Fusobacterium nucleatum induces invasive growth and angiogenic responses in malignant oral keratinocytes that are cell line- and bacterial strain-specific

IF 4.6 2区医学 Q2 IMMUNOLOGY

Frontiers in Cellular and Infection Microbiology Pub Date : 2024-09-02 DOI:10.3389/fcimb.2024.1417946

Ajith Selvaraj, Gavin McManus, Claire M. Healy, Gary P. Moran

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Abstract

Fusobacterium nucleatum is an anaerobic commensal of the oral cavity recently reported to be associated with cancers of the gastrointestinal tract and oral squamous cell carcinoma (OSCC). In this study, we investigate the impact on oral keratinocytes of infection with a genetically diverse set of strains of F. nucleatum subsp. polymorphum recovered from patients with oral dysplasia (n=6). We employed H357 oral keratinocytes derived from a stage 1 OSCC and H376 cells derived from a stage 3 OSCC. Adhesion phenotypes were strain specific, with 3/6 clinical isolates examined exhibiting higher adherence to the stage 3 H376 cell line. Conversely, intracellular invasion was greatest in the H357 cells and was associated with specific transcriptional responses including autophagy and keratinization. Infection of both H357 and H376 cell lines induced transcriptional and cytokine responses linked to cancer cell migration and angiogenesis. F. nucleatum infection induced greater levels of MMP9 secretion in the H376 cell line which was associated with enhanced motility and invasion phenotypes. Additionally, the degree of F. nucleatum induced invasive growth by H376 cells varied between different clinical isolates of F. nucleatum subsp. polymorphum. Blockage of CCL5 signalling using the inhibitor metCCL5 resulted in reduced keratinocyte invasion. F. nucleatum infection also induced expression of the pro-angiogenic chemokine MCP-1 and the angiogenic growth factor VEGF-A resulting in increased capillary-like tube formation in HUVEC cells, most significantly in H376 cells. Treatment of HUVEC cells with resveratrol, a VEGF-A signalling inhibitor, significantly attenuated F. nucleatum induced tube formation. Our data indicate that the outcomes of F. nucleatum-oral cell interactions can vary greatly depending on the bacterial genotype and the malignant phenotype of the host cell.

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核分枝杆菌诱导恶性口腔角朊细胞的侵袭性生长和血管生成反应，这种反应具有细胞系和细菌菌株特异性

核叉杆菌是一种口腔厌氧共生菌，最近有报道称它与胃肠道癌症和口腔鳞状细胞癌（OSCC）有关。在本研究中，我们调查了从口腔发育不良患者（6 人）中回收的多形性核酸核菌亚种基因多样性菌株感染对口腔角朊细胞的影响。我们使用了来自一期 OSCC 的 H357 口腔角质细胞和来自三期 OSCC 的 H376 细胞。粘附表型具有菌株特异性，受检的 3/6 临床分离株对 3 期 H376 细胞系的粘附性更高。相反，H357细胞的胞内侵袭能力最强，并与特定的转录反应有关，包括自噬和角质化。感染H357和H376细胞系会诱导与癌细胞迁移和血管生成有关的转录和细胞因子反应。在H376细胞系中，F. nucleatum感染诱导了更高水平的MMP9分泌，这与细胞运动和侵袭表型的增强有关。此外，不同临床分离的多形核因子亚种F. nucleatum诱导H376细胞侵袭生长的程度也不同。使用抑制剂 metCCL5 阻断 CCL5 信号可减少角质形成细胞的侵袭。F. nucleatum 感染还能诱导促血管生成趋化因子 MCP-1 和血管生成生长因子 VEGF-A 的表达，从而增加 HUVEC 细胞中毛细血管样管的形成，其中以 H376 细胞最为显著。用白藜芦醇（一种 VEGF-A 信号抑制剂）处理 HUVEC 细胞可明显减少 F. nucleatum 诱导的管形成。我们的数据表明，F. nucleatum与口腔细胞相互作用的结果会因细菌基因型和宿主细胞恶性表型的不同而有很大差异。

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来源期刊

Frontiers in Cellular and Infection Microbiology IMMUNOLOGY-MICROBIOLOGY

CiteScore

7.90

自引率

7.00%

发文量

1817

审稿时长

14 weeks

期刊介绍： Frontiers in Cellular and Infection Microbiology is a leading specialty journal, publishing rigorously peer-reviewed research across all pathogenic microorganisms and their interaction with their hosts. Chief Editor Yousef Abu Kwaik, University of Louisville is supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Frontiers in Cellular and Infection Microbiology includes research on bacteria, fungi, parasites, viruses, endosymbionts, prions and all microbial pathogens as well as the microbiota and its effect on health and disease in various hosts. The research approaches include molecular microbiology, cellular microbiology, gene regulation, proteomics, signal transduction, pathogenic evolution, genomics, structural biology, and virulence factors as well as model hosts. Areas of research to counteract infectious agents by the host include the host innate and adaptive immune responses as well as metabolic restrictions to various pathogenic microorganisms, vaccine design and development against various pathogenic microorganisms, and the mechanisms of antibiotic resistance and its countermeasures.

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