抑癌基因 MEG3 通过下调 METTL3/MYC 轴诱导 microRNA-493-5p 的表达，降低急性髓系白血病细胞对阿糖胞苷的化疗耐药性。
Tumor-suppressive MEG3 induces microRNA-493-5p expression to reduce arabinocytosine chemoresistance of acute myeloid leukemia cells by downregulating the METTL3/MYC axis.
机构信息
Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Erqi District, No. 1, Eastern Jianshe Road, Zhengzhou, 450052, Henan, People's Republic of China.
出版信息
J Transl Med. 2022 Jun 27;20(1):288. doi: 10.1186/s12967-022-03456-x.
BACKGROUND
Chemoresistance serves as a huge obstacle for acute myeloid leukemia (AML) patients. To counteract the chemoresistance in AML cells, we discussed the role of maternally expressed gene 3 (MEG3) in arabinocytosine (AraC) chemoresistance in AML cells.
METHODS
MEG3, microRNA (miR)-493-5p, methyltransferase-like 3 (METTL3) and MYC expression in AML cells was determined and then their interactions were also analyzed. Then, the viability and apoptosis of AML cells were determined through loss- and gain- function assay. The level of m6A modification in AML cells was examined. AML mouse models were also established to validate the potential roles of MEG3.
RESULTS
MEG3 and miR-493-5p were downregulated in AML cells, and they were lower in resistant cells than in parental cells. MEG3 led to elevated expression of miR-493-5p which targeted METTL3. METTL3 increased expression of MYC by promoting its m6A levels. Overexpression of MEG3 and miR-493-5p or knockdown of METTL3 inhibited HL-60 and Molm13 cell proliferation and promoted their apoptosis. Overexpressed MEG3 induced heightened sensitivity of AML cells to AraC. However, the suppression of miR-493-5p reversed the effects of overexpressed MEG3 on AML cells.
CONCLUSIONS
Collectively, MEG3 could upregulate miR-493-5p expression and suppress the METTL3/MYC axis through MYC m6A methylation, by which MEG3 promoted the chemosensitivity of AML cells.
背景
化疗耐药性是急性髓细胞白血病（AML）患者面临的巨大障碍。为了克服 AML 细胞的化疗耐药性，我们探讨了母系表达基因 3（MEG3）在 AML 细胞中阿糖胞苷（AraC）化疗耐药性中的作用。
方法
检测 AML 细胞中的 MEG3、微小 RNA（miR）-493-5p、甲基转移酶样 3（METTL3）和 MYC 的表达，并分析它们之间的相互作用。然后，通过缺失和获得功能测定法测定 AML 细胞的活力和凋亡。检查 AML 细胞中 m6A 修饰的水平。还建立了 AML 小鼠模型以验证 MEG3 的潜在作用。
结果
MEG3 和 miR-493-5p 在 AML 细胞中下调，耐药细胞中的表达低于亲本细胞。MEG3 导致 miR-493-5p 的表达升高，miR-493-5p 靶向 METTL3。METTL3 通过促进其 m6A 水平增加 MYC 的表达。过表达 MEG3 和 miR-493-5p 或敲低 METTL3 抑制 HL-60 和 Molm13 细胞增殖并促进其凋亡。过表达 MEG3 可提高 AML 细胞对 AraC 的敏感性。然而，抑制 miR-493-5p 逆转了过表达 MEG3 对 AML 细胞的影响。
结论
总之，MEG3 可通过 MYC m6A 甲基化上调 miR-493-5p 的表达并抑制 METTL3/MYC 轴，从而增强 AML 细胞的化疗敏感性。
Zotero 插件