Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Xiamen, China; Department of Clinical Laboratory, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China.
Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Xiamen, China.
Int Immunopharmacol. 2024 Jun 15;134:112272. doi: 10.1016/j.intimp.2024.112272. Epub 2024 May 17.
A subset of neutrophils isolated from the peripheral blood mononuclear cells (PBMC) layer has recently been described in cancer patients.
Double-gradient centrifugation was used to separate the neutrophil subsets. Western blotting and immunohistochemical assays were performed to assess CCDC25 expression levels.
In this study, we found that low-density neutrophils (LDNs) were more highly enriched in metastatic hepatocellular carcinoma (HCC) patients than in non-metastatic HCC patients. We then showed a CD61 LDNs subset, which displayed distinct functions and gene expression, when compared with high-density neutrophils (HDNs) and CD61 LDNs. Transcriptomic analysis revealed that the CD61 LDNs were predominantly enhanced in the transcription of glycolysis and angiogenesis associated gene, HMGB1 associated gene and granulation protein gene. These CD61 LDNs displayed a prominent ability to trigger metastasis, compared with HDNs and CD61 LDNs. Specifically, CD61 LDN-derived HMGB1 protein increased the invasion of HCC cells by upregulating CCDC25. Mechanistically, the CD61 LDN-derived HMGB1 protein enhanced the invasiveness of HCC cells and triggered their metastatic potential, which was mediated by TLR9-NF-κB-CCDC25 signaling. Blocking this signaling pathway reversed the invasion of the CD61 LDN-induced HCC cells. In vivo, we consistently showed that CD61 LDN-derived HMGB1 enhances HCC metastasis to the lungs.
Overall, our findings showed that a subset of CD61 LDNs has pro-metastatic effects on HCC, and may be used to target HCC in the clinical setting.
最近在癌症患者的外周血单个核细胞（PBMC）层中分离出了一组中性粒细胞亚群。
使用双梯度离心法分离中性粒细胞亚群。采用 Western blot 和免疫组织化学检测评估 CCDC25 的表达水平。
在这项研究中，我们发现低密度中性粒细胞（LDNs）在转移性肝细胞癌（HCC）患者中的富集程度高于非转移性 HCC 患者。然后，我们展示了一个 CD61 LDN 亚群，与高密度中性粒细胞（HDNs）和 CD61 LDNs 相比，其具有独特的功能和基因表达。转录组分析表明，CD61 LDNs 在糖酵解和血管生成相关基因、HMGB1 相关基因和颗粒蛋白基因的转录中主要增强。与 HDNs 和 CD61 LDNs 相比，这些 CD61 LDNs 具有明显的触发转移的能力。具体来说，CD61 LDN 衍生的 HMGB1 蛋白通过上调 CCDC25 增加了 HCC 细胞的侵袭。在机制上，CD61 LDN 衍生的 HMGB1 蛋白增强了 HCC 细胞的侵袭性并触发了它们的转移潜力，这是由 TLR9-NF-κB-CCDC25 信号通路介导的。阻断该信号通路可逆转 CD61 LDN 诱导的 HCC 细胞的侵袭。在体内，我们一致表明 CD61 LDN 衍生的 HMGB1 增强了 HCC 向肺部的转移。
总的来说，我们的研究结果表明，CD61 LDN 的一个亚群对 HCC 具有促转移作用，可能用于 HCC 的临床治疗。
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