Yuan Yuan, Li Jiajia, Wang Meng, Jin Yan, Xia Ruixiang
Department of Hematology, The First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, 230022, Anhui Province, China.
Department of Hematology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China.
Hum Cell. 2025 Jul 3;38(5):123. doi: 10.1007/s13577-025-01251-6.
Dysregulation of circRNAs has been found to engage in the progression of many hematologic malignancies including acute myeloid leukemia (AML). In this study, we identified significantly downregulated circTADA2A, derived from linear transcriptional adaptor 2A (TADA2A) gene, in AML associated circRNAs microarrays using GEO2R tool. We aimed to elucidate the roles of circTADA2A in AML and the mechanisms involved. Quantitative reverse transcription PCR was used for verification of circTADA2A levels in AML specimens, and its diagnostic value and clinical significance were assessed. The effects of circTADA2A on proliferation and ferroptosis on THP-1 and HL-60 cells were carried out using cell counting kit-8, 5'-ethynyl-2'-deoxyuridine, Fe, lipid reactive oxygen species (ROS) and malondialdehyde (MDA) assays. Luciferase reporter, fluorescence in situ hybridization, RNA immunoprecipitation, and RNA pull-down assays were implemented to investigate the potential miRNAs that mediated circTADA2A functioning. We confirmed that circTADA2A levels were lowly expressed in plasma and bone marrow of AML patients, and associated with bone marrow blasts and cytogenetic risk. Plasma circTADA2A had a high sensitivity and specificity with an area under the curve value of 0.793 in differentiating AML patients from healthy individuals. THP-1 and HL-60 cells stably overexpressing circTADA2A exhibited reduced cell proliferation, and sensitized cell to ferroptosis by a ferroptosis inducer RSL3. Moreover, circTADA2A could counteracted Ferrostatin-1-induced inhibition of ferroptosis. Mechanistically, circTADA2A act as a sponge for miR-638, and upregulation of miR-638 expression could restore cellular phenotypes induced by circTADA2A. Our findings demonstrated that circTADA2A suppresses cell proliferation and promotes ferroptosis by sponging miR-638 during AML progression.
环状RNA（circRNAs）失调已被发现参与包括急性髓系白血病（AML）在内的多种血液系统恶性肿瘤的进展。在本研究中，我们使用GEO2R工具在AML相关circRNAs微阵列中鉴定出源自线性转录衔接子2A（TADA2A）基因的显著下调的circTADA2A。我们旨在阐明circTADA2A在AML中的作用及其相关机制。采用定量逆转录PCR验证AML标本中circTADA2A水平，并评估其诊断价值和临床意义。使用细胞计数试剂盒-8、5'-乙炔基-2'-脱氧尿苷、铁、脂质活性氧（ROS）和丙二醛（MDA）检测，研究circTADA2A对THP-1和HL-60细胞增殖和铁死亡的影响。采用荧光素酶报告基因、荧光原位杂交、RNA免疫沉淀和RNA下拉检测，研究介导circTADA2A功能的潜在微小RNA（miRNAs）。我们证实，circTADA2A水平在AML患者的血浆和骨髓中低表达，并与骨髓原始细胞和细胞遗传学风险相关。血浆circTADA2A在区分AML患者与健康个体方面具有较高的敏感性和特异性，曲线下面积值为0.793。稳定过表达circTADA2A的THP-1和HL-60细胞表现出细胞增殖减少，并对铁死亡诱导剂RSL3诱导的铁死亡敏感。此外，circTADA2A可以抵消铁死亡抑制剂Ferrostatin-1诱导的铁死亡抑制作用。机制上，circTADA2A作为miR-638的海绵，miR-638表达上调可恢复circTADA2A诱导的细胞表型。我们的研究结果表明，circTADA2A在AML进展过程中通过海绵化miR-638抑制细胞增殖并促进铁死亡。
