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首页> 外文期刊>Journal of cellular biochemistry. >Knockdown of LncRNA‐UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA‐125a/hexokinase 2 pathway
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Knockdown of LncRNA‐UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA‐125a/hexokinase 2 pathway

机译：LNCRNA-UCA1的敲低通过抑制通过MicroRNA-125A /六酮酶2途径抑制糖溶解的细胞AML的化学抑制剂

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Abstract Dysregulation of lncRNAs is implicated in chemoresistance in varieties of tumor including acute myeloid leukemia (AML). LncRNA urothelial carcinoma‐associated 1 (UCA1) was reported to play an oncogenic role in AML. However, whether UCA1 was involved in chemoresistance in pediatric AML remains unclear. UCA1 expression in AML patients after adriamycin (ADR)‐based chemotherapy and ADR‐resistant AML cells was examined by qRT‐PCR. The effects of UCA1 on the cytotoxicity of ADR and glycolysis were evaluated by MTT assay and measuring the glucose consumption and lactate production in HL60 and HL60/ADR cells, repectively. The protein levels of hypoxia‐inducible factor 1α (HIF‐1α) and hexokinase 2 (HK2) were determined by Western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the relationships between UCA1, HK2, and miR‐125a. We found that UCA1 expression was upregulated following ADR‐based chemotherapy. Knockdown of UCA1 increased the cytotoxic effect of ADR and inhibited HIF‐1α‐dependent glycolysis in ADR‐resistant AML cells. Additionally, UCA1 functioned as a ceRNA of miR‐125a by directly binding to miR‐125a. HK2, a target of miR‐125a, was positively regulated by UCA1 in HL60 and HL60/ADR cells. More notably, UCA1 overexpression overturned miR‐125‐mediated inhibition on HIF‐1α‐dependent glycolysis in HL60 and HL60/ADR cells. Furthermore, 2‐deoxy‐glucose (2‐DG) exposure inhibited HIF‐1α‐dependent glycolysis, and attenuated UCA1‐induced increase of chemoresistance in HL60 and HL60/ADR cells. We conclude that knockdown of UCA1 plays a positive role in overcoming the chemoresistance of pediatric AML, through suppressing glycolysis by the miR‐125a/HK2 pathway, contributing to a better understanding of the molecular mechanism of chemoresistance in AML.
机译：摘要LNCRNA的失调涉及在肿瘤各种肿瘤中的化学抑制，包括急性髓细胞白血病（AML）。据报道，LNCRNA尿路上皮癌相关的1（UCA1）在AML中发挥致癌作用。然而，UCA1是否参与儿科AML中的化学抑制仍然不清楚。通过QRT-PCR检查AML患者在AML患者中的uCA1表达和QRT-PCR检查ADR抗性AML细胞。通过MTT测定法评估UCA1对AdR和糖醇分解细胞毒性的影响，并通过MTT测定重复测量HL60和HL60 / ADR细胞中的葡萄糖消耗和乳酸盐产生。缺氧诱导因子1α（HIF-1α）和六酮酶2（HK2）的蛋白质水平通过Western印迹测定。荧光素酶报告器测定和RNA免疫沉淀（RIP）测定用于确认UCA1，HK2和MIR-125A之间的关系。我们发现，在ADR的化疗后，UCA1表达上调。 UCA1的敲低增加了ADR的细胞毒性作用，并抑制了ADR抗性AML细胞中的HIF-1α依赖性糖酵解。另外，通过直接绑定到miR-125a，UCA1用作MIR-125A的CERNA。 HK2，miR-125a的靶标通过UCA1在HL60和HL60 / ADR细胞中正面调节。更值得注意的是，UCA1过度表达在HF和HL60 / ADR细胞中推翻了对HIF-1α依赖性糖酵解的MiR-125介导的抑制。此外，2-脱氧 - 葡萄糖（2-DG）曝光抑制HIF-1α依赖性糖酵解，并衰减的UCA1诱导的HL60和HL60 / ADR细胞中的化学抑制增加。我们得出结论，UCA1的敲低通过抑制MIR-125A / HK2途径抑制糖酵解的糖类克制糖酵解来发挥积极作用，有助于更好地理解AML中的化学化学的分子机制。

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