TRIB2 regulates the expression of miR‑33a‑5p through the ERK/c‑Fos pathway to affect the imatinib resistance of chronic myeloid leukemia cells.

Abstract

Chronic myeloid leukemia (CML) is a hematological disease, and imatinib (IM) resistance represents a major problem for its clinical treatment. In the present study, the role of tribbles pseudokinase 2 (TRIB2) in IM resistance of CML and the possible mechanism were investigated. It was found that TRIB2 was highly expressed in IM-resistant patients with CML through the Oncomine database and this conclusion was confirmed using reverse transcription-quantitative PCR and western blot experiments. Knockdown of TRIB2 was found to increase the drug sensitivity of KG cells to IM using Cell-Counting Kit-8 (CCK-8) assays, and the low-expression TRIB2 mice were further found to be more sensitive to the IM and have a higher survival rate in leukemia model mice. Moreover, using western blot and luciferase experiments, it was found that TRIB2 could regulate c-Fos through the ERK signaling pathway, and c-Fos suppressed the transcriptional activity and the expression of miR-33a-5p. Further investigation identified that the binding site for c-Fos to function on miR-33a-5p was the -958-965 region. Finally, CCK-8 assays and western blot experiments demonstrated that miR-33a-5p could inhibit the proliferation of KG cells and reduce IM resistance by suppressing the expression of HMGA2. In conclusion, it was demonstrated that TRIB2 regulates miR-33a-5p to reverse IM resistance in CML, which may help identify novel targets and therapeutic strategies for the clinical treatment of IM resistance.