IMPACT OF HPV-16 E6/E7 SELECTIVE OVEREXPRESSION IN THE ANAL SQUAMOUS EPITHELIA OVER THE ANAL CARCINOGENESIS.

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

Buenos Aires

Congreso; Reunion Anual de la Sociedad de Biociencias 2021; 2021

Anal SCC is a rare malignancy of the lower gastrointestinal tract. However, it is one of the most common reported malignancy among people with HIV infection. Moreover, infection with human papillomavirus (HPV) has been demonstrated to be the primary causative agent in the development of SCC of the anogenital tract, including other cancers. HPV infection has been reported to be associated with 75% to 90% of anal SCC. The exact pathogenesis of anal SCC remains unknown. Previously, we have validated the K14CreERTAM driver mouse line to target the anal mucosa. Aimed to selectively explore the role of HPV-related oncoproteins in anal carcinogenesis, without HPV virus infection, we developed a specific HPV-16 E6/E7 genetically engineered mouse model (GEMM) by crossing the K14CreERTAM mice with the linker line Rosa26-rtTA-IRES-EGFP-rtTAflox and then with Tet-E6/E7 mice (E6/E7-GEM). In this model expression is achieved, in a Cre-dependent manner, only after doxycycline (DOX) administration. Up to 2 months after induction of the system E6/E7-GEM (N=8) and their control littermates (N=8) did not present any overt phenotype without significant differences in survival. However, histological evaluation revealed an abnormal anal epithelium as well as tongue and vaginal mucosa changes. The anal epithelium developed hyperplasia with hyperorthokeratosis, acanthosis and increased proliferative activity in the basal layers. DOX withdrawal reverts the above mentioned proliferative phenotype. Also, we confirmed the expression of EGFP specifically in the anal mucosa targeted by this system upon tamoxifen treatment as well as E6 expression by immunohistochemistry in E6/E7-GEM. In addition, the increase in basal proliferation was confirmed through labeling with bromodeoxyuridine. We conclude that this GEMM can be further combined with pathway-specific manipulations to unveil the contribution of different regulatory elements involved in the anal carcinogenesis.