AGING AND ORAL CANCER DEVELOPMENT

Abstract

Background Cell aging or cellular senescence is a potent antitumor response characterized by an irreversible cell growth arrest. Paradoxically, aging is considered a risk factor for the development of cancer, with compelling evidence of senescent cells acting as cancer promoters. Senescent cells remain metabolically active and adopt a proinflammatory phenotype known as senescence-associated secretory phenotype (SASP) characterized by the secretion of different factors including IL-6 and IL-8, 2 well-known cancer-associated cytokines. Objective To study the senescence response of normal and dysplastic (OD) oral keratinocytes and to explore pharmacological ways to reduce its potential oncogenic effects. Methods Primary normal and dysplastic keratinocytes were grown until senescence was achieved and changes in gene and protein expression were analyzed. Senescent cells were treated with 2 different drugs (a Rho kinase and cGAS inhibitor) to explore possible ways to modify the SASP. To understand mechanisms regulating senescence, OD cells were genetically modified using the CRISPR/Cas9 system. Results Senescent normal oral keratinocytes and ODs develop a SASP characterized by a significant increase of IL-1α, IL-1β, IL-6, and IL-8, which is accompanied by a decrease in the IL-1 receptor antagonist (IL-1RA). Rock inhibitors are successful in reducing cytokine secretion by senescent cells, whereas cGAS inhibitors can only do it partially. Knock-out of IL-1RA suggests that IL-1RA has important functions in the regulation of senescence. Conclusions Our study shows that senescent oral keratinocytes adopt a proinflammatory state, rich in cytokines known to have oncogenic effects, which can be pharmacologically modified without affecting the senescence response.