Cigarette smoke induces expression of senescence markers and pro‐inflammatory SASP in oral mucosa: Potential implications for early carcinogenic processes

Sep 30, 2025International journal of cancer

Cigarette smoke increases aging and inflammation signals in mouth lining, which may relate to early cancer development

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Abstract

Smoker biopsies exhibited a significant increase in p21 and p16 expression and a decrease in laminB1 compared to non-smokers.

Cigarette smoke exposure is linked to increased cellular senescence and inflammation in oral mucosa.
In smokers, higher levels of senescence markers were observed, suggesting a response to tobacco carcinogens.
In vitro studies showed that concentrations of ≥2% cigarette smoke extract induced similar senescence patterns in oral cells.
The three-dimensional oral mucosa model exhibited consistent changes in senescence markers following exposure to cigarette smoke.
Increased activity of a specific enzyme associated with senescence was noted in oral fibroblasts exposed to cigarette smoke.

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Oral squamous cell carcinoma, a leading global cause of cancer-related morbidity, is strongly associated with tobacco cigarette use. This study investigates the role of cigarette smoke in inducing cellular senescence and inflammation in oral mucosa, which may contribute to the development of oral cancer through mechanisms such as the senescence-associated secretory phenotype (SASP). Biopsies from smokers and non-smokers were analyzed using quantitative polymerase chain reaction to assess the expression of senescence markers p21, p16, and laminB1. Immunohistochemistry was performed to evaluate p21 and p16 expression in the tissues. In vitro experiments were conducted using primary oral keratinocytes (human oral keratinocytes [hOK]) and fibroblasts (human oral fibroblast [hOF]) exposed to increasing concentrations of cigarette smoke extract (CSE) for 72 h. Additionally, a three-dimensional (3D) reconstituted oral mucosa model was exposed to 5% CSE for 72 h, and senescence markers were analyzed by real-time quantitative polymerase chain reaction. Flow cytometry was performed in hOF after 72 h at 2% CSE to assess senescence-associated beta-galactosidase (SA-β-gal) activity. Smokers' biopsies showed a significant increase in p21 and p16 expression and a decrease in laminB1 compared with non-smokers. Immunohistochemistry confirmed increased p21 and p16 in smokers. In vitro, ≥2% CSE induced similar senescence patterns in hOK and hOF, with dose-dependent interleukin (IL)-6 and IL-8 secretion. The 3D oral mucosa model showed comparable changes in all three senescence markers. Exposure to 2% CSE increased SA-β-gal activity in hOF. Taken together, cigarette smoke exposure induces cellular senescence and inflammation in the oral mucosa. The pro-inflammatory response associated with SASP may contribute to the development of a pro-tumoral microenvironment in the oral cavity, promoting early oral carcinogenesis.

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Cigarette smoke induces expression of senescence markers and pro‐inflammatory SASP in oral mucosa: Potential implications for early carcinogenic processes

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