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      The regulatory ZFAS1/miR-150/ST6GAL1 crosstalk modulates sialylation of EGFR via PI3K/Akt pathway in T-cell acute lymphoblastic leukemia

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          Abstract

          Background

          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). 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.

          Methods

          Here, 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.

          Results

          Elevated 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.

          Conclusion

          Results 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.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-019-1208-x) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.

          Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.
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            High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia.

            To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.
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              PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability.

              Mutations in the phosphatase and tensin homolog (PTEN) gene leading to PTEN protein deletion and subsequent activation of the PI3K/Akt signaling pathway are common in cancer. Here we show that PTEN inactivation in human T cell acute lymphoblastic leukemia (T-ALL) cells is not always synonymous with PTEN gene lesions and diminished protein expression. Samples taken from patients with T-ALL at the time of diagnosis very frequently showed constitutive hyperactivation of the PI3K/Akt pathway. In contrast to immortalized cell lines, most primary T-ALL cells did not harbor PTEN gene alterations, displayed normal PTEN mRNA levels, and expressed higher PTEN protein levels than normal T cell precursors. However, PTEN overexpression was associated with decreased PTEN lipid phosphatase activity, resulting from casein kinase 2 (CK2) overexpression and hyperactivation. In addition, T-ALL cells had constitutively high levels of ROS, which can also downmodulate PTEN activity. Accordingly, both CK2 inhibitors and ROS scavengers restored PTEN activity and impaired PI3K/Akt signaling in T-ALL cells. Strikingly, inhibition of PI3K and/or CK2 promoted T-ALL cell death without affecting normal T cell precursors. Overall, our data indicate that T-ALL cells inactivate PTEN mostly in a nondeletional, posttranslational manner. Pharmacological manipulation of these mechanisms may open new avenues for T-ALL treatment.
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                Author and article information

                Contributors
                liuxixi30154@sina.com
                674730154@qq.com
                1071992302@qq.com
                785045118@qq.com
                892253742@qq.com
                841874892@qq.com
                2448437973@qq.com
                1016067554@qq.com
                +86 41186110386 , linjian0198@sina.com
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                16 May 2019
                16 May 2019
                2019
                : 38
                : 199
                Affiliations
                [1 ]ISNI 0000 0000 9558 1426, GRID grid.411971.b, College of Laboratory Medicine, , Dalian Medical University, ; Dalian 116044, 9 Lushunnan Road Xiduan, Dalian, 116044 Liaoning Province China
                [2 ]GRID grid.459365.8, Department of Clinical Laboratory, , Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital University of Medicine Sciences, ; Beijing, 100010 China
                [3 ]GRID grid.452828.1, Department of Medicine Oncology, , Second Affiliated Hospital of Dalian Medical University, ; Dalian, 116027 Liaoning Province China
                [4 ]ISNI 0000 0000 9558 1426, GRID grid.411971.b, Department of Microbiology, , Dalian Medical University, ; Dalian, 116044 Liaoning Province China
                [5 ]ISNI 0000 0000 9558 1426, GRID grid.411971.b, Department of Biochemistry, , Dalian Medical University, ; Dalian, 116044 Liaoning Province China
                Article
                1208
                10.1186/s13046-019-1208-x
                6524305
                31096997
                daa0433f-a685-48a9-8b59-36d5322458d7
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 March 2019
                : 2 May 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81472014
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                t-all,st6gal1,mir-150,zfas1,egfr/pi3k/akt pathway
                Oncology & Radiotherapy
                t-all, st6gal1, mir-150, zfas1, egfr/pi3k/akt pathway

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