Neutrophil extracellular traps mediate TLR9/Merlin axis to resist ferroptosis and promote triple negative breast cancer progression
Neutrophil extracellular traps mediate TLR9/Merlin axis to resist ferroptosis and promote triple negative breast cancer progression
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DOI：
10.1007/s10495-023-01866-w
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发表时间：
2023-06
期刊：
影响因子：
7.2
通讯作者：
Linli Yao;Xiaonan Sheng;Xinrui Dong;Wei Zhou;Ye Li;Xueyun Ma;Yong-Gang Song;Huijuan Dai;Yueyao Du
中科院分区：
文献类型：
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作者：
Linli Yao;Xiaonan Sheng;Xinrui Dong;Wei Zhou;Ye Li;Xueyun Ma;Yong-Gang Song;Huijuan Dai;Yueyao Du
据报道，中性粒细胞和中性粒细胞胞外陷阱（NETs）与肿瘤的发展有关，但其确切作用和具体机制仍然知之甚少，特别是在三阴性乳腺癌（TNBC）中。在本研究中，我们的研究结果显示TNBC组织中NETs的形成高于非TNBC组织，并且NETs的形成与TNBC患者的肿瘤大小、ki67水平和淋巴结转移有明显的相关性。随后的体内实验表明，抑制NETs可抑制TNBC肿瘤生长和肺转移。进一步的体外实验发现，NETs对TNBC细胞的致瘤功能可能依赖于TLR9的表达。我们还发现TNBC术后发热患者外周血中性粒细胞容易形成NETs，并能增强TNBC细胞的增殖和侵袭。从机制上讲，我们发现NETs可以与TLR9相互作用，降低Merlin磷酸化，从而促进TNBC细胞耐铁凋亡。我们的工作为NETs促进TNBC进展的机制提供了新的见解，阻断NETs的关键调节剂可能是TNBC的一种有希望的治疗策略。
Neutrophil and neutrophil extracellular traps (NETs) were reported to be associated with tumor development, but the exact role and concrete mechanisms are still poorly understood, especially in triple negative breast cancer (TNBC). In this study, our results exhibited that NETs formation in TNBC tissues was higher than that in non-TNBC tissues, and NETs formation was distinctly correlated with tumor size, ki67 level and lymph node metastasis in TNBC patients. Subsequent in vivo experiments demonstrated that NETs inhibition could suppress TNBC tumor growth and lung metastasis. Further in vitro experiments uncovered that oncogenic function of NETs on TNBC cells were possibly dependent on TLR9 expression. We also found that neutrophils from peripheral blood of TNBC patients with postoperative fever were prone to form NETs and could enhance the proliferation and invasion of TNBC cells. Mechanistically, we revealed that NETs could interact with TLR9 to decrease Merlin phosphorylation which contributed to TNBC cell ferroptosis resistance. Our work provides a novel insight into the mechanism of NETs promoting TNBC progression and blocking the key modulator of NETs might be a promising therapeutic strategy in TNBC.