NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling
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Sheryl Coutermarsh-Ott1, Alysha Simmons1, Vittoria Capria1, Tanya LeRoith1, Justin E. Wilson2, Bettina Heid1, Casandra W. Philipson3, Qizhi Qin1, Raquel Hontecillas-Magarzo3, Josep Bassaganya-Riera3, Jenny P-Y Ting2, Nikolaos Dervisis4, Irving C. Allen1
1Department of Biological Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA
2Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
3Virginia Tech, Virginia Bioinformatics Institute, Nutritional Immunology and Molecular Medicine Laboratory, Blacksburg, VA, USA
4Department of Small Animal Clinical Sciences, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA
Irving C. Allen, e-mail: [email protected]
Keywords: NLR, Nod-like receptor, urethane, cancer, inflammation
Received: September 09, 2015 Accepted: March 28, 2016 Published: April 20, 2016
Histiocytic sarcoma is an uncommon malignancy in both humans and veterinary species. Research exploring the pathogenesis of this disease is scarce; thus, diagnostic and therapeutic options for patients are limited. Recent publications have suggested a role for the NLR, NLRX1, in acting as a tumor suppressor. Based on these prior findings, we hypothesized that NLRX1 would function to inhibit tumorigenesis and thus the development of histiocytic sarcoma. To test this, we utilized Nlrx1-/- mice and a model of urethane-induced tumorigenesis. Nlrx1-/- mice exposed to urethane developed splenic histiocytic sarcoma that was associated with significant up-regulation of the NF-κB signaling pathway. Additionally, development of these tumors was also significantly associated with the increased regulation of genes associated with AKT signaling, cell death and autophagy. Together, these data show that NLRX1 suppresses tumorigenesis and reveals new genetic pathways involved in the pathobiology of histiocytic sarcoma.
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