Downregulation of miR-224 and let-7i contribute to cell survival and chemoresistance in chronic myeloid leukemia cells by regulating ST3GAL IV expression.

Acquired resistance to imatinib is frequently associated with poor clinical outcome of chronic myeloid leukemia (CML) patient. To date, evidence indicates that protein glycosylation and its upstream regulators might be implicated in tumorigenesis and chemoresistance occurrence. In current study we initially explored N-glycan profiles on the surface of CML cell lines and bone marrow mononuclear cells (BMMC) of CML patients by using mass spectrometry (MS) analysis. An elevated sialylation was detected in K562R cells (CML cells with imatinib resistance phenotype) compare to K562 cells. By quantitative real time-PCR (qRT-PCR) and western blotting analysis we observed that imatinib resistant K562R cells exhibited marked high levels of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase (ST3Gal IV) as compared to imatinib sensitive K562 cells. Further studies revealed that manipulated expression of ST3GAL IV led to the significant alterations of cell cycle distribution, apoptotic signal, cell proliferation and the effectiveness of imatinib treatment. Using microRNA array, miRNA database searching and luciferase reporter assay, we identified that miR-224 and let-7i directly regulate the expression of ST3GAL IV gene. Moreover, engineered expression of miR-224 and let-7i in K562 and K562R cells could significantly affect ST6Gal IV-induced proliferation rate and drug-resistance. Thus we propose that miR-224 and let-7i regulate the proliferation and chemosensitivity of CML cells probably via targeting ST3GAL IV.