EVI-1-Mediated Up-Regulation of lncRNA TUG1 Interacts with miR-186-5p to Promote Proliferation and Drug Resistance in Pediatric Acute Myeloid Leukemia

Abstract

Background:Deregulated lncRNAs have been well-documented to be closely associated with resistance to chemotherapeutic agents in malignancies including acute myeloid leukemia (AML). Herein, we intended to explore the roles and underlying mechanism of lncRNA taurine-upregulated gene 1 (TUG1) in pediatric AML cell adriamycin (ADR) resistance.Methods:TUG1 and ecotropic viral integration site-1 (EVI-1) expressions in pediatric AML patients and cells were detected by using qRT-PCR and western blot, respectively. Western blot analysis, flow cytometry and CCK-8 assays were conducted for evaluating the drug sensitivity, apoptosis, and cell viability. Luciferase reporter assay and qRT-PCR were implemented to determine the interaction between miR-186-5p and TUG1. The western blot was employed to analyze the changes of proteins.Results:TUG1 was upregulated with a high positive correlation with EVI-1 in pediatric AML patients. TUG1 was transcriptionally activated by EVI-1 and functioned as a miR-186-5p ceRNA to inhibit its expression in AML cells. An enhanced cell proliferation as well as a resistance to ADR in HL60 cells was observed after TUG1 overexpression and miR-186-5p knockdown, while an opposite effect was elicited by TUG1 silencing and miR-186-5p restoration. Mechanistically, robust expression of TUG1 increased P-gp level and induced the PI3K/Akt/mTOR cascade activation in HL60 cells while loss of TUG1 expression exerted reverse effects in HL60/ADR cells. Moreover, TUG1 overexpression abolished miR-186-5p-induced inactivation of the PI3K/Akt/mTOR cascade in HL60/ADR cells.Conclusion:Taken together, in pediatric AML, EVI-1-mediated upregulation of the oncogenic lncRNA TUG1 promotes proliferation and ADR resistance by sponging miR-186-5p through the PI3K/Akt/mTOR signals.