Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China.
Myelodysplastic Syndrome Center, Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Technol Cancer Res Treat. 2023 Jan-Dec;22:15330338231207765. doi: 10.1177/15330338231207765.
Dual specificity phosphatase 1 (DUSP1) is high-expressed in various cancers and plays an important role in the cellular response to agents that damage DNA. We aimed to investigate the expressions and mechanisms of DUSP1 signaling pathway regulating cytarabine (Ara-C) resistance in acute myeloid leukemia (AML). Immunohistochemistry was performed on bone marrow biopsy specimens from AML and controls to explore the expression of DUSP1. Western blot and Q-PCR were used to detect the protein and mRNA expression levels. MTT assay was used to detect the proliferation of cells. Cell apoptosis was detected by flow cytometry. The immune protein-protein interaction (PPI) network of DUSP1 was analyzed in the platform of Pathway Commons, and immune infiltration analysis was used to study the immune microenvironment of AML. We found that the expression levels of DUSP1 in AML patients exceeded that in controls. Survival analysis in public datasets showed that AML patients with higher levels of DUSP1 had poor clinical outcomes. Further public data analysis indicated that DUSP1 was overexpressed in NRAS mutated AML. DUSP1 knockdown by siRNA could sensitize AML cells to Ara-C treatments. The phosphorylation level of mitogen-activated protein kinase (MAPK) pathway was significantly elevated in DUSP1 down-regulated NRAS G13D mutated AML cells. The PPI analysis showed DUSP1 correlated with immune gene CREB1 and CXCL8 in NRAS mutated AML. We also revealed a correlation between tumor-infiltrating immune cells in RAS mutated AML microenvironment. : Our findings suggest that DUSP1 signaling pathways may regulate Ara-C sensitivity in AML.
双重特异性磷酸酶 1（DUSP1）在各种癌症中高表达，在细胞对损伤 DNA 药物的反应中发挥重要作用。我们旨在研究 DUSP1 信号通路的表达和机制，调节急性髓系白血病（AML）中阿糖胞苷（Ara-C）耐药性。通过免疫组化检测 AML 和对照骨髓活检标本中 DUSP1 的表达。Western blot 和 Q-PCR 用于检测蛋白和 mRNA 表达水平。MTT 法检测细胞增殖。流式细胞术检测细胞凋亡。在 Pathway Commons 平台上分析 DUSP1 的免疫蛋白-蛋白相互作用（PPI）网络，并进行免疫浸润分析以研究 AML 的免疫微环境。我们发现 AML 患者中 DUSP1 的表达水平高于对照组。公共数据集的生存分析表明，DUSP1 水平较高的 AML 患者临床结局较差。进一步的公共数据分析表明，NRAS 突变型 AML 中 DUSP1 表达过度。siRNA 下调 DUSP1 可使 AML 细胞对 Ara-C 治疗敏感。DUSP1 下调 NRAS G13D 突变 AML 细胞中丝裂原活化蛋白激酶（MAPK）通路的磷酸化水平显著升高。PPI 分析表明 DUSP1 与 NRAS 突变型 AML 中的免疫基因 CREB1 和 CXCL8 相关。我们还揭示了 RAS 突变型 AML 微环境中肿瘤浸润免疫细胞之间的相关性。我们的研究结果表明，DUSP1 信号通路可能调节 AML 中 Ara-C 的敏感性。
