Department of Clinical Laboratory Science, Wonkwang Health Science University, Iksan, South Korea.
Department of Biomedical Laboratory Science, Eulji University School of Medicine, Daejeon, South Korea.
Front Immunol. 2020 Aug 6;11:1258. doi: 10.3389/fimmu.2020.01258. eCollection 2020.
S100A8 and S100A9 function as essential factors in inflammation and also exert antitumor or tumorigenic activity depending on the type of cancer. Chronic eosinophilic leukemia (CEL) is a rare hematological malignancy having elevated levels of eosinophils and characterized by the presence of the fusion gene. In this study, we examined the pro-apoptotic mechanisms of S100A8 and S100A9 in FIP1L1-PDGFRα+ eosinophilic cells and hypereosinophilic patient cells. S100A8 and S100A9 induce apoptosis of the FIP1L1-PDGFRα+ EoL-1 cells via TLR4. The surface TLR4 expression increased after exposure to S100A8 and S100A9 although total TLR4 expression decreased. S100A8 and S100A9 suppressed the FIP1L1-PDGFRα-mediated signaling pathway by downregulating FIP1L1-PDGFRα mRNA and protein expression and triggered cell apoptosis by regulating caspase 9/3 pathway and Bcl family proteins. S100A8 and S100A9 also induced apoptosis of imatinib-resistant EoL-1 cells (EoL-1-IR). S100A8 and S100A9 blocked tumor progression of xenografted EoL-1 and EoL-1-IR cells in NOD-SCID mice and evoked apoptosis of eosinophils derived from hypereosinophilic syndrome as well as chronic eosinophilic leukemia. These findings may contribute to a progressive understanding of S100A8 and S100A9 in the pathogenic and therapeutic mechanism of hematological malignancy.
S100A8 和 S100A9 作为炎症的重要因素，根据癌症的类型发挥抗肿瘤或致瘤活性。慢性嗜酸性粒细胞白血病（CEL）是一种罕见的血液系统恶性肿瘤，其嗜酸性粒细胞水平升高，并以融合基因的存在为特征。在这项研究中，我们研究了 S100A8 和 S100A9 在 FIP1L1-PDGFRα+嗜酸性细胞和高嗜酸性粒细胞患者细胞中的促凋亡机制。S100A8 和 S100A9 通过 TLR4 诱导 FIP1L1-PDGFRα+ EoL-1 细胞凋亡。尽管总 TLR4 表达减少，但暴露于 S100A8 和 S100A9 后，表面 TLR4 表达增加。S100A8 和 S100A9 通过下调 FIP1L1-PDGFRα mRNA 和蛋白表达抑制 FIP1L1-PDGFRα 介导的信号通路，并通过调节半胱天冬酶 9/3 途径和 Bcl 家族蛋白触发细胞凋亡。S100A8 和 S100A9 还诱导伊马替尼耐药的 EoL-1 细胞（EoL-1-IR）凋亡。S100A8 和 S100A9 阻断了 NOD-SCID 小鼠异种移植的 EoL-1 和 EoL-1-IR 细胞的肿瘤进展，并诱导高嗜酸性粒细胞综合征和慢性嗜酸性粒细胞白血病衍生的嗜酸性粒细胞凋亡。这些发现可能有助于深入了解 S100A8 和 S100A9 在血液系统恶性肿瘤的发病机制和治疗机制中的作用。
