NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-κB signaling.
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.
Department of Biological Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA.
Sheryl
S
Coutermarsh-Ott
Department of Biological Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA.
Alysha
A
Simmons
Department of Biological Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA.
Vittoria
V
Capria
Department of Biological Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA.
Tanya
T
LeRoith
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Justin E
JE
Wilson
Department of Biological Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA.
Bettina
B
Heid
Virginia Tech, Virginia Bioinformatics Institute, Nutritional Immunology and Molecular Medicine Laboratory, Blacksburg, VA, USA.
Casandra W
CW
Philipson
Department of Biological Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA.
Qizhi
Q
Qin
Virginia Tech, Virginia Bioinformatics Institute, Nutritional Immunology and Molecular Medicine Laboratory, Blacksburg, VA, USA.
Raquel
R
Hontecillas-Magarzo
Virginia Tech, Virginia Bioinformatics Institute, Nutritional Immunology and Molecular Medicine Laboratory, Blacksburg, VA, USA.
Josep
J
Bassaganya-Riera
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Jenny P-Y
JP
Ting
Department of Small Animal Clinical Sciences, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA.
Nikolaos
N
Dervisis
Department of Biological Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA.
Irving C
IC
Allen
D000818:Animals; D063646:Carcinogenesis; D004195:Disease Models, Animal; D005260:Female; D054747:Histiocytic Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D024101:Mitochondrial Proteins; D016328:NF-kappa B; C527006:NLRX1 protein, human; C555655:NLRX1 protein, mouse
NLR; Nod-like receptor; cancer; inflammation; urethane