Tristetraprolin expression by keratinocytes protects against skin carcinogenesis.

Assiya Assabban,Wenqian Hu,Brittany L Snyder,Perry J Blackshear,Maxime Melchior,Séverine Thomas,Rosalba Salcedo,Abdulkader Azouz,Cyril Gueydan,Giorgio Trinchieri,Gaëlle Lapouge,Bérengère De Toeuf,Stanislas Goriely,Cédric Blanpain,Laurye Van Maele,Véronique Kruys,Caroline La,Muriel Nguyen,Ingrid Dubois-Vedrenne,Shu Fen Wu ,Long Zhou

doi:10.1172/jci.insight.140669

Abstract

Cancer is caused primarily by genomic alterations resulting in 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 cutaneous chemical carcinogenesis, we show that TTP represents a critical regulator of skin tumorigenesis. We provide evidence that TTP controlled both tumor-associated inflammation and key oncogenic pathways in neoplastic epidermal cells. We identify Areg as a direct target of TTP in keratinocytes and show that EGFR signaling potentially contributed to exacerbated tumor formation. Finally, single-cell RNA-Seq analysis indicated that ZFP36 was downregulated in human malignant keratinocytes. We conclude that TTP expression by epidermal cells played a major role in the control of skin tumorigenesis.

Highlights

Tumors arise when gene regulatory circuits in key growth, apoptosis, or DNA repair pathways are dysregulated
We show here that TTP played a major role in the pathogenesis of skin carcinogenesis
When its regulated expression was increased throughout the body by genetically removing the AU-rich elements (AREs) instability elements that are located in its own mRNA 3′UTR (Zfp36ΔARE knockin mice), DMBA/TPA-induced tumor burden was greatly reduced

Summary

Introduction

Tumors arise when gene regulatory circuits in key growth, apoptosis, or DNA repair pathways are dysregulated. Oncogenic events, such as mutations in protooncogenes, can radically affect cell physiology through downstream effects on gene expression, for example, by aberrant activation of transcription factors. Up to 10% of mammalian mRNAs harbor AU-rich elements (AREs) in their 3′-untranslated regions, allowing the recruitment of RNA-binding proteins that control their turnover and subcellular localization. One of these ARE-binding proteins is tristetraprolin (TTP; encoded by ZFP36).

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Conclusion