Exosomal miR92a Promotes Cytarabine Resistance in Myelodysplastic Syndromes by Activating Wnt/β-catenin Signal Pathway

Abstract

Cytarabine (Ara-C) has been one of the frontline therapies for clonal hematopoietic stem cell disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but Ara-C resistance often occurs and leads to treatment failure. Exosomal microRNAs (miRNAs, miRs) as small noncoding RNA that play important roles in post-transcriptional gene regulation, can be delivered into recipient cells by exosomes and regulate target genes’ expression. miR92a has been reported to be dysregulated in many cancers, including MDS and AML. However, the effects of exosomal miR92a in hematologic malignancies have not been fully investigated. In this study, qualitative analysis showed the significantly enhanced expression of exosomal miR92a in MDS/AML plasma. Subsequent functional assays indicated that exosomal miR92a can be transported and downregulate PTEN in recipient cells and, furthermore, activate the Wnt/β-catenin signaling pathway and interfere with the Ara-C resistance of receipt MDS/AML cells in vitro and in vivo. Altogether, our findings offer novel insights into plasma exosomal miR92a participating in Ara-C resistance in MDS/AML and we propose miR92a as a potential therapeutic target for MDS/AML.

Interplay between Wnt signaling molecules and exosomal miRNAs in breast cancer (Review)

“…In cancer cells, exosome-derived miR-375 targets DIP2C and regulates Wnt signaling, thus promoting osteoblastic metastasis ( 119 ). Li et al ( 120 ) revealed that exosomal miR-92a promotes cytarabine resistance through activating the Wnt/β-catenin signaling pathway ( 120 ). In conclusion, exosomal miRNAs may influence tumor progression through regulating Wnt signaling.…”

The Role of Non-Coding RNAs in Myelodysplastic Neoplasms

“…In another study of 42 MDS patients, investigators identified five circulating miRNAs, namely miR-423-5p, miR-126-3p, miR-151a-3p, miR-125a-5p, and miR-199a-3p, whose combined expression levels in plasma could predict response to azacytidine therapy [76]. Finally, beyond HMAs, in a recent study, investigators found that overexpression of exosomal miR-92a (member of miR17-92 cluster) in plasma promoted cytarabine resistance in MDS/AML by activating the Wnt/β-catenin signaling pathway, rendering miR-92a both a potential predictive biomarker and a therapeutic target for patients with MDS [89].…”