title: Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6.
abstract: M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75 mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12 weeks significantly decreased colon cancer incidence, multiplicity and tumor size by 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE2 and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE2/PPARδ and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE2 or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis-associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE2 and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer.
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Liver, Biliary And Pancreatic Tumors, Hubei Cancer Hospital, Wuhan 430079, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Zunqiong
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Tang
authors.affiliation: Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Chai
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China; Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States.
authors.forename: Austin M
authors.initials: AM
authors.lastname: Guo
authors.affiliation: Department of Pathology and Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071, China. Electronic address: hl-chen@whu.edu.cn.
authors.forename: Honglei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China. Electronic address: yangjingliu2013@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D003092:Colitis / Q000150:complications / Q000473:pathology*; D003106:Colon / Q000166:cytology / Q000187:drug effects; D003110:Colonic Neoplasms / Q000517:prevention & control*; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006035:Glycyrrhiza / Q000737:chemistry*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D000093242:Interleukin-6 Inhibitors
chemical_list: D047188:Chalcones; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C494087:Stat3 protein, mouse; C040920:isoliquiritigenin
keywords: COX-2; Colitis-associated tumorigenesis; IL-6; Inflammation; Isoliquiritigenin; Macrophage