title: Concerted actions of ameliorated colitis, aberrant crypt foci inhibition and 15-hydroxyprostaglandin dehydrogenase induction by sonic hedgehog inhibitor led to prevention of colitis-associated cancer.
abstract: The sonic hedgehog (Shh) signaling has been known to contribute to carcinogenesis in organ, where hedgehog exerted organogenesis and in cancers, which are developed based on mutagenic inflammation. Therefore, colitis-associated cancer (CAC) can be a good model to prove whether Shh inhibitors can be applied to prevent, as the efforts to discover potent anti-inflammatory agent are active to prevent CAC. Here, under the hypothesis that Shh inhibitors can prevent CAC, mouse model was generated to develop CAC by azoxymethane (AOM)-initiated, dextran sodium sulfate-promoted carcinogenesis. Shh inhibitors, cerulenin and itraconazole were treated by oral gavage and the mice were sacrificed at early phase of 3 weeks and late phase of 16 weeks. Compared to control group, the number of aberrant crypt foci at 3 weeks and tumor incidence at 16 weeks were all significantly decreased with Shh inhibitor. Significant attenuations of macrophage infiltration accompanied with significant decreases of IL-6, COX-2, STAT3 and NF-κB as well as significant ameliorations of β-catenin nuclear translocation, cyclin D1 and CDK4 were imposed with Shh inhibitors. Especially, CAC was accompanied with significant cancellation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), but their levels were significantly preserved with Shh inhibitors. Among inflammatory mediators, significantly decreased levels of IL-6 and TNF-α, regulated with repressed NF-κb and STAT3, were prominent with Shh inhibitor, whereas significant inductions of apoptosis were noted with Shh inhibitors. In conclusion, Shh inhibitors significantly prevented CAC covering either ameliorating oncogenic inflammation or suppressing tumor proliferation, especially supported with significant inhibition of IL-6 and STAT3 signaling, 15-PGDH preservation and apoptosis induction.
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, South Korea.|Department of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand.
authors.forename: Napapan
authors.initials: N
authors.lastname: Kangwan
authors.affiliation: Department of Gastroenterology, Gachon University Gil Medical Center, Incheon, South Korea.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, South Korea.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Han
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, South Korea.
authors.forename: Migyeong
authors.initials: M
authors.lastname: Jeong
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, South Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, South Korea.|Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, South Korea.
authors.forename: Ki-Baik
authors.initials: KB
authors.lastname: Hahm
mesh_terms: D058739:Aberrant Crypt Foci / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D053823:Hedgehog Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D051176:beta Catenin; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2
keywords: 15-PGDH; ACF; Shh inhibitor; cancer prevention; colitis-associated cancer; sonic hedgehog