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PMID: 21118981 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 107 ·No. 50 ·2010-12-14 ·Pages 21635-40

Hu B, Elinav E, Huber S, Booth CJ, Strowig T, Jin C, Eisenbarth SC, Flavell RA

Abstract

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.

MeSH Terms
Animals Apoptosis Regulatory Proteins/genetics,metabolism Calcium-Binding Proteins/genetics,metabolism Caspase 1/genetics,metabolism Colitis/chemically induced,metabolism,pathology Colon/metabolism,pathology Colonic Neoplasms/metabolism,pathology Dextran Sulfate/adverse effects Humans Inflammation/metabolism,pathology Mice Mice, Inbred C57BL Mice, Knockout
Chemicals
Apoptosis Regulatory Proteins Calcium-Binding Proteins Ipaf protein, mouse Dextran Sulfate Caspase 1
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Hu Bo
Department of Immunobiology, Section of Comparative Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Elinav Eran
Huber Samuel
Booth Carmen J
Strowig Till
Jin Chengcheng
Eisenbarth Stephanie C
Flavell Richard A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1016814108
Published
2010-12-14
Epub
2010-00-30
Pages
21635-40
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3003083
Subset
IM
Grants
NHLBI NIH HHS · T32 HL007974 · United States
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · T32HL007974 · United States
External Links
PubMed source DOI: 10.1073/pnas.1016814108 PMC Full Text View journal details
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