Loss of tristetraprolin (TTP) promotes development of dysplastic lesions in tongue epithelium

FERRI D; ANA R RAIMONDI; VEGGETTI M; STEDILE M N; KORDON E

Mar del Plata

Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2016

Sociedad Argentina de Investigación Clínica

Oral squamous cell carcinoma (OSCC) constitutesthe sixth leading cause of cancer worldwide. The early events in OSCCcarcinogenesis have been less studied and still poorly understood. In thisregard, a common feature amongrelevant RNAs of OSCC and other types of cancer is the presence of regionsenriched in adenine and uracil (AREs) situated in 3´untranslated regions(3´UTR). The stability of RNAs with AREs is regulated by a group of proteinscalled AUBPs (ARE ? binding proteins) which bind these regions. Here we focusedon a particular AUBP, tristetraprolin (TTP). This protein promotes degradationof mRNAs with AREs in their 3´UTR. Recently, expression of TTP has beenreported diminished in cell lines and biopsies of OSCC.  Consideringthis background, we hypothesize that lack of TTP in basal tongue cells producestissue abnormalities associated to early carcinogenesis events. To test thishypothesis, we generated double transgenic mice in a tissue ? specific andconditional manner (K14-CreERtam/TTPloxP+/+ = TTP KO). Tongue tissue from these mice wasused to study proliferation and differentiation markers by immunohistochemistry. During the evaluation period (8 months) micewere healthy. However, we found a significant decrease in transgenic miceweight compared with wild type mice (p< 0, 01). Histologic analysisof TTP-KO tongues revealed moderate dysplastic areas which exhibited chronicinflammation with infiltrated macrophages and increased vascularization.Immunohistochemistry of epithelial TTP ? KO tongue showed an abnormal expressionof PCNA (proliferation marker) and deregulated expression of cytokeratins 1, 6and 14 (differentiation markers). Particularly, PCNA and cytokeratin 14 werefound in suprabasal layers, which are typically expressed in the basal layerof   normal tissue.  We conclude that lack of TTP is sufficient toderegulate proliferation and differentiation in tongue epithelium and contributesto progressive accumulation of dysplastic changes.