MAGI2-AS3 restrains proliferation, glycolysis, and triggers apoptosis in acute lymphoblastic leukemia via regulating miR-452-5p/FOXN3 pathway

Document Type : Original Article


Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, P.R. China


Objective(s): MAGI2-AS3 is a cancer suppressor gene of multiple malignancies. Acute lymphoblastic leukemia (ALL) is an important type of leukemia that especially occurs in children. Our work evaluated the modulation of MAGI2-AS3 in ALL.
Materials and Methods: qPCR and Western blotting were adopted for detection of target molecular expression. Growth and apoptosis were determined by CCK8 assay and Annexin V/PI staining. Glycolysis was detected by commercial kits. The direct binding between miR-452-5p and MAGI2-AS3 or FOXN3 was assessed by luciferase reporter assay. Tumor growth was measured in nude mice in vivo.
Results: MAGI2-AS3 was down-regulated in ALL. Enforced expression of MAGI2-AS3 inhibited growth and glycolysis while promoting apoptosis of ALL cells. Moreover, MAGI2-AS3 up-regulated FOXN3 via sponging miR-452-5p. FOXN3 depletion abrogated MAGI2-AS3-mediated anti-cancer action. More importantly, MAGI2-AS3 repressed ALL cell growth in nude mice through regulation of miR-452-5p/FOXN3. 
Conclusion: MAGI2-AS3 inhibits ALL development via modulating miR-452-5p/FOXN3.


1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63:11-30.
2. Li C, Zhao T, Nie L, Zou Y, Zhang Q. MicroRNA-223 decreases cell proliferation, migration, invasion, and enhances cell apoptosis in childhood acute lymphoblastic leukemia via targeting Forkhead box O 1. Biosci Rep 2020; 40-50.
3. Robison LL, Bhatia S. Late-effects among survivors of leukaemia and lymphoma during childhood and adolescence. Br J Haematol 2003; 122:345-359.
4. Gugnoni M, Ciarrocchi A. Long Noncoding RNA and epithelial mesenchymal transition in cancer. Int J Mol Sci 2019; 20.
5. Hosseini ES, Meryet-Figuiere M, Sabzalipoor H, Kashani HH, Nikzad H, Asemi Z. Dysregulated expression of long noncoding RNAs in gynecologic cancers. Mol Cancer 2017; 16:107-119.
6. Farooqi AA, Attar R, Yulaevna IM, Berardi R. Interaction of long non-coding RNAs and circular RNAs with microRNAs for the regulation of immunological responses in human cancers. Semin Cell Dev Biol 2021.
7. Xu K, Zhang Z, Qian J, Wang S, Yin S, Xie H, et al. LncRNA FOXD2-AS1 plays an oncogenic role in hepatocellular carcinoma through epigenetically silencing CDKN1B(p27) via EZH2. Exp Cell Res 2019; 380:198-204.
8. Gu X, Chu Q, Zheng Q, Wang J, Zhu H. The dual functions of the long noncoding RNA CASC15 in malignancy. Biomed Pharmacother 2021; 135:111212.
9. Bahari G, Hashemi M, Naderi M, Sadeghi-Bojd S, Taheri M. Long non-coding RNA PAX8-AS1 polymorphisms increase the risk of childhood acute lymphoblastic leukemia. Biomed Rep 2018; 8:184-190.
10. Xue C, Li G, Lu J, Luo J, Jia J. Novel insights for lncRNA MAGI2-AS3 in solid tumors. Biomed Pharmacother 2021; 137:111429.
11. Garitano-Trojaola A, Jose-Eneriz ES, Ezponda T, Unfried JP, Carrasco-Leon A, Razquin N, et al. Deregulation of linc-PINT in acute lymphoblastic leukemia is implicated in abnormal proliferation of leukemic cells. Oncotarget 2018; 9:12842-12852.
12. Chen L, Fan X, Zhu J, Chen X, Liu Y, Zhou H. LncRNA MAGI2-AS3 inhibits the self-renewal of leukaemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukaemia. RNA Biol 2020; 17:784-793.
13. Liu X, Cai H, Sheng W, Huang H, Long Z, Wang Y. microRNAs expression profile related with response to preoperative radiochemotherapy in patients with locally advanced gastric cancer. BMC Cancer 2018; 18:1048-1056.
14. Inoue J, Inazawa J. Cancer-associated miRNAs and their therapeutic potential. J Hum Genet 2021; 66: 937-945.
15. Lin X, Han L, Gu C, Lai Y, Lai Q, Li Q, et al. MiR-452-5p promotes colorectal cancer progression by regulating an ERK/MAPK positive feedback loop. Aging (Albany NY) 2021; 13:7608-7626.
16. Gan XN, Gan TQ, He RQ, Luo J, Tang RX, Wang HL, et al. Clinical significance of high expression of miR-452-5p in lung squamous cell carcinoma. Oncol Lett 2018; 15:6418-6430.
17. Zhang J, Wang Y, Mo W, Zhang R, Li Y. The clinical and prognostic significance of FOXN3 downregulation in acute myeloid leukaemia. Int J Lab Hematol 2020; 42:270-276.
18. Kong X, Zhai J, Yan C, Song Y, Wang J, Bai X, et al. Recent advances in understanding FOXN3 in breast cancer, and other malignancies. Front Oncol 2019; 9:1-14.
19. Nagel S, Pommerenke C, Meyer C, Kaufmann M, MacLeod RAF, Drexler HG. Identification of a tumor suppressor network in T-cell leukemia. Leuk Lymphoma 2017; 58:2196-2207.
20. Li J, Huang Q, Long X, Guo X, Sun X, Jin X, et al. Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress. Oncogene 2017; 36:4901-4912.
21. Kai-Xin L, Cheng C, Rui L, Zheng-Wei S, Wen-Wen T, Peng X. Roles of lncRNA MAGI2-AS3 in human cancers. Biomed Pharmacother 2021; 141:111812.
22. Ren H, Li Z, Tang Z, Li J, Lang X. Long noncoding MAGI2-AS3 promotes colorectal cancer progression through regulating miR-3163/TMEM106B axis. J Cell Physiol 2020; 235:4824-4833.
23. Xu X, Yuan X, Ni J, Guo J, Gao Y, Yin W, et al. MAGI2-AS3 inhibits breast cancer by downregulating DNA methylation of MAGI2. J Cell Physiol 2021; 236:1116-1130.
24. Cheng W, Shi X, Lin M, Yao Q, Ma J, Li J. LncRNA MAGI2-AS3 Overexpression sensitizes esophageal cancer cells to irradiation through down-regulation of HOXB7 via EZH2. Front Cell Dev Biol 2020; 8:552822.
25. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016; 23:27-47.
26. Liberti MV, Locasale JW. Correction to: ‘The Warburg effect: How does it benefit cancer cells?’: Trends Biochem Sci 2016; 41:211-218.
27. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324:1029-1033.
28. Hulleman E, Kazemier KM, Holleman A, VanderWeele DJ, Rudin CM, Broekhuis MJ, et al. Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood 2009; 113:2014-2021.
29. Tan VP, Miyamoto S. HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection. Autophagy 2015; 11:963-964.
30. Luengo A, Gui DY, Vander Heiden MG. Targeting Metabolism for Cancer Therapy. Cell Chem Biol 2017; 24:1161-1180.
31. Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ, et al. AMPK is essential to balance glycolysis and mitochondrial metabolism to control T-ALL cell stress and survival. Cell Metab 2016; 23:649-662.
32. Feng J, Li J, Wu L, Yu Q, Ji J, Wu J, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res 2020; 39:126-144.
33. Zolzer F, Basu O, Devi PU, Mohanty SP, Streffer C. Chromatin-bound PCNA as S-phase marker in mononuclear blood cells of patients with acute lymphoblastic leukaemia or multiple myeloma. Cell Prolif 2010; 43:579-583.
34. Lehnerdt GF, Franz P, Bankfalvi A, Grehl S, Kelava A, Nuckel H, et al. The regulatory BCL2 promoter polymorphism (-938C>A) is associated with relapse and survival of patients with oropharyngeal squamous cell carcinoma. Ann Oncol 2009; 20:1094-1099.
35. Rong MH, Cai KT, Lu HP, Guo YN, Huang XY, Zhu ZH, et al. Overexpression of MiR-452-5p in hepatocellular carcinoma tissues and its prospective signaling pathways. Int J Clin Exp Pathol 2019; 12:4041-4056.
36. Song X, Wang H, Wu J, Sun Y. Long noncoding RNA SOX2-OT knockdown inhibits proliferation and metastasis of prostate cancer cells through modulating the miR-452-5p/HMGB3 axis and inactivating wnt/beta-catenin pathway. Cancer Biother Radiopharm 2020; 35:682-695.
37. Zhu L, Yang N, Chen J, Zeng T, Yan S, Liu Y, et al. LINC00052 upregulates EPB41L3 to inhibit migration and invasion of hepatocellular carcinoma by binding miR-452-5p. Oncotarget 2017; 8:63724-63737.
38. Dai Y, Wang M, Wu H, Xiao M, Liu H, Zhang D. Loss of FOXN3 in colon cancer activates beta-catenin/TCF signaling and promotes the growth and migration of cancer cells. Oncotarget 2017; 8:9783-9793.
39. Zhao C, Mo L, Li C, Han S, Zhao W, Liu L. FOXN3 suppresses the growth and invasion of papillary thyroid cancer through the inactivation of Wnt/beta-catenin pathway. Mol Cell Endocrinol 2020; 515:110925.