BACKGROUND The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value. METHODS The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays. RESULTS NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model. CONCLUSIONS NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis.

中文翻译：

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嗜中性粒细胞外陷阱的增加通过引起肿瘤性炎症反应而促进肝细胞癌的转移潜力。

背景技术在多种炎症条件下证明了活化的嗜中性粒细胞形成细胞外捕获物（NET）的倾向。在这项研究中，我们调查了NETs在肝细胞癌（HCC）转移中的作用，并进一步探讨了NETs如何影响转移的潜在机制以及治疗价值。方法从人肝癌患者的血液中分离出嗜中性粒细胞，并用于评估NETs的形成。在肿瘤标本中检测到NET标记物的表达。LPS诱导的NET模型用于研究NETs在HCC转移中的作用。进行RNA-seq鉴定由NETs触发的关键分子事件，并使用体外和体内试验探索其潜在机制和治疗意义。结果肝细胞癌患者，特别是转移性肝细胞癌患者中性粒细胞的NET形成增加。NETs捕获HCC细胞并随后诱导细胞死亡抗性并增强侵袭性以触发其转移潜能，这是由NETs内化到捕获的HCC细胞和激活Toll样受体TLR4 / 9-COX2信号传导介导的。抑制TLR4 / 9-COX2信号消除了网络引起的转移潜力。DNase 1直接破坏网与抗炎药阿司匹林/羟氯喹的组合可有效减少小鼠模型中的HCC转移。结论NETs触发肿瘤炎症反应并促进HCC转移。靶向NETs而不是嗜中性粒细胞本身可以是对抗HCC转移的实践策略。特别是那些具有转移性肝癌的人。NETs捕获HCC细胞并随后诱导细胞死亡抗性并增强侵袭性以触发其转移潜能，这是由NETs内化到捕获的HCC细胞和激活Toll样受体TLR4 / 9-COX2信号传导介导的。抑制TLR4 / 9-COX2信号消除了网络引起的转移潜力。DNase 1直接破坏网与抗炎药阿司匹林/羟氯喹的组合可有效减少小鼠模型中的HCC转移。结论NETs触发肿瘤炎症反应并促进HCC转移。靶向NETs而不是嗜中性粒细胞本身可以是对抗HCC转移的实践策略。特别是那些具有转移性肝癌的人。NETs捕获HCC细胞并随后诱导细胞死亡抗性并增强侵袭性以触发其转移潜能，这是由NETs内化到捕获的HCC细胞和激活Toll样受体TLR4 / 9-COX2信号传导介导的。抑制TLR4 / 9-COX2信号消除了网络引起的转移潜力。DNase 1直接破坏网与抗炎药阿司匹林/羟氯喹的组合可有效减少小鼠模型中的HCC转移。结论NETs触发肿瘤炎症反应并促进HCC转移。靶向NETs而不是嗜中性粒细胞本身可以是对抗HCC转移的实践策略。NETs捕获HCC细胞并随后诱导细胞死亡抗性并增强侵袭性以触发其转移潜能，这是由NETs内化到捕获的HCC细胞和激活Toll样受体TLR4 / 9-COX2信号传导介导的。抑制TLR4 / 9-COX2信号消除了网络引起的转移潜力。DNase 1直接破坏网与抗炎药阿司匹林/羟氯喹的组合可有效减少小鼠模型中的HCC转移。结论NETs触发肿瘤炎症反应并促进HCC转移。靶向NETs而不是嗜中性粒细胞本身可以是对抗HCC转移的实践策略。NETs捕获HCC细胞并随后诱导细胞死亡抗性并增强侵袭性以触发其转移潜能，这是由NETs内化到捕获的HCC细胞和激活Toll样受体TLR4 / 9-COX2信号传导介导的。抑制TLR4 / 9-COX2信号消除了网络引起的转移潜力。DNase 1直接破坏网与抗炎药阿司匹林/羟氯喹的组合可有效减少小鼠模型中的HCC转移。结论NETs触发肿瘤炎症反应并促进HCC转移。靶向NETs而不是嗜中性粒细胞本身可以是对抗HCC转移的实践策略。抑制TLR4 / 9-COX2信号消除了网络引起的转移潜力。DNase 1直接破坏网与抗炎药阿司匹林/羟氯喹的组合可有效减少小鼠模型中的HCC转移。结论NETs触发肿瘤炎症反应并促进HCC转移。靶向NETs而不是嗜中性粒细胞本身可以是对抗HCC转移的实践策略。抑制TLR4 / 9-COX2信号消除了网络引起的转移潜力。DNase 1直接破坏网与抗炎药阿司匹林/羟氯喹的组合有效降低了小鼠模型中的HCC转移。结论NETs触发肿瘤炎症反应并促进HCC转移。靶向NETs而不是嗜中性粒细胞本身可以是对抗HCC转移的实践策略。