TNFa blockade increases survival of mice displaying premalignant lesions induced by TTP ablation and K-ras activation in the tongue

DARIO FERRI ; MARINA AYRE; LIZETH ARIZA BAREÑO; VALERIA SÁNCHEZ ; ALEJANDRO J. URTREGER; MARIA LUISA PAPARELLA; EDITH C. KORDON; ANA ROSA RAIMONDI

Mar del Plata

Congreso; LXVII Reunión Científica de la Sociedad Argentina de Investigación Clínica (SAIC); 2022

Sociedad Argentina de Investigación Clínica (SAIC)

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth mostcommon cancer worldwide, being tongue SCC the most common malignancyfound in the oral cavity. Tristetraprolin (TTP) is a RNA binding protein that binds totarget mRNA and destabilizes it, reducing protein expression. TTP has the ability toregulate proinflammatory mediators such as TNFα and IL6 that promotetumorigenesis. Previously, we have characterized a mouse model where TTP isablated in the oral cavity (TTP KO: K14-CreERTAM/TTPflox/flox). These micedeveloped mild dysplastic lesions in the tongue over time along with inflammatoryinfiltrate in the connective tissue (mast cells and CD11b cells). Besides, weanalyzed the status of the NFkB pathway and we found increased levels of p65and p-p65. Furthermore, we generated K14-CreERtam/TTP-/-/K-rasG12D+/- animals(compound mice) that exhibited a complete oral phenotype and presented asignificant reduction in survival time. Here, to asses the mechanism underlyingthe development of the mentioned lesions together with the inflammatoryinfiltrate we tested the role of TNFα in this model. We treated TTP KO andcompound mice with a TNFα decoy receptor (Etanercept: 0.01mg/g of body weight,3 times a week during 2 months and 2-3 weeks respectively). Etanercept treatmentreduced 37% mast cells infiltration in TTP-KO mice vs untreated control group(TB+/mm2, p