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Published on: May 27, 2016
Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid
Arzu Zeynep Karabay1, Tulin Ozkan2, Aynur Karadag Gurel3
1Department of Biochemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey. akarabay@ankara.edu.tr.
Abstract:
Chemotherapy resistance is a major obstacle in cancer therapy, and identifying novel druggable targets to reverse this phenomenon is essential. The exosome-mediated transmittance of drug resistance has been shown in various cancer models including ovarian and prostate cancer models. In this study, we aimed to investigate the role of exosomal miRNA transfer in chronic myeloid leukemia drug resistance. For this purpose, firstly exosomes were isolated from imatinib sensitive (K562S) and resistant (K562R) chronic myeloid leukemia (CML) cells and named as Sexo and Rexo, respectively. Then, miRNA microarray was used to compare miRNA profiles of K562S, K562R, Sexo, Rexo, and Rexo-treated K562S cells. According to our results, miR-125b-5p and miR-99a-5p exhibited increased expression in resistant cells, their exosomes, and Rexo-treated sensitive cells compared to their sensitive counterparts. On the other hand, miR-210-3p and miR-193b-3p were determined to be the two miRNAs which exhibited decreased expression profile in resistant cells and their exosomes compared to their sensitive counterparts. Gene targets, signaling pathways, and enrichment analysis were performed for these miRNAs by TargetScan, KEGG, and DAVID. Potential interactions between gene candidates at the protein level were analyzed via STRING and Cytoscape software. Our findings revealed CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, and GIT2 as novel gene targets that may play roles in exosomal imatinib resistance transfer as well as mTOR, STAT3, MCL1, LAMC1, and KRAS which are already linked to imatinib resistance. MDR1 mRNA exhibited higher expression in Rexo compared to Sexo as well as in K562S cells treated with Rexo compared to K562S cells which may suggest exosomal transfer of MDR1 mRNA.
Insights
Exosomes from imatinib-resistant chronic myeloid leukemia (CML) cells transfer drug resistance via specific microRNAs (miRNAs) and MDR1 mRNA. This exosomal transfer highlights novel targets for overcoming CML chemotherapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Chemotherapy resistance is a significant challenge in treating chronic myeloid leukemia (CML).
- Exosomes are known to mediate drug resistance transfer in various cancers.
- Understanding exosomal miRNA transfer in CML is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the role of exosomal microRNA (miRNA) transfer in imatinib resistance in chronic myeloid leukemia (CML).
- To identify specific miRNAs and gene targets involved in exosomal drug resistance.
Main Methods:
- Isolation of exosomes from imatinib-sensitive (K562S) and resistant (K562R) CML cells.
- miRNA microarray analysis to compare miRNA profiles.
- Bioinformatic analysis (TargetScan, KEGG, DAVID, STRING, Cytoscape) to identify gene targets and pathways.
Main Results:
- Specific miRNAs (miR-125b-5p, miR-99a-5p, miR-210-3p, miR-193b-3p) showed altered expression in resistant cells and their exosomes.
- Novel gene targets (CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, GIT2) and known targets (mTOR, STAT3, MCL1, LAMC1, KRAS) were identified.
- Multidrug resistance 1 (MDR1) mRNA expression was higher in resistant exosomes and sensitive cells treated with resistant exosomes, suggesting exosomal transfer.
Conclusions:
- Exosomal miRNAs and MDR1 mRNA play a role in transferring imatinib resistance in CML.
- Identified gene targets and pathways offer potential for novel therapeutic interventions.
- This study provides insights into the mechanisms of exosomal drug resistance in CML.
