Huang Xianye, He Rongquan, Jiang Yanfeng, Tang Jing, Xu Xiaoyu, Laoguo Shixue, Chen Gang, Ma Jie
Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region 530021, China.
Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region 530021, China.
J Leukoc Biol. 2025 Mar 14;117(3). doi: 10.1093/jleuko/qiae235.
Neutrophil extracellular traps (NETs) are promising promoters in venous thromboembolism (VTE). In the present study, we have investigated the potential thrombogenic role of NETs in colorectal cancer (CRC). A total of 583 patients with gastrointestinal malignancies who were diagnosed with or without VTE by extremities arteriovenous ultrasound and computed tomography were enrolled. The incidence of VTE in CRC was as high as 17.53%. In serological ELISA experiments, Cit-H3, myeloperoxidase, and cfDNA were significantly overexpressed in CRC patients with VTE compared with CRC patients without VTE and healthy individuals. Neutrophils from CRC patients with VTE produced appreciable amounts of NETs after stimulation with phorbol-12-myristate-13-acetate, which were lacking in CRC patients without VTE and healthy individuals. CfDNA was positively correlated with plasmin-α2-antiplasmin complex and tissue plasmin activator inhibitor-1 complex, and Cit-H3 was positively correlated with plasmin-α2-antiplasmin complex, suggesting that NETs are associated with increased fibrinolytic activity. We screened some NETs-related genes by analyzing several high-throughput sequencing datasets of VTE and NETs. FCGR1A was identified as the optimal target gene by pan-cancer expression analysis and survival analysis. FCGR1A was significantly overexpressed in the peripheral blood of CRC patients without VTE compared with healthy individuals and showed a positive correlation with cfDNA. Neutrophil-derived NETs were significantly reduced by FCGR1A inhibitor exposure. These findings indicate that NETs are actively involved in VTE in CRC. NETs are promising thrombotic marker and therapeutic target in CRC to prevent the thrombotic consequences of cancer.
中性粒细胞胞外诱捕网（NETs）是静脉血栓栓塞症（VTE）中很有前景的促发因素。在本研究中，我们调查了NETs在结直肠癌（CRC）中潜在的致血栓形成作用。共纳入了583例经四肢动静脉超声和计算机断层扫描诊断为有或无VTE的胃肠道恶性肿瘤患者。CRC中VTE的发生率高达17.53%。在血清学ELISA实验中，与无VTE的CRC患者及健康个体相比，有VTE的CRC患者中瓜氨酸化组蛋白H3、髓过氧化物酶和游离DNA（cfDNA）显著过表达。用佛波酯-肉豆蔻酸酯-乙酸盐刺激后，有VTE的CRC患者的中性粒细胞产生了大量NETs，而无VTE的CRC患者和健康个体则没有。CfDNA与纤溶酶-α2-抗纤溶酶复合物及组织纤溶酶原激活物抑制剂-1复合物呈正相关，瓜氨酸化组蛋白H3与纤溶酶-α2-抗纤溶酶复合物呈正相关，这表明NETs与纤溶活性增加有关。我们通过分析几个VTE和NETs的高通量测序数据集筛选了一些与NETs相关的基因。通过泛癌表达分析和生存分析，FCGR1A被确定为最佳靶基因。与健康个体相比，无VTE的CRC患者外周血中FCGR1A显著过表达，且与cfDNA呈正相关。FCGR1A抑制剂处理后，中性粒细胞衍生的NETs显著减少。这些发现表明NETs积极参与CRC中的VTE。NETs是CRC中有前景的血栓形成标志物和治疗靶点，可预防癌症的血栓形成后果。
