Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.
Department of Pathology, Eye & ENT Hospital, Fudan University, Shanghai, China.
Cancer. 2022 Sep 1;128(17):3170-3184. doi: 10.1002/cncr.34338. Epub 2022 Jul 5.
Dysbiosis of the laryngeal microbiota has been demonstrated to the development of head and neck squamous cell carcinoma (HNSCC), but the association of Fusobacterium and Fusobacterium nucleatum (F. nucleatum) with DNA mismatch repair (MMR) and microsatellite instability (MSI) has not been investigated.
The abundance of Fusobacterium and F. nucleatum, the status of deficient MMR (dMMR) and MSI, and MMR-related gene expression were analyzed in 171 HNSCC tissues, 61 paired para-tumor tissues, and 60 vocal cord polyp tissues. The molecular mechanism of F. nucleatum and MMR-related gene expression were investigated in two human HNSCC cell lines (Tu 686 and FD-LSC-1).
Our results demonstrated that a high Fusobacterium abundance was detected in the HNSCC tissues and was exaggerated in the recurrent patients. We further found that a high Fusobacterium abundance was detected in the HNSCC tissues with dMMR and MSI. The Fusobacterium abundance was negatively correlated with the expression of MLH1, MSH2, and MSH6 in the HNSCC tissues. The Fusobacterium abundance was closely associated with the F. nucleatum abundance in the HNSCC tissues. F. nucleatum increased miR-205-5p expression to suppress MLH1, MSH2, and MSH6 expression via the TLR4- and MYD88-dependent innate immune signaling pathway, resulting in dMMR, DNA damage, and cell proliferation in HNSCC.
F. nucleatum impacts HNSCC epigenetic changes in tissues with dMMR to promote DNA damage and cell proliferation by suppressing MMR-related gene expression via the TLR4/MYD88/miR-205-5p signaling pathway, which is valuable in the development of efficient strategies for HNSCC prevention and treatment.
This study clearly indicates that Fusobacterium induced head and neck squamous cell carcinoma (HNSCC) aggressiveness to affect poor prognosis in HNSCC patients by epigenetic alteration of DNA mismatch repair (MMR) and microsatellite instability. Moreover, the research has shown that Fusobacterium nucleatum ( F. nucleatum ) impacts HNSCC epigenetic changes in tissues with deficient MMR to promote DNA damage and cell proliferation by suppressing MMRrelated gene expression via the TLR4/MYD88/miR-205-5p signaling pathway.
喉微生物组的失调已被证明与头颈部鳞状细胞癌（HNSCC）的发展有关，但尚未研究梭杆菌属和具核梭杆菌（F. nucleatum）与 DNA 错配修复（MMR）和微卫星不稳定性（MSI）的关联。
分析了 171 例 HNSCC 组织、61 对癌旁组织和 60 例声带息肉组织中梭杆菌属和 F. nucleatum 的丰度、MMR 缺陷（dMMR）和 MSI 状态以及 MMR 相关基因表达。在两个人类 HNSCC 细胞系（Tu 686 和 FD-LSC-1）中研究了 F. nucleatum 和 MMR 相关基因表达的分子机制。
我们的结果表明，HNSCC 组织中检测到高丰度的梭杆菌属，且在复发性患者中更为明显。我们进一步发现，dMMR 和 MSI 的 HNSCC 组织中检测到高丰度的梭杆菌属。HNSCC 组织中梭杆菌属的丰度与 MLH1、MSH2 和 MSH6 的表达呈负相关。HNSCC 组织中梭杆菌属的丰度与 F. nucleatum 的丰度密切相关。F. nucleatum 通过 TLR4-和 MYD88 依赖性先天免疫信号通路增加 miR-205-5p 的表达，从而抑制 MLH1、MSH2 和 MSH6 的表达，导致 HNSCC 中 dMMR、DNA 损伤和细胞增殖。
F. nucleatum 通过 TLR4/MYD88/miR-205-5p 信号通路抑制 MMR 相关基因表达，对 dMMR 组织中的 HNSCC 表观遗传变化产生影响，从而促进 DNA 损伤和细胞增殖，这在开发有效的 HNSCC 预防和治疗策略方面具有重要价值。
本研究清楚地表明，梭杆菌属通过 DNA 错配修复（MMR）和微卫星不稳定性的表观遗传改变，诱导头颈部鳞状细胞癌（HNSCC）侵袭性，影响 HNSCC 患者的不良预后。此外，研究表明，具核梭杆菌（F. nucleatum）通过 TLR4/MYD88/miR-205-5p 信号通路抑制 MMR 相关基因表达，对 dMMR 组织中的 HNSCC 表观遗传变化产生影响，从而促进 DNA 损伤和细胞增殖。
