Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Hematology, Xinyang Hospital Affiliated to Zhengzhou University, Xinyang, Henan, China.
Cancer Biol Ther. 2022 Dec 31;23(1):234-242. doi: 10.1080/15384047.2022.2054243.
Metallothioneins (MTs) are a group of low-molecular weight cysteine-rich proteins that play vital roles in oxidative stress, metal homeostasis, carcinogenesis and drug resistance. However, few studies have analyzed the roles of MTs in acute myeloid leukemia (AML). In this study, we revealed that the expression of metallothionein1X (MT1X), a main isoform of MTs, was highly expressed and acted as a candidate of prognostic indicator in AML patients. In vitro cell function experiments verified that silencing MT1X inhibited the proliferation of AML cells, sensitized cells to doxorubicin, and increased their apoptosis. We also showed that the downregulation of MT1X expression suppressed nuclear factor-κB (NF-κB) signaling by reducing p65, p-IκB-α, and downstream effectors. Elevated p65 and MT1X levels were indicators in AML. Moreover, we revealed that miR-376a-3p had binding sites with 3'-UTR of MT1X, suggesting that MT1X was negatively regulated by miR-376a-3p. Cell functional assay results indicated that miR-376a-3p overexpression significantly inhibited the proliferation, arrested the AML cells in the G0/G1 phase and induced cell apoptosis. The rescue experiments further confirmed that miR-376a-3p could reverse the promotion of MT1X overexpression on the progress of AML cells. Taken together, our results revealed that elevated MT1X expression might be involved in the mechanism underlying AML progression, indicating that the miR-376a/MT1X axis might serve as a promising novel target for the effective treatment of patients with AML.
金属硫蛋白（MTs）是一组富含半胱氨酸的低分子量蛋白质，在氧化应激、金属稳态、致癌作用和耐药性中发挥重要作用。然而，很少有研究分析 MTs 在急性髓系白血病（AML）中的作用。在这项研究中，我们揭示了金属硫蛋白 1X（MT1X）的表达高度上调，并且作为 AML 患者的预后指标候选物。体外细胞功能实验验证了沉默 MT1X 抑制 AML 细胞的增殖，使细胞对阿霉素敏感，并增加其凋亡。我们还表明，下调 MT1X 表达通过减少 p65、p-IκB-α 和下游效应物来抑制核因子-κB（NF-κB）信号。降低的 MT1X 表达水平和升高的 p65 水平是 AML 的标志物。此外，我们揭示了 miR-376a-3p 与 MT1X 的 3'-UTR 具有结合位点，表明 MT1X 受 miR-376a-3p 的负调控。细胞功能测定结果表明，miR-376a-3p 过表达显著抑制了 AML 细胞的增殖，将 AML 细胞阻滞在 G0/G1 期并诱导细胞凋亡。挽救实验进一步证实，miR-376a-3p 可以逆转 MT1X 过表达对 AML 细胞进展的促进作用。总之，我们的结果表明，升高的 MT1X 表达可能参与了 AML 进展的机制，表明 miR-376a/MT1X 轴可能作为治疗 AML 患者的有效治疗的有前途的新靶点。
