LOSS OF TRISTETRAPROLIN (TTP) PROMOTES DEVELOPMENT OF DYSPLASTIC LESIONS IN TONGUE EPITHELIUM

MICAELA STEDILE; DARÍO FERRI; MARIELA VEGGETTI; EDITH C. KORDON; ANA RAIMONDI

Congreso; LXI Reunión Anual SAIC; 2016

Oral squamous cell carcinoma (OSCC) constitutes the sixthleading cause of cancer worldwide. The early events in carcinogenesis have been less studied and still poorly understood.In this regard, a common feature among relevant RNAs of OSCCand other types of cancer is the presence of regions enrichedin adenine and uracil (AREs) situated in 3´untranslated regions(3´UTR). The stability of RNAs with AREs is regulated by a groupof proteins called AUBPs (ARE ? binding proteins) which bindthese regions. Here we focused on a particular AUBP, tristetraprolin(TTP). This protein promotes degradation of mRNAs with AREsin their 3´UTR. Recently, expression of TTP has been reporteddiminished in cell lines and biopsies of OSCC. Considering thisbackground, we hypothesize that lack of TTP in basal tongue cellsproduces tissue abnormalities associated to early carcinogenesisevents. To test this hypothesis, we generated double transgenicmice in a tissue ? specific and conditional manner (K14-CreERtam/TTPloxP+/+ = TTP KO). Tongue tissue from these mice was usedto study proliferation and differentiation markers by immunohistochemistry.During the evaluation period (8 months) mice werehealthy. However, we found a significant decrease in transgenicmice weight compared with wild type mice (p< 0, 01). Histologicanalysis of TTP-KO tongues revealed moderate dysplastic areaswhich exhibited chronic inflammation with infiltrated macrophagesand increased vascularization. Immunohistochemistry of epithelialTTP ? KO tongue showed an abnormal expression of PCNA (proliferationmarker) and deregulated expression of cytokeratins 1, 6and 14 (differentiation markers). Particularly, PCNA and cytokeratin14 were found in suprabasal layers, which are typically expressedin the basal layer of normal tissue. We conclude that lack ofTTP is sufficient to deregulate proliferation and differentiation intongue epithelium and contributes to progressive accumulation ofdysplastic changes.