肠道来源的物质通过调节PDPN-CLEC-2信号通路对结直肠癌发挥抗癌作用。

Gut-derived exerts anti-cancer effects on colorectal cancer by modulating PDPN-CLEC-2 signaling pathway.

作者信息

Yang Xiaojuan, Liu Miao, Wang Ting, Ma Xinjuan, Guan Zhirong, Ma Bin, Duan Xiangguo, Su Chunxia

机构信息

School of Inspection, Ningxia Medical University, Yinchuan, China.

The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, China.

出版信息

mSystems. 2025 Jul 22:e0014825. doi: 10.1128/msystems.00148-25.

Abstract

Dynamic changes in microbial composition are related to the progression of colorectal cancer (CRC); however, specific microbes with anti-CRC properties have not been identified. Here, we aimed to determine the effect of on CRC progression. In this study, the effect of was assessed in an azoxymethane (AOM)/dextran sulfate sodium salt (DSS)-induced CRC mouse model as well as in human CRC cell lines. Changes in anti-tumor immune responses were evaluated by flow cytometry. The functional metabolites produced by were identified by gas chromatography‒mass spectrometry (GC‒MS). The subcutaneously injected BALB/c mice with CT26 CRC cells were used to evaluate the effect of acetate produced by . We found that supplementation with suppressed CRC in an AOM/DSS-induced CRC mouse model as well as in the human CRC cell lines SW620 and HT-29. GC‒MS revealed that acetate is a functional tumor-suppressive metabolite produced by , and the tumor volume and tumor weight in the CRC model were inhibited by acetate administration. Mechanistically, produced acetate, which suppressed the expression of PDPN on CD8 T cells and that of C-type lectin-like receptor 2 (CLEC-2) on tumor cells. As a consequence, CD8 T-cell immunity was increased both and . In addition, we revealed that the acetate produced by can modulate podoplanin (PDPN)/CLEC-2/PI3K/AKT/mTOR signaling in CRC. In summary, produced acetate inhibits CRC by promoting CD8 T-cell immunity and modulating the PDPN-CLEC-2 pathway. Our data indicate that is a potential probiotic for cancer prevention and treatment.IMPORTANCEThis study identified as a novel probiotic that suppresses colorectal cancer (CRC) via acetate, which enhances CD8 T-cell immunity by blocking PDPN-CLEC-2 and induces tumor cell apoptosis through PI3K/AKT/mTOR pathway. These findings validated and acetate as dual-action therapeutic candidates through immune response activation and intrinsic tumor targeting by murine models and human CRC cell lines, thereby providing innovative strategies for CRC treatment.

摘要

微生物组成的动态变化与结直肠癌(CRC)的进展有关;然而,具有抗CRC特性的特定微生物尚未被鉴定出来。在此,我们旨在确定[具体微生物名称未给出]对CRC进展的影响。在本研究中,在氧化偶氮甲烷(AOM)/葡聚糖硫酸钠(DSS)诱导的CRC小鼠模型以及人CRC细胞系中评估了[具体微生物名称未给出]的作用。通过流式细胞术评估抗肿瘤免疫反应的变化。通过气相色谱 - 质谱联用(GC - MS)鉴定[具体微生物名称未给出]产生的功能性代谢产物。将皮下注射CT26 CRC细胞的BALB/c小鼠用于评估[具体微生物名称未给出]产生的乙酸盐的作用。我们发现,在AOM/DSS诱导的CRC小鼠模型以及人CRC细胞系SW620和HT - 29中,补充[具体微生物名称未给出]可抑制CRC。GC - MS显示乙酸盐是[具体微生物名称未给出]产生的一种功能性肿瘤抑制代谢产物,在CRC模型中,给予乙酸盐可抑制肿瘤体积和肿瘤重量。从机制上讲,[具体微生物名称未给出]产生乙酸盐,其抑制CD8 T细胞上PDPN的表达以及肿瘤细胞上C型凝集素样受体2(CLEC - 2)的表达。结果,[具体微生物名称未给出]和[具体微生物名称未给出]两者的CD8 T细胞免疫均增强。此外,我们发现[具体微生物名称未给出]产生的乙酸盐可调节CRC中的血小板内皮细胞黏附分子(PDPN)/CLEC - 2/PI3K/AKT/mTOR信号通路。总之,[具体微生物名称未给出]产生的乙酸盐通过促进CD8 T细胞免疫和调节PDPN - CLEC - 2途径来抑制CRC。我们的数据表明[具体微生物名称未给出]是一种潜在的用于癌症预防和治疗的益生菌。

重要性

本研究鉴定出[具体微生物名称未给出]是一种新型益生菌,它通过乙酸盐抑制结直肠癌(CRC),乙酸盐通过阻断PDPN - CLEC - 2增强CD8 T细胞免疫,并通过PI3K/AKT/mTOR途径诱导肿瘤细胞凋亡。这些发现通过小鼠模型和人CRC细胞系验证了[具体微生物名称未给出]和乙酸盐作为通过免疫反应激活和内在肿瘤靶向的双重作用治疗候选物,从而为CRC治疗提供了创新策略。

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