title: Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice.
abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding β-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of β-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic β-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by β-catenin and activation of the NF-κB pathway. This led to a specific inflammatory response, the intensity of which determined the degree of tumor aggressiveness. The chemokine-like chemotactic factor leukocyte cell-derived chemotaxin 2 (LECT2) and invariant NKT (iNKT) cells were identified as key interconnected effectors of liver β-catenin-induced inflammation. In genetic deletion models lacking the gene encoding LECT2 or iNKT cells, hepatic β-catenin signaling triggered the formation of highly malignant HCCs with lung metastasis. Thus, our results identify inflammation as a key player in β-catenin-induced liver tumorigenesis. We provide strong evidence that, by activating pro- and antiinflammatory mediators, β-catenin signaling produces an inflammatory microenvironment that has an impact on tumoral development. Our data are consistent with the fact that most β-catenin-activated HCCs are of better prognosis.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France. 2CNRS, UMR8104, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Anson
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Crain-Denoyelle
authors.forename: Véronique
authors.initials: V
authors.lastname: Baud
authors.forename: Fanny
authors.initials: F
authors.lastname: Chereau
authors.forename: Angélique
authors.initials: A
authors.lastname: Gougelet
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamagoe
authors.forename: Sabine
authors.initials: S
authors.lastname: Colnot
authors.forename: Mireille
authors.initials: M
authors.lastname: Viguier
authors.forename: Christine
authors.initials: C
authors.lastname: Perret
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Couty
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology*; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051176:beta Catenin / Q000235:genetics* / Q000276:immunology*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D036341:Intercellular Signaling Peptides and Proteins; C491213:Lect2 protein, mouse; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051176:beta Catenin