Exposure to Microbial Metabolite Butyrate Prolongs the Survival Time and Changes the Growth Pattern of Human Papillomavirus 16 E6/E7-Immortalized Keratinocytes in Vivo

• DOI: 10.1016/j.ajpath.2021.06.005
• Publication Date: 2021-06-29T08:56:07Z
• Authors: Mengtao Li; Eva M. McGhee; Lauryn Shinno; Kellie Lee; Yi-Ling Lin
• Keywords: Keratinocytes; Male; 0301 basic medicine; Biomedical and clinical sciences; Cell Survival; Papillomavirus E7 Proteins; Oncology and Carcinogenesis; Oropharynx; Cervical Cancer; Medical and Health Sciences; Cell Line; Mice; 03 medical and health sciences; Clinical Research; Pathology; 2.2 Factors relating to the physical environment; Animals; Viral; Dental/Oral and Craniofacial Disease; Aetiology; Cancer; Cell Line, Transformed; Cell Proliferation; Oncogene Proteins; Biomedical and Clinical Sciences; Bacteria; Cell Death; Health sciences; Regular Article; Cell Differentiation; Oncogene Proteins, Viral; Newborn; 3. Good health; Repressor Proteins; Butyrates; Infectious Diseases; Transformed; Animals, Newborn; HIV/AIDS; Sexually Transmitted Infections; Female; Infection

Human papillomavirus (HPV) is a ubiquitous human pathogen that can be cleared by host immunity. Nonetheless, a small percentage of the patients develop persistent infection with oncogenic HPV, which poses an increased risk of developing HPV-associated malignancy. Although cell-mediated immunity is a known systemic factor, local factors that influence persistent HPV infection have not been fully investigated. HPV-related head/neck cancers have a strong site preference for the oropharynx, suggesting the existence of unique local factors that promote HPV-induced oncogenesis. The human oropharynx often harbors anaerobic bacteria that produce a variety of byproducts, including butyrate. Because butyrate is a potent epigenetic modulator, it could be an environmental factor influencing the development of HPV-positive oropharyngeal malignancy. In this study, we showed that butyrate treatment changed the property of HPV16 E6/E7-immortalized keratinocytes. In vitro, the treatment increased the cells' migration ability, slowed the growth, and increased the genotoxic resistance. When implanted in the syngeneic mice, the treated keratinocytes survived longer and exhibited a different growth pattern. The survival advantage obtained after butyrate exposure may increase the susceptibility of HPV-infected oropharyngeal keratinocytes to further malignant transformation. These results suggest that fermentation products of tonsillar bacteria may play an important role in the long-term persistence of high-risk HPV infection, which is a critical risk factor for developing HPV-positive oropharyngeal malignancy.