circCRKL, a circRNA derived from CRKL, regulates BCR-ABL via sponging miR-877-5p to promote chronic myeloid leukemia cell proliferation

Abstract

Background The BCR-ABL fusion protein is the key factor that results in the occurrence of chronic myeloid leukemia (CML). Imatinib (IM) is a targeted inhibitor of BCR-ABL to achieve complete remission. However, remission failure occurs due to acquired resistance caused by secondary BCR-ABL mutations, underlining the need for novel BCR-ABL-targeting strategies. Circular RNAs (circRNAs) derived from tumor-related genes have been revealed as possible therapeutic targets for relevant cancers in recent investigations. In CML, the roles of this kind of circRNA are yet obscure. Methods Firstly, RT-qPCR was used for determining circCRKL expression level in cell lines and clinical samples, RNase R and Actinomycin D were employed to verify the stability of circCRKL. Then shRNAs were designed to specifically knockdown circCRKL. The function of circCRKL in vitro was investigated using CCK-8, colony formation assay, and flow cytometry, while a CML mouse model was constructed to explore the function in vivo. Finally, a dual-luciferase reporter assay, RNA pull-down, RNA immunoprecipitation, and rescue experiments were conducted to investigate the mechanism of circCRKL functioning. Results Here, we determined circCRKL, which derives from CML-relevant gene CRKL, is over-expressed in BCR-ABL+ cells. Then we noticed knocking down circCRKL using shRNA lentivirus dampens the proliferation of BCR-ABL+ cells both in vitro and in vivo, and augments susceptibility of resistant cells to IM. Intriguingly, we observed that circCRKL has a considerable impact on the expression level of BCR-ABL. Mechanistically, circCRKL could behave like a decoy for miR-877-5p to enhance the BCR-ABL level, allowing BCR-ABL+ cells to maintain viability. Conclusions Overall, the current study uncovers that circCRKL is specifically expressed and regulates BCR-ABL expression level via decoying miR-877-5p in BCR-ABL+ cells, highlighting that targeting circCRKL along with imatinib treatment could be utilized as a potential therapeutic strategy for CML patients.

Identification of MicroRNAs Associated with Prediabetic Status in Obese Women

“…MiR-877-5p has not been described in relation to glucose homeostasis or insulin sensitivity. It is a marker for different types of cancer [29,30] and was identified as potential synaptosomal miRNA upregulated with progression of Alzheimer's disease [31]. Of note, miR-23a [22], miR-148b-3p and miR-27a-3p [32], which have previously been implicated in prediabetes, were not differentially abundant in our study, possibly due to sex differences since the cohorts used in the other studies were largely male.…”

The Promising Role of Non-Coding RNAs as Biomarkers and Therapeutic Targets for Leukemia

“…When circBA1 is overexpressed in leukemia cells, it may promote cell growth and medication resistance [74]. A circRNA generated from CRKL called circCRKL controls BCR-ABL by sponging miR-877-5p to enhance the proliferation of CML cells [75]. In the PBMCs of CML patients, hsa-circ-0058493 is overexpressed, and an increased level of circ-0058493 was linked to imatinib's subpar clinical effectiveness.…”

CircANXA4 (hsa_circ_0055087) regulates the miR-1256/PRM1 axis to promote tumor progression in colorectal cancer

“…CircRNAs can bind miRNAs to regulate target gene expression competitively, thus circRNAs have great implications for new biomarkers and therapeutic targets for many cancers, including CRC [ [5] , [6] , [7] ]. For example, circCRKL regulates the expression level BCR-ABL by sponging miR-877–5p and has been reported as a potential therapeutic biomolecule to treat chronic myeloid leukemia [ 8 ]. CircFOXP1 facilitates CRC progression by inhibiting FOXP1 expression through DNMT1-mediated promotor hypermethylation [ 9 ].…”