LncRNA MEG3 contributes to drug resistance in acute myeloid leukemia by positively regulating ALG9 through sponging miR-155

Int J Lab Hematol. 2020 Aug;42(4):464-472. doi: 10.1111/ijlh.13225. Epub 2020 May 2.

Abstract

Introduction: The development of drug resistance is the main obstacle for successful treatment in acute myeloid leukemia (AML). Noncoding RNAs have been implicated in biological function in AML drug resistance. Aberrant protein glycosylation is associated with AML progression. The aim of the study was to explore the potential regulatory mechanism of lncRNA MEG3/miR-155/ALG9 axis in drug resistance of AML.

Methods: QRT-PCR and Western blot were used for comparison analyses of ALG9, MEG3, and miR-155 levels. CCK-8 and colony formation assays were determined for drug sensitivity and proliferative capability of AML cells. Luciferase reporter assay was used to confirm the targets of miR-155.

Results: The mannosyltransferase ALG9 and MEG3 was downregulated in peripheral blood mononuclear cells (PBMCs) of M5/multidrug resistance (MDR) AML patients and adriamycin (ADR)-resistant AML cell lines, which determined a positive correlation in AML patients. Low expression of ALG9 and MEG3 predicted poor prognosis of AML patients. The altered level of ALG9 was found corresponding to the drug-resistant phenotype and sphere formation of AML cells. MiR-155 was overexpressed in M5/MDR patients and ADR-resistant AML cells, as well as inversely correlated to ALG9 expression. MEG3 was a direct target of miR-155 and could sponge miR-155 in AML cells. MEG3 interacted with miR-155 to regulate ALG9 expression, which reversed the effects of ALG9 regulation on proliferation and drug resistance in AML cells.

Conclusion: MEG3 sponged miR-155 by competing endogenous RNA (ceRNA) mechanism, which further modulated ALG9 expression and AML procession, providing a novel therapeutic target for AML chemoresistance.

Keywords: ALG9; MEG3; acute myeloid leukemia; drug resistance; miR-155.

MeSH terms

  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mannosyltransferases / biosynthesis*
  • Mannosyltransferases / genetics
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • THP-1 Cells
  • U937 Cells

Substances

  • MEG3 non-coding RNA, human
  • MIRN155 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Neoplasm Proteins
  • RNA, Long Noncoding
  • RNA, Neoplasm
  • ALG9 protein, human
  • Mannosyltransferases