Tristetraprolin expression by keratinocytes protects against skin carcinogenesis

Cancer is caused primarily by somatic mutations of proto-oncogenes, leading to deregulation of gene regulatory circuits in key growth, apoptosis or DNA repair pathways. Multiple genes associated with the initiation and development of tumors are also regulated at the level of mRNA decay, through the recruitment of RNA binding proteins to AU-rich elements (AREs) located in their 3'-untranslated regions. One of these ARE-binding proteins, tristetraprolin (TTP, encoded by Zfp36) is consistently dysregulated in many human malignancies. Herein, using regulated overexpression or conditional ablation in the context of chemical cutaneous carcinogenesis, we show that TTP represents a critical regulator of skin tumorigenesis. We provide evidence that TTP controls both tumor-associated inflammation and key oncogenic pathways in malignant epidermal cells. We identify Areg as a direct target of TTP in keratinocytes, and show that EGFR signaling contributes to exacerbated tumor formation. We conclude that TTP expression by epidermal cells plays a major role in the control of early steps leading to tumorigenesis. Overall design: 18 mouse samples: 3 cell types (Mock/Treated/Tumoral keratinocytes) x 2 conditions (Zfp36 ?K14/Zfp36 fl/fl) x 3 replicates