Upregulation of miR-101-3p Overcomes Ibrutinib Resistance by Targeting ABCC5 in Diffuse Large B-Cell Lymphoma (DLBCL)

抄録

Diffuse large B-cell lymphoma (DLBCL) seriously threatens public health, and drug resistance is a formidable obstacle to DLBCL therapy. MicroRNAs (miRNAs) have been certified to act as a momentous regulator in drug resistance of DLBCL. This study aimed to ascertain the latent function and mechanism of miR-101-3p in modulating the resistance of DLBCL cells to ibrutinib. The differentially expressed miRNAs were identified by bioinformatics analysis of GSE117063 and GSE173080 datasets. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to measure the expression levels of miR-101-3p and ATP-binding cassette subfamily C member 5 (ABCC5). The resistance of DLBCL cells to ibrutinib was determined by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and Western blot assays. The relationship between miR-101-3p expression level and ABCC5 expression level was analyzed using dual-luciferase reporter assay and Pearson correlation test. MiR-101-3p was significantly downregulated in DLBCL cells according to the results of the bioinformatics analysis. A low miR-101-3p expression level predicted resistance of DLBCL cells to ibrutinib. Upregulation of miR-101-3p sensitized the constructed ibrutinib-resistant DLBCL (DLBCL/ibR). Our findings revealed that ABCC5 was targeted by miR-101-3p, and ABCC5 was abundantly expressed in DLBCL/ibR tissue samples and cells. Furthermore, miR-101-3p mimics overturned the influences of ABCC5 upregulation on the resistance of DLBCL cells to ibrutinib. MiR-101-3p played a suppressive function in the resistance of DLBCL cells to ibrutinib via inhibiting ABCC5 expression, which might represent a potent therapeutic target for DLBCL.