Nicotine-induced CHRNA5 activation modulates CES1 expression, impacting head and neck squamous cell carcinoma recurrence and metastasis via MEK/ERK pathway.
Humans
Nicotine
/ pharmacology
Receptors, Nicotinic
/ metabolism
Squamous Cell Carcinoma of Head and Neck
/ genetics
Animals
Cell Line, Tumor
MAP Kinase Signaling System
/ drug effects
Mice
Cell Proliferation
/ drug effects
Mice, Nude
Cell Movement
/ drug effects
Head and Neck Neoplasms
/ pathology
Neoplasm Recurrence, Local
/ genetics
Gene Expression Regulation, Neoplastic
/ drug effects
Neoplasm Metastasis
Nerve Tissue Proteins
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
08
06
2024
accepted:
22
10
2024
revised:
18
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
The mucosal epithelium of the head and neck region (including the oral cavity, nasal cavity, pharynx, nasopharynx, and larynx) is the primary site exposed to tobacco smoke, and its presence of nicotinic acetylcholine receptors (nAChRs) has been observed in the mucosal epithelial cells of this area. It remains unclear whether HNSC cells can migrate and invade through nAChR signaling. A model of HNSC cells exposed to nicotine is established. Cell proliferation following nicotine exposure is assessed using the CCK-8 assay, while migration and invasion are evaluated through wound healing and Transwell assays. The effects of CHRNA5 knockdown and overexpression are also investigated. Immunofluorescence staining is used to analyze CHRNA5 expression and localization, and clonogenic assays are performed to measure colony proliferation after CHRNA5 knockdown and overexpression. The interaction between CHRNA5 and CES1 is examined using molecular docking, co-immunoprecipitation, and immunofluorescence. Differentially expressed genes are subjected to pathway enrichment analysis, and MEK/ERK protein expression and phosphorylation are validated via western blot. Tumor formation assays are performed in nude mice using sh-CHRNA5 Cal27 cells, followed by western blot and immunohistochemical staining. Additionally, laryngeal and hypopharyngeal cancer tissues are analyzed through immunohistochemistry. Nicotine significantly enhanced the proliferation, migration, and invasion capabilities of head and neck tumor cells, including Cal27, Fadu, HN6, and Tu686 cells, through the expression of CHRNA5. Knockdown of CHRNA5 can reduce cell migration, invasion, and proliferation, whereas nicotine exposure can reverse this trend. Additionally, the mRNA and protein expression of CES1 decreases with the knockdown of CHRNA5, indicating a regulatory relationship between the two. Transcriptomics revealed that the knockdown of CHRNA5 is associated with the MEK/ERK signaling pathway. Further cellular- and tissue-level evidence confirmed that the levels of p-MEK/MEK, p-ERK/ERK, and CES1 decreased following knockdown of CHRNA5, a trend that nicotine can reverse. Nicotine promotes the proliferation, migration, and invasion of HNSC by upregulating CHRNA5 expression. Knockdown of CHRNA5 reduces these effects, which can be reversed by nicotine. Nicotine exposure activates CHRNA5, regulating CES1 expression via the MEK/ERK pathway, contributing to the recurrence and metastasis of head and neck squamous carcinoma.
Identifiants
pubmed: 39472448
doi: 10.1038/s41419-024-07178-4
pii: 10.1038/s41419-024-07178-4
doi:
Substances chimiques
Nicotine
6M3C89ZY6R
Receptors, Nicotinic
0
CHRNA5 protein, human
0
Nerve Tissue Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
785Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82072989
Organisme : Shanghai Shen Kang Hospital Development Center
ID : SHDC12020120
Organisme : Natural Science Foundation of Shanghai (Natural Science Foundation of Shanghai Municipality)
ID : 23ZR1451100
Informations de copyright
© 2024. The Author(s).
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