title: ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice.
abstract: The aryl hydrocarbon receptor (AhR) plays a suppressive role in cecal carcinogenesis by CUL4B/AhR-mediated ubiquitylation and degradation of β-catenin, which is activated by xenobiotics and natural ligands. AhR-deficient (AhR(-)(/-)) mice develop cecal tumors with severe inflammation. To elucidate whether the tumors develop autonomously in AhR(-/-) mice due to impaired β-catenin degradation or in association with accelerated inflammation, we performed two kinds of experiments using germ-free (GF) AhR(-/-) mice and compound mutant mice lacking genes for AhR and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which plays an essential role in caspase-1 activation in inflammasomes. Both GF AhR(-/-) and AhR(-/-)•ASC(-/-) mice showed considerably reduced tumor development compared with that in AhR(-/-) mice albeit in a 'cancer-prone' state with aberrant β-catenin accumulation. Blocking of the interleukin (IL)-1β signaling pathway by treatment with a caspase-1 inhibitor, YVAD, reduced cecal tumorigenesis in AhR(-/-) mice. Signal transducers and activators of transcription 3 (STAT3) activation was detected in the cecal epithelium of the AhR(-/-) mice due to enhanced IL-6 production. An inhibitor of the STAT3 signaling pathway, AG490 suppressed the tumor formation. ASC-mediated inflammation was also found to play a critical role in tumor development in Apc(Min/+) mice, a mouse model of familial adenomatous polyposis. Collectively, these results revealed an important role of the bacteria-triggered or ASC-mediated inflammation signaling pathway in the intestinal tumorigenesis of mice and suggest a possible chemical therapeutic intervention, including AhR ligands and inhibitors of the inflammation pathway.
authors: Department of Cancer Prevention, Research Institute for Clinical Oncology, 818 Komuro, Ina, Saitama 362–0806, Japan.
authors: Togo
authors: T
authors: Ikuta
authors: Yasuhito
authors: Y
authors: Kobayashi
authors: Masato
authors: M
authors: Kitazawa
authors: Kazuhiro
authors: K
authors: Shiizaki
authors: Naoki
authors: N
authors: Itano
authors: Tetsuo
authors: T
authors: Noda
authors: Sven
authors: S
authors: Pettersson
authors: Lorenz
authors: L
authors: Poellinger
authors: Yoshiaki
authors: Y
authors: Fujii-Kuriyama
authors: Shun'ichiro
authors: S
authors: Taniguchi
authors: Kaname
authors: K
authors: Kawajiri
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000276:immunology / Q000473:pathology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002430:Cecal Neoplasms / Q000276:immunology / Q000473:pathology*; D002460:Cell Line; D004789:Enzyme Activation; D005260:Female; D005856:Germ-Free Life; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020239:Receptor Cross-Talk; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D051176:beta Catenin / Q000276:immunology / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D051792:Basic Helix-Loop-Helix Proteins; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1; D061945:Caspase Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; D051176:beta Catenin; C484722:Ahr protein, mouse; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; C494087:Stat3 protein, mouse; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C577686:interleukin-6, mouse