OVEREXPRESSION OF HPV-16 E6/E7 PRODUCES DYSPLASTIC EPITHELIAL CHANGES IN THE ORAL TONGUE IN A CONDITIONAL TRANSGENIC MOUSE MODEL.

AYRE M.; DI GAUDIO A.; GONZALO FERNANDEZ UGAZIO; COSO O A; ANA R RAIMONDI

Mar del Plata

Congreso; Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2023

Sociedad Argentina de Investigacion Clinica

Oral squamous-cell carcinomas (OSCC) is a heterogeneous group of tumors involving distinct anatomical sites with varying etiological factors including smoking as well as infection with high risk human papilloma viruses (HPV-16 and 18). Incidences of HPV-associated anal SCC and OSCC have raised, particularly oropharyngeal SCC. Previously, we have established and validated specific HPV-16 E6/E7 genetically engineered mouse model to study HPV related carcinogenesis by crossing the driver line K14CreERTAM with a Rosa26-rtTA-IRES-EGFP-rtTAflox/Tet-E6/E7 bi-transgenic line (E6/E7 mice). In this model expression is achieved, in a Cre-dependent manner, after doxycycline (DOX) administration. Here, we study the oral phenotype in order to characterize the impact of E6/E7 overexpression in the oral mucosa. Up to 2 months after induction of the system, E6/E7 mice (N=8) and their control littermates (N=8) did not present any overt phenotype and had no significant differences in survival time. However, histological evaluation revealed hyperplasia, acanthosis and increased proliferative activity in the basal layers of the tongue epithelium (80%, 4/5) and one case of mild dysplasia (20%, 1/5). DOX withdrawal reverts the above mentioned phenotype (100%, 3/3). After 4 months of E6/E7 overexpression the transgenic tongue developed dysplastic changes (100%, 5/5) which ranged from mild to moderate. The dysplastic areas showed increased Keratin 14 expression. Since mTOR activation is a widespread feature of OSCC we studied pS6 expression, downstream target of the PI3K/Akt/mTOR pathway. E6/E7 tongues (2 months) did not present differences versus control however dysplastic areas of tongues from 4 months showed increased expression of pS6. We conclude that lingual epithelium was susceptible to a prolonged overexpression of E6/E7. These results warrant further analysis in order to understand the possible role of PI3K/Akt/mTOR pathway in the development of these E6/E7 premalignant lesions.