Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4.
Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1-deficient (Casp1(-/-)) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1-deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.
Department of Immunobiology, Section of Comparative Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Bo
B
Hu
Eran
E
Elinav
Samuel
S
Huber
Carmen J
CJ
Booth
Till
T
Strowig
Chengcheng
C
Jin
Stephanie C
SC
Eisenbarth
Richard A
RA
Flavell
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; D016264:Dextran Sulfate; D020170:Caspase 1