Fusobacterium nucleatum impairs DNA mismatch repair and stability in patients with squamous cell carcinoma of the head and neck

Abstract

Background 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. Methods 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). Results 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. Conclusions 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. LAY SUMMARY 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.

Extracellular vesicles from Aggregatibacter actinomycetemcomitans exhibit potential antitumorigenic effects in oral cancer: a comparative in vitro study

“…Our findings support recent observations that higher tumoral levels of F. nucleatum were associated with better clinical outcomes in patients with head and neck cancers (Chen et al 2020 ; Neuzillet et al 2021 ). In contrast, one study showed that a higher abundance of F. nucleatum predicted recurrence and shorter disease-free survival in patients with laryngeal cancer (Hsueh et al 2022 ). This disagreement between studies may, however, result from variations in the tumor microenvironment between the larynx and oral cavity.…”

Integrative methylome and transcriptome analysis reveals epigenetic regulation of Fusobacterium nucleatum in laryngeal cancer

“…Fusobacterium species in metastatic tumours are highly similar to those found in primary tumours, suggesting that the microbiota maintains stability between primary and metastatic tumours [18]. Reportedly, F. nucleatum is significantly increased in patients with lymph node metastasis and F. nucleatum upregulates keratin 7-antisense/keratin 7 (KRT7-AS/KRT7) through the nuclear factor kappa B pathway and promoted CRC cell migration [19]. F. nucleatum regulates the TLR4/MYD88/miR-205–5 p pathway and induces epigenetic alterations, thus promoting DNA damage and cell proliferation [19].…”

“…Reportedly, F. nucleatum is significantly increased in patients with lymph node metastasis and F. nucleatum upregulates keratin 7-antisense/keratin 7 (KRT7-AS/KRT7) through the nuclear factor kappa B pathway and promoted CRC cell migration [19]. F. nucleatum regulates the TLR4/MYD88/miR-205–5 p pathway and induces epigenetic alterations, thus promoting DNA damage and cell proliferation [19]. F. nucleatum induces the epithelial–mesenchymal transition (EMT) by regulating the long non-coding RNA MIR4435-2HG [20].…”

Oral microbiome as a new research-target for supportive care and precision oncology

“…Fusobacteria at the treatment baseline was correlated with nonresponders [18]. Changes in the oral epithelium in vivo are strongly related to Socransky's red complex bacteria [19], mainly Porphyromonas gingivalis [14,20,21], Porphyromonas catoniae [22], and Fusobacterium nucleatum [23,24], for their immune-receptor upregulation and tight junction degradation capacity [25].…”