中性粒细胞胞外陷阱来源的DNA激活ITGB1/FAK通路促进肺腺癌转移
Neutrophil Extracellular Trap-Derived DNA Activates the ITGB1/FAK Pathway to Promote Lung Adenocarcinoma Metastasis.
作者
作者单位
- The First Affiliated Hospital, Sun Yat-sen University Guangzhou, Guangdong China.
- The First Affiliated Hospital, Sun Yat-sen University Guangzhou China.
- the First Affiliated Hospital of Sun Yat-sen University Guangzhou, Guangdong China.
- The First Affiliated Hospital, Sun Yat-sen University China.
摘要
中文
中性粒细胞胞外陷阱(NET)近期已成为癌症进展和转移的关键调节因子。然而,更全面地了解其潜在机制有助于找到预防和治疗NET介导的转移的有效策略。在此,我们观察到转移性原发性肺腺癌(LUAD)中瘤内NET显著积聚。CXCL2表达升高的肿瘤细胞不仅通过CXCR2相互作用招募中性粒细胞,还促进NET形成。反过来,NET来源的DNA(NET-DNA)通过特定的DNA基序直接结合整合素β1(ITGB1)的胞外域,从而激活FAK信号并促进侵袭和转移。NET-DNA能够通过MAPK-ELK1增强CXCL2表达,从而建立正反馈环路,维持持续的中性粒细胞募集和NET形成。在体外和体内模型中,靶向NET或ITGB1-FAK信号均显著抑制LUAD转移。这些发现提示CXCL2-NET-ITGB1-FAK信号轴在驱动NET介导的转移中发挥关键作用,这为靶向该信号通路抑制LUAD转移提供了理论依据。
English
Neutrophil extracellular traps (NETs) have recently emerged as key modulators of cancer progression and metastasis. However, a more comprehensive understanding of the underlying mechanisms could help identify effective strategies to prevent and treat NET-mediated metastasis. Here, we observed a marked accumulation of intratumoral NETs in metastatic primary lung adenocarcinoma (LUAD). Tumor cells with elevated CXCL2 expression not only recruited neutrophils via interactions with CXCR2 but also facilitated NET formation. In turn, NET-derived DNA (NET-DNA), through specific DNA motifs, directly bound to the extracellular domain of integrin β1 (ITGB1), thereby activating FAK signaling and promoting invasion and metastasis. NET-DNA was capable of enhancing CXCL2 expression through MAPK-ELK1, thereby establishing a positive feedback loop that maintained continuous neutrophil recruitment and NET formation. In both in vitro and in vivo models, targeting either NETs or ITGB1-FAK signaling significantly inhibited LUAD metastasis. These findings suggest that the CXCL2-NET-ITGB1-FAK signaling axis plays a pivotal role in driving NET-mediated metastasis, which provides a rationale for targeting this signaling pathway to inhibit LUAD metastasis.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 22.6
- 新锐分区
- 1区