Silencing long non-coding RNA XIST suppresses drug resistance in acute myeloid leukemia through down-regulation of MYC b
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Molecular Medicine
Open Access
RESEARCH ARTICLE
Silencing long non‑coding RNA XIST suppresses drug resistance in acute myeloid leukemia through down‑regulation of MYC by elevating microRNA‑29a expression Chong Wang*, Lingling Li, Mengya Li, Weiqiong Wang, Yanfang Liu and Shujuan Wang
Abstract Background: Long non-coding RNAs (lncRNAs) are biomarkers participating in multiple disease development including acute myeloid leukemia (AML). Here, we investigated molecular mechanism of X Inactive-Specific Transcript (XIST) in regulating cellular viability, apoptosis and drug resistance in AML. Methods: XIST, miR-29a and myelocytomatosis oncogene (MYC) expression in AML bone marrow cells collected from 62 patients was evaluated by RT-qPCR and Western blot analysis. Besides, the relationship among XIST, miR-29a and MYC was analyzed by dual luciferase reporter assay, RIP, and RNA pull down assays. AML KG-1 cells were treated with anti-tumor drug Adriamycin. The role of XIST/miR-29a/MYC in cellular viability, apoptosis and drug resistance in AML was accessed via gain- and loss-of-function approaches. At last, we evaluated role of XIST/miR-29a/MYC on tumorigenesis in vivo. Results: XIST and MYC were up-regulated, and miR-29a was down-regulated in AML bone marrow cells. Silencing XIST inhibited cellular activity and drug resistance but promoted cellular apoptosis of KG-1 cells by down-regulating MYC. XIST inhibited miR-29a expression to up-regulate MYC. Moreover, silencing XIST inhibited tumorigenesis of AML cells in vivo. Conclusions: Overall, down-regulation of XIST decreased MYC expression through releasing the inhibition on miR29a, thereby reducing drug resistance, inhibiting viability and promoting apoptosis of AML cells. Keywords: Long non-coding XIST, microRNA-29a, Myelocytomatosis oncogene, Acute myeloid leukemia, Drug resistance Background Acute myeloid leukemia (AML) is a common aggressive bone marrow malignancy distinguished by deregulated proliferation and impaired differentiation of immature myeloid cells (Corces et al. 2017; Karjalainen and Repasky 2016). In recent years, deep understanding of the molecular and cytogenetic heterogeneity of AML has improved *Correspondence: [email protected] Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou 450052, Henan, P. R. China
patient outcomes (Brinda et al. 2018). However, the prognosis of AML is still poor, and even younger patients receiving the strongest anti-leukemia treatment showed higher risk of recurrence for resistance to chemotherapy (Bruserud et al. 2017). In view of this, it is crucial to study the mechanisms underlying drug resistance to find new therapies to promote AML treatment. Long non-coding RNAs (lncRNAs) can mediate resistance to anti-cancer drug by modulating DNA repair, drug efflux, and cellular apoptosis in cancer cells (Chen et al. 2017). Different lncRNAs are abnormally expressed
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