巨噬细胞中 ETS1 的缺失通过减少 F4/80+TIM4+ 巨噬细胞群抑制结直肠癌的进展

IF 3.3 3区 医学 Q2 ONCOLOGY
Yuanyuan Cao, Anning Guo, Muxin Li, Xinghua Ma, Xiaofeng Bian, YiRong Chen, Caixia Zhang, Shijia Huang, Wei Zhao, Shuli Zhao
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引用次数: 0

摘要

肿瘤相关巨噬细胞(TAMs)在肿瘤微环境(TME)中发挥着举足轻重的复杂作用;然而,人们对它们在肿瘤微环境中的异质性仍然知之甚少。ETS 原癌基因 1(ETS1)是一种主要在淋巴细胞中表达的转录因子。然而,它在结直肠癌(CRC)相关巨噬细胞中的表达和免疫调节作用仍不清楚。研究发现,ETS1在CRC微环境中CD68+巨噬细胞中的表达水平明显高于匹配的癌旁组织。重要的是,ETS1 提高了脂多糖刺激的 THP-1 细胞中趋化因子 C-C motif chemokine ligand 2(CCL2)和 C-X-C motif chemokine ligand 10(CXCL10)的水平。在体外共培养过程中,它还能促进 CRC 细胞的迁移和侵袭。在 ETS1 条件性基因敲除小鼠模型中,巨噬细胞中 ETS1 的缺乏可改善 DSS 诱导的溃疡性结肠炎小鼠模型的组织学变化,并延长偶氮甲烷/右旋糖酐硫酸钠(AOM/DSS)诱导的 CRC 模型的存活时间。巨噬细胞中 ETS1 的缺乏大大抑制了肿瘤的形成,减少了肠系膜淋巴结中的 F4/80+TIM4+ 巨噬细胞,并降低了肿瘤组织中的 CCL2 和 CXCL10 蛋白水平。此外,巨噬细胞中 ETS1 的缺乏能有效阻止 CRC 的肝转移,并减少 TAMs 对转移部位的浸润。随后的研究表明,ETS1 在 CCL2/CXCL10 的自分泌作用下,通过信号转导和激活转录 1 信号通路激活巨噬细胞中 T 细胞免疫球蛋白粘蛋白受体 4 的表达。总之,巨噬细胞中ETS1的缺乏可通过抑制CCL2和CXCL10的表达增强抗肿瘤免疫反应,从而为CRC的潜在治疗策略提供启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ETS1 deficiency in macrophages suppresses colorectal cancer progression by reducing the F4/80+TIM4+ macrophage population.

Tumor-associated macrophages (TAMs) take on pivotal and complex roles in the tumor microenvironment (TME); however, their heterogeneity in the TME remains incompletely understood. ETS proto-oncogene 1 (ETS1) is a transcription factor that is mainly expressed in lymphocytes. However, its expression and immunoregulatory role in colorectal cancer (CRC)-associated macrophages remain unclear. In the study, the expression levels of ETS1 in CD68+ macrophages in the CRC microenvironment were significantly higher than those in matched paracarcinoma tissues. Importantly, ETS1 increased the levels of chemokines C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) in lipopolysaccharide-stimulated THP-1 cells. It also boosted the migration and invasion of CRC cells during the in vitro co-culture. In the ETS1 conditional knockout mouse model, ETS1 deficiency in macrophages ameliorated the histological changes in DSS-induced ulcerative colitis mouse models and prolonged the survival in an azomethane/dextran sodium sulfate (AOM/DSS)-induced CRC model. ETS1 deficiency in macrophages substantially inhibited tumor formation, reduced F4/80+TIM4+ macrophages in the mesenteric lymph nodes, and decreased CCL2 and CXCL10 protein levels in tumor tissues. Moreover, ETS1 deficiency in macrophages effectively prevented liver metastasis of CRC and reduced the infiltration of TAMs into the metastasis sites. Subsequent studies have indicated that ETS1 upregulated the expression of T-cell immunoglobulin mucin receptor 4 in macrophages through the signal transducer and activator of the transcription 1 signaling pathway activated by the autocrine action of CCL2/CXCL10. Collectively, ETS1 deficiency in macrophages potentiates antitumor immune responses by repressing CCL2 and CXCL10 expression, shedding light on potential therapeutic strategies for CRC.

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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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