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      Oncogenic Long Noncoding RNA DARS-AS1 in Childhood Acute Myeloid Leukemia by Binding to microRNA-425

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          Abstract

          Objective:

          Acute myeloid leukemia (AML) represents a hematological cancer. The aim of the investigation was to probe the regulatory relevance of long non-coding RNA (lncRNA) aspartyl-tRNA synthetase anti-sense 1 (DARS-AS1)/microRNA-425 (miR-425)/transforming growth factor-beta 1 (TGFB1) to the development of AML.

          Methods:

          The DARS-AS1 expression in bone marrow tissues was first analyzed in healthy subjects and AML patients. Subsequently, AML cell lines with DARS-AS1 knockdown were constructed, followed by cell proliferation and apoptosis assays. Afterward, downstream miRNA of DARS-AS1 and target mRNA of the miRNA were analyzed by bioinformatics, and their binding relationships were verified. Functional rescue experiments were then implemented. Finally, activation of the Smad2/3 signaling in MV4-11 and BF-24 cells were detected by western blot.

          Results:

          DARS-AS1 was overexpressed in bone marrow tissues of AML patients and cells, and DARS-AS1 knockdown suppressed the proliferation of AML cells and induced apoptosis. DARS-AS1 bound to and negatively correlated with miR-425. Further results suggested that TGFB1 might be a target gene of miR-425 and could promote Smad2/3 phosphorylation and nuclear translocation. Finally, DARS-AS1 depletion could diminish the tumor volume in vivo.

          Conclusion:

          All in all, we highlighted here that DARS-AS1 enhanced the expression of TGFB1 through binding to miR-425 to modulate AML progression via the Smad2/3 pathway, which might perform as a therapeutic target for AML.

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          Most cited references30

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          Acute Myeloid Leukemia.

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            The emerging role of lncRNAs in cancer.

            It is increasingly evident that many of the genomic mutations in cancer reside inside regions that do not encode proteins. However, these regions are often transcribed into long noncoding RNAs (lncRNAs). The recent application of next-generation sequencing to a growing number of cancer transcriptomes has indeed revealed thousands of lncRNAs whose aberrant expression is associated with different cancer types. Among the few that have been functionally characterized, several have been linked to malignant transformation. Notably, these lncRNAs have key roles in gene regulation and thus affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. This review aims to summarize current knowledge of lncRNAs from the cancer perspective. It discusses the strategies that led to the identification of cancer-related lncRNAs and the methodologies and challenges involving the study of these molecules, as well as the imminent applications of these findings to the clinic.
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              Therapeutic advances in acute myeloid leukemia.

              The choice of treatment approach and outcome in acute myeloid leukemia (AML) depends on the age of the patient. In younger patients, arbitrarily defined as being younger than 60 years, 70% to 80% enter complete disease remission with several anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or stem-cell transplantation in high-risk patients will restrict overall relapse to approximately 50%. A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1). These are increasingly being used to direct postinduction therapy, but they are also molecular targets for a new generation of small molecule inhibitors that are in early development; however, randomized data have yet to emerge. In older patients who comprise the majority, which will increase with demographic change, the initial clinical decision to be made is whether the patient should receive an intensive or nonintensive approach. If the same anthracycline/cytarabine-based approach is deployed, the remission rate will be around 50%, but the risk of subsequent relapse is approximately 85% at 3 years. This difference from younger patients is explained partly by the ability of patients to tolerate effective therapy, and also the aggregation of several poor risk factors compared with the young. There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy. Their survival is approximately 4 months, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.
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                Author and article information

                Journal
                Technol Cancer Res Treat
                Technol Cancer Res Treat
                TCT
                sptct
                Technology in Cancer Research & Treatment
                SAGE Publications (Sage CA: Los Angeles, CA )
                1533-0346
                1533-0338
                19 October 2020
                2020
                : 19
                : 1533033820965580
                Affiliations
                [1 ]Department of Paediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
                [2 ]Department of Ultrasound, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
                Author notes
                [*]Guangyao Sheng, Department of Paediatrics, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou 450000, Henan, People’s Republic of China. Email: SGuangYao4251@ 123456163.com
                Author information
                https://orcid.org/0000-0002-1756-5257
                Article
                10.1177_1533033820965580
                10.1177/1533033820965580
                7592321
                33073700
                d98ac50a-bfab-4f79-9e68-7e12cb60d885
                © The Author(s) 2020

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 22 July 2020
                : 9 September 2020
                : 22 September 2020
                Categories
                Original Article
                Custom metadata
                January-December 2020
                ts3

                acute myeloid leukemia,dars-as1,microrna-425,tgfb1,smad2/3 signaling

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