Silencing LINC00987 ameliorates adriamycin resistance of acute myeloid leukemia via miR-4458/HMGA2 axis.

IF 5.7 2区生物学 Q1 BIOLOGY

Biology Direct Pub Date : 2024-06-24 DOI:10.1186/s13062-024-00490-1

Yue Liu, Xiao-Ya Zhu, Li-Li Liao, Zhan-Hui Zhang, Tao-Sheng Huang, Ling Zhang, Xi-Wen Jiang, Yi Ma

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引用次数: 0

Abstract

Background: Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have been implicated in chemoresistance in AML. Unfortunately, the effects of lincRNAs which participate in regulating the Adriamycin (ADR) resistance in AML cells remain unclear. Thus, the purpose of this study is to determine LINC00987 function in ADR-resistant AML.

Methods: In this study, ADR-resistant cells were constructed. LINC00987, miRNAs, and HMGA2 mRNA expression were measured by qRT-PCR. P-GP, BCRP, and HMGA2 protein were measured by Western blot. The proliferation was analyzed by MTS and calculated IC50. Soft agar colony formation assay and TUNEL staining were used to analyze cell colony formation and apoptosis. Xenograft tumor experiment was used to analyze the xenograft tumor growth of ADR-resistant AML.

Results: We found that higher expression of LINC00987 was observed in AML patients and associated with poor overall survival in AML patients. LINC00987 expression was increased in ADR-resistant AML cells, including ADR/MOLM13 and ADR/HL-60 cells. LINC00987 downregulation reduces ADR resistance in ADR/MOLM13 and ADR/HL-60 cells in vitro and in vivo, while LINC00987 overexpression enhanced ADR resistance in MOLM13 and HL-60 cells. Additionally, LINC00987 functions as a competing endogenous RNA for miR-4458 to affect ADR resistance in ADR/MOLM13 and ADR/HL-60 cells. HMGA2 is a target of miR-4458. LINC00987 knockdown and miR-4458 overexpression reduced HMGA2 expression. HMGA2 overexpression enhanced ADR resistance, which reversed the function of LINC00987 silencing in suppressing ADR resistance of ADR/MOLM13 and ADR/HL-60 cells.

Conclusions: Downregulation of LINC00987 weakens ADR resistance by releasing miR-4458 to deplete HMGA2 in ADR/MOLM13 and ADR/HL-60. Therefore, LINC00987 may act as the therapeutic target for treating chemoresistant AML.

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沉默LINC00987可通过miR-4458/HMGA2轴改善急性髓性白血病的阿霉素耐药性

背景：大多数急性髓性白血病（AML）患者最终会产生耐药性，导致不良预后。长基因非编码 RNA（lincRNA）的失调与急性髓性白血病的化疗耐药性有关。遗憾的是，参与调节急性髓细胞白血病细胞阿霉素（ADR）耐药性的长基因非编码 RNAs 的作用仍不清楚。因此，本研究旨在确定LINC00987在ADR耐药AML中的功能：方法：本研究构建了 ADR 抗性细胞。通过 qRT-PCR 检测 LINC00987、miRNAs 和 HMGA2 mRNA 的表达。通过 Western 印迹检测 P-GP、BCRP 和 HMGA2 蛋白。用 MTS 分析增殖并计算 IC50。软琼脂集落形成试验和 TUNEL 染色用于分析细胞集落形成和凋亡。异种移植肿瘤实验用于分析ADR耐药AML的异种移植肿瘤生长情况：结果：我们发现 LINC00987 在急性髓细胞性白血病患者中表达较高，并且与急性髓细胞性白血病患者的总生存率较低有关。LINC00987在ADR耐药的AML细胞（包括ADR/MOLM13和ADR/HL-60细胞）中表达增加。LINC00987 下调可降低 ADR/MOLM13 和 ADR/HL-60 细胞在体外和体内对 ADR 的耐药性，而 LINC00987 过表达则会增强 MOLM13 和 HL-60 细胞对 ADR 的耐药性。此外，LINC00987作为miR-4458的竞争内源RNA，影响了ADR/MOLM13和ADR/HL-60细胞的ADR耐药性。HMGA2是miR-4458的靶标。LINC00987 敲除和 miR-4458 过表达会降低 HMGA2 的表达。HMGA2的过表达增强了ADR耐药性，从而逆转了LINC00987沉默抑制ADR/MOLM13和ADR/HL-60细胞ADR耐药性的功能：结论：在ADR/MOLM13和ADR/HL-60细胞中，下调LINC00987可通过释放miR-4458来消耗HMGA2，从而削弱ADR耐药性。因此，LINC00987 可作为治疗化疗耐药 AML 的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biology Direct 生物-生物学

CiteScore

6.40

自引率

10.90%

发文量

审稿时长

7 months

期刊介绍： Biology Direct serves the life science research community as an open access, peer-reviewed online journal, providing authors and readers with an alternative to the traditional model of peer review. Biology Direct considers original research articles, hypotheses, comments, discovery notes and reviews in subject areas currently identified as those most conducive to the open review approach, primarily those with a significant non-experimental component.