TTP as Tumor Suppressor and Inflammatory Regulator in Oral Carcinogenesis.

Abstract

The stability of messenger RNA (mRNA) is controlled by proteins that bind to adenosine-uridine-rich sequences (AREs) in their 3' untranslated regions (3'UTR), known as AU-binding proteins. One of these proteins is tristetraprolin (TTP; encoded by Zfp36), which promotes degradation of mRNAs with AREs in their 3'UTR. TTP accelerates the decay of its target transcripts, many of which encode proinflammatory mediators that promote tumorigenesis. TTP underexpression has been reported in multiple cancer types. Oral squamous cell carcinoma is an aggressive disease characterized by high morbidity and few therapeutic options. The role of TTP has not been studied in oral epithelium homeostasis nor in its carcinogenesis. Herein, using tissue-specific TTP knockout mice (TTP-KO), we show that TTP expression is relevant for oral epithelium homeostasis. TTP-KO mice developed dysplastic lesions in the tongue along with inflammatory infiltrates in the connective tissue. Analysis of the inflammatory infiltrate revealed the presence of mast cells (MCs), CD45+ cells, and CD11b+ cells, with the MCs being the most abundant cell type and associated with cyclooxygenase-2 expression. Recruitment of MCs was dependent on tumor necrosis factor-α (TNFα) upon TTP ablation in the tongue. Although the infiltration of MCs was dependent on TNFα activity, this did not affect the development of tongue dysplasia. We analyzed the status of the NF-κB pathway, finding its activation. In addition, we demonstrate that K-ras activation combined with Zfp36 deletion leads to the rapid onset of the oral tongue phenotype and significantly reduces mouse survival. Our results support the notion that TTP expression protects against oral carcinogenesis, regulates the inflammatory infiltrate, and maintains the epithelial microenvironment, potentially serving as a barrier to tumorigenesis.