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Human Papillomavirus (HPV), a non-enveloped epitheliotropic double stranded DNA virus, is an etiological agent of oral cancer, and can be cleared by host immunity. A small percentage of patients that develop persistent infection with oncogenic HPV show an increased risk of developing an HPV-associated malignancy. Head and neck, oropharyngeal cancer is related to the persistent infection by high-risk HPV type 16, E6/E7 oncoproteins. The E6/E7 oncoproteins significantly contribute to the carcinogenic genomic instability effect of high-risk HPV through the degradation of two proteins, p53 and pRB, respectively. The human oropharynx often harbors anaerobic bacteria that produce a variety of byproducts, including butyrate. Butyrate is a modulator of induced genomic instability, influencing the development of HPV oral cancer when implanted in a syngeneic mouse model. In this study, we investigate butyrate co-treatment with HPV E6/E7 in vitro. This treatment increased cellular proliferation, DNA double strand breaks, and genetic instability processes associated with apoptosis regulation. These data indicate that in connection with butyrate, HPV E6/E7 oncoproteins can promote increased upregulation of apoptosis, disrupt cell cycle regulation, and decrease DNA double strand break repair. Epigenetics and chromosomal instability events have been noted, specifically, the deletion of the distal region of chromosome 11q22-23 in E6/E7 transfected keratinocytes. These results indicate that HPV-16, E6/E7 oncoproteins plus butyrate treatment can influence genomic changes in mouse keratinocytes, which may further promote oral carcinogenesis. Citation Format: Eva McGhee, Mengtao Li, Yi-Ling Lin, Brooke Su-Velez, Nefertari Carr, Chinelo Njubigbo, Rohun Sadeghi, Matin Sadegh, Julian Handler, Adin Handler, Naomi Long, Jay Vadgama. Exposure to butyrate metabolite mediates genomic instability in oropharyngeal keratinocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1510. |
