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Published on: May 27, 2016
Exosomal circ_0058493 promotes imatinib resistance via miR-548b-3p/U2SURP axis in CML cells
Bing-Jie Tang1, Lei Chen1, Shu-Ting Huang1
1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan, China.
Abstract:
The prognosis of CML is affected not only by BCR::ABL1-independent resistance but also by BCR::ABL1-dependent resistance, particularly kinase mutations, both of which cause severe harm and have attracted worldwide attention. Circular RNAs (circRNA) have been assessed as potent regulators of tumor progression and drug resistance by manipulating the expression of target genes in cells and intercellular transmission via exosomes. In our previously study, we screened and identified a novel circRNA, circ_0058493, which presented significant negative relevance with imatinib resistance in CML. However, the underlying mechanism remains obscure. In this study, we found that circ_0058493 could be transmitted from imatinib-resistant cells to sensitive cells and induce sensitive cells to develop imatinib resistance. More critically, we showed that circ_0058493 competitively binds with miR-548b-3p, upregulating its target gene U2SURP expression and affecting the imatinib sensitivity of CML cells. Moreover, U2SURP knockdown suppressed the expression of p-ERK, a crucial protein in Ras/MAPK cancerous signaling pathway. Compared with imatinib optimal responders, the level of miR-548b-3p significantly decreased in PBMCs from patients who failed in imatinib treatment. The analysis of clinical database revealed that elevated U2SURP in HSCs was correlated with the occurrence of CML. In conclusion, our data suggested that targeting circ_0058493/miR-548b-3p/U2SURP axis and exosomal circ_0058493 is a potential therapeutic strategy for improving imatinib efficacy in CML.
Insights
A novel circular RNA, circ_0058493, promotes imatinib resistance in chronic myeloid leukemia (CML) by regulating the miR-548b-3p/U2SURP pathway. Targeting this axis may enhance CML treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Drug resistance, particularly BCR::ABL1-dependent and -independent, significantly impacts chronic myeloid leukemia (CML) prognosis.
- Circular RNAs (circRNAs) are emerging regulators of cancer progression and drug resistance, acting through gene expression modulation and exosomal transfer.
- Our prior research identified circ_0058493 as negatively correlated with imatinib resistance in CML, but its mechanism was unknown.
Purpose of the Study:
- To elucidate the mechanism by which circ_0058493 influences imatinib sensitivity in CML.
- To investigate the intercellular transfer and regulatory role of circ_0058493 in mediating imatinib resistance.
- To explore the potential of targeting the circ_0058493 pathway as a therapeutic strategy for CML.
Main Methods:
- Investigated the intercellular transfer of circ_0058493 between CML cells.
- Utilized molecular assays to determine the interaction between circ_0058493, miR-548b-3p, and its target U2SURP.
- Analyzed the impact of U2SURP knockdown on p-ERK expression and Ras/MAPK signaling.
- Correlated miR-548b-3p levels in patient PBMCs with imatinib treatment response.
- Examined U2SURP expression in hematopoietic stem cells (HSCs) from CML patients.
Main Results:
- circ_0058493 is transferable between CML cells, inducing imatinib resistance in sensitive cells.
- circ_0058493 acts as a molecular sponge for miR-548b-3p, leading to U2SURP upregulation.
- U2SURP knockdown reduced p-ERK levels, indicating modulation of the Ras/MAPK pathway.
- Lower miR-548b-3p levels were observed in CML patients resistant to imatinib.
- Elevated U2SURP expression in HSCs correlated with CML development.
Conclusions:
- Exosomal circ_0058493 promotes imatinib resistance in CML by sponging miR-548b-3p and upregulating U2SURP.
- The circ_0058493/miR-548b-3p/U2SURP axis influences imatinib sensitivity via the Ras/MAPK pathway.
- Targeting exosomal circ_0058493 or the circ_0058493/miR-548b-3p/U2SURP axis offers a potential therapeutic avenue for overcoming imatinib resistance in CML.
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