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ABSTRACT
Senescence frequently occurs in cancer cells in response to chemotherapy (called therapy-induced senescence). Senescent cells can exert paracrine effects through the senescence-associated secretory phenotype (SASP) promoting cancer recurrence and chemoresistance. The altered gut microbiota has been closely associated with cancer progression through the direct interaction with cancer cells. However, little is known about the relationship between the gut microbiota and therapy-induced senescent cells. This study aimed to explore the impact of the gut microbiota on therapy-induced senescent cells and the SASP. We found that esophageal squamous cell carcinoma (ESCC) cells were induced into senescence following platinum-based chemotherapy, accompanied by the secretion of a robust SASP. Furthermore, senescent ESCC cells exerted a tumor-promoting effect through the SASP both in vitro and in vivo. Through 16S rRNA gene sequencing and fluorescence in situ hybridization, we identified that Fusobacterium nucleatum (F. nucleatum) was abundant in human ESCC cancerous tissues and correlated with poor prognosis in ESCC patients. Notably, F. nucleatum further promoted the secretion of the SASP by senescent ESCC cells. Compared with the conditioned medium from senescent ESCC cells, the conditioned medium from F. nucleatum-treated senescent ESCC cells accelerated tumor growth in xenograft models, enhanced migration and invasion abilities, and potentiated chemoresistance both in vitro and in vivo. Mechanistically, F. nucleatum invaded and survived in senescent ESCC cells and induced an increase in DNA damage to further activate the DNA damage response pathway, thus enhancing the SASP. Altogether, these findings reveal for the first time that F. nucleatum promotes the secretion of chemotherapy-induced SASP to drive ESCC progression and chemoresistance, which supports F. nucleatum as a potential target for ESCC therapy.
Abbreviations
| ESCC | = | esophageal squamous cell carcinoma |
| CDDP | = | cisplatin |
| SASP | = | senescence-associated secretory phenotype |
| F. nucleatum | = | Fusobacterium nucleatum |
| SA-β-Gal | = | senescence-associated beta-galactosidase |
| CM | = | conditioned medium |
| FISH | = | fluorescence in situ hybridization |
| FadA | = | Fusobacterium adhesin A |
| MOI | = | multiplicity of infection |
Acknowledgments
We appreciate the excellent technical assistance from pathologists at Renmin Hospital of Wuhan University.
Author contributions
Jian-Wei Zhang: Conceptualization, Methodology, Project administration, Funding acquisition, Writing – original draft. Dan Zhang: Data curation, Validation, Formal analysis, Visualization. Hai-Sen Yin: Investigation, Validation, Resources. Han Zhang: Investigation, Resources. Kun-Qiao Hong: Investigation, Software, Formal analysis. Jing-Ping Yuan: Resources, Data curation. Bao-Ping Yu: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.
Disclosure statement
No potential conflict of interest was reported by the authors.
Consent for publication
All authors have read and approved the final draft of the manuscript.
Data availability statement
All sequencing data associated with this study have been uploaded to the NCBI (Sequence Read Archive) SRA database under the accession number PRJNA866879 (http://www.ncbi.nlm.nih.gov/bioproject/866879).
Ethics approval
This study was approved by the Ethics Committee of Renmin Hospital of Wuhan University (Ethics No: WDRY2021-K062). Informed consent was obtained from all patients included in this study. All animal experiments were approved by the Laboratory Animal Welfare and Ethics Committee of Renmin Hospital of Wuhan University (IACCU Issue No: 20201203).
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2197836.
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.