Oncotarget

Research Papers:

IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin

Denada Dibra, Abhisek Mitra, Melissa Newman, Xueqing Xia, Camille Keenan, Jeffry J. Cutrera, J. Michael Mathis, Xiao-Jing Wang, Jeffrey Myers and Shulin Li _

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Oncotarget. 2016; 7:77138-77151. https://doi.org/10.18632/oncotarget.12581

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Abstract

Denada Dibra1, Abhisek Mitra1, Melissa Newman2, Xueqing Xia1, Camille Keenan3, Jeffry J. Cutrera1, J. Michael Mathis4, Xiao-Jing Wang5, Jeffrey Myers6, Shulin Li1

1Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2Banfield Pet Hospital, Sugar Land, TX 77479, USA

3The University of Texas Health Science Center at Houston, Medical School, Houston, TX 77030, USA

4Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA

5Department of Pathology, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA

6Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Correspondence to:

Shulin Li, email: [email protected]

Denada Dibra, email: [email protected]

Keywords: ET1/ETAR, IL27, IL27RA, KRAS, inflammation

Received: December 14, 2015    Accepted: September 02, 2016    Published: October 12, 2016

ABSTRACT

Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b-/- mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin—a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas.


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