistance in ovarian cancer (OC) have not been reported to date. The current study aimed to analyze the drug resistance‑associated exosomal miRNAs in original OC cells and their derived exosomes using microarray data downloaded from the Gene Expression Omnibus database (series GSE76449). The chemosensitive OC cell lines SKOV3_ip1, A2780_PAR and HEYA8, as well as the chemoresistant cell lines SKOV3_TR, A2780_CP20 and HEYA8_MDR, were investigated. Differentially expressed miRNAs (DE‑miRNAs) were identified using the limma method, and their mRNA targets were predicted using the miRWalk and LinkedOmics database. Functions of target genes were analyzed with DAVID tool, while TCGA data were used to explore the survival association of identified miRNAs. According to the results, 28 DE‑miRNAs were found to be common in exosomal and original samples of A2780_CP20 cells, among which the functions of 5 miRNAs were predicted (including miR‑146b‑5p, miR‑509‑5p, miR‑574‑3p, miR‑574‑5p and miR‑760). In addition, 16 and 35 DE‑miRNAs were detected for HEYA8_MDR and SKOV3_TR, respectively, with the functions of 4 of these miRNAs predicted for each cell line (HEYA8_MDR: miR‑30a‑3p, miR‑30a‑5p, miR‑612 and miR‑617; SKOV3_TR: miR‑193a‑5p, miR‑423‑3p, miR‑769‑5p and miR‑922). It was also reported that miR‑183‑5p was the only one common miRNA among the three cell lines. Furthermore, miR‑574‑3p, miR‑30a‑5p and miR‑922 may regulate CUL2 to mediate HIF‑1 cancer signaling pathway, while miR‑183‑5p may modulate MECP2, similar to miR‑760, miR‑30a‑5p and miR‑922, to influence cell proliferation. Finally, the downregulated miR‑612 may promote the expression of TEAD3 via the Hippo signaling pathway, and this miRNA was associated with poor prognosis. In conclusion, the findings of the present study suggested several underlying miRNA targets for improving the chemotherapy sensitivity of OC.

Dataset Information

The Role of Exosomal microRNA in Cancer Drug Resistance.

Publications

The Role of Exosomal microRNA in Cancer Drug Resistance.

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