Abstract
BackgroundNoncoding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are becoming key parts in the development of multidrug resistance (MDR) in T-cell acute lymphoblastic leukemia (T-ALL). Abnormal expression in sialyated N-glycans have been observed in MDR leukemia. However, the role of sialylation regulated MDR remains poorly understood. The aim of this work is to analyze the alternation of N-glycans in T-ALL MDR.MethodsHere, mass spectrometry (MS) is analyzed to screen the N-glycan profiles from ALL cell line CR and adriamycin (ADR)-resistant CR (CR/A) cells. The expression of sialyltransferase (ST) genes in T-ALL cell lines and bone marrow mononuclear cells (BMMCs) of T-ALL patients were analyzed using qRT-PCR. Functionally, T-ALL cell proliferation and MDR are detected through CCK8 assay, colony formation assay, western blot and flow cytometry. RIP assay and Dual-luciferase reporter gene assay confirm the binding association between ZFAS1 and miR-150. Xenograft nude mice models are used to determine the role of ST6GAL1 in vivo.ResultsElevated expression of α2, 6-sialyltransferase 1 (ST6GAL1) has been detected. The altered level of ST6GAL1 was corresponding to the drug-resistant phenotype of T-ALL cell lines both in vitro and in vivo. ZFAS1/miR-150/ST6GAL1 axis was existed in T-ALL cell lines. MiR-150 was downregulated and inversely correlated to ST6GAL1 expression. ZFAS1 was a direct target of miR-150 and positively modulated ST6GAL1 level by binding miR-150. ZFAS1/miR-150/ST6GAL1 axis functioned to regulate ADR-resistant cell growth and apoptosis. Besides, EGFR was demonstrated to be a substrate of ST6GAL1, and the sialylated EGFR had an impact on the PI3K/Akt pathway.ConclusionResults suggested that ZFAS1/miR-150/ST6GAL1 axis involves in the progression of T-ALL/MDR further mediates sialylated EGFR via PI3K/Akt pathway. This work might have an application against T-ALL MDR.
Highlights
Noncoding RNAs, including microRNAs and long non-coding RNAs are becoming key parts in the development of multidrug resistance (MDR) in T-cell acute lymphoblastic leukemia (T-ALL)
When the full portraits of N-glycan diversity of both cell lines were represented quantitatively, it seems likely that high-mannose N-glycans were major components
The results showed ZFAS1/miR-150/ST6GAL1 axis mediated the sialylation of Epidermal growth factor receptor (EGFR), and further activated Phosphatidylinositol 3-kinases (PI3K)/Akt pathway
Summary
Noncoding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are becoming key parts in the development of multidrug resistance (MDR) in T-cell acute lymphoblastic leukemia (T-ALL). Increasing evidence indicates that abnormal sialylation is closely related to malignant tumor phenotypes, including proliferation, invasion, metastasis and drug-resistance [3,4,5,6]. Sialytransferases (STs) are a family of anabolic enzymes, consisting of 20 members that are subjected into three families These glycosyltransferases could convert sialic acid from cystidine- 5-monophospho-N-acetylneuraminic acid to glycoproteins or glycolipids. Evidence has demonstrated that altered sialylation involves in a variety of biological processes, including cell-cell communication, cell-matrix interaction, adhesion and protein targeting ST6GAL1 is the main sialyltransferase responsible for α2, 6-linked sialic acid formation on N-glycans, which is highly associated with poor outcomes [7]. There is limited information regarding the molecular details of how α2, 6-sialylated proteins, catalyzed by ST6GAL1, mediate T-ALL function
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