title: SOX9 is an atypical intestinal tumor suppressor controlling the oncogenic Wnt/ß-catenin signaling.
abstract: SOX9 inactivation is frequent in colorectal cancer (CRC) due to SOX9 gene mutations and/or to ectopic expression of MiniSOX9, a dominant negative inhibitor of SOX9. In the present study, we report a heterozygous L142P inactivating mutation of SOX9 in the DLD-1 CRC cell line and we demonstrate that the conditional expression of a wild type SOX9 in this cell line inhibits cell growth, clonal capacity and colonosphere formation while decreasing both the activity of the oncogenic Wnt/ß-catenin signaling pathway and the expression of the c-myc oncogene. This activity does not require SOX9 transcriptional function but, rather, involves an interaction of SOX9 with nuclear ß-catenin. Furthermore, we report that SOX9 inhibits tumor development when conditionally expressed in CRC cells injected either subcutaneous or intraperitoneous in BALB/c mice as an abdominal metastasis model. These observations argue in favor of a tumor suppressor activity for SOX9. As an siRNA targeting SOX9 paradoxically also inhibits DLD-1 and HCT116 CRC cell growth, we conclude that there is a critical level of endogenous active SOX9 needed to maintain CRC cell growth.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Institut régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Prévostel
authors.affiliation: Université de Montpellier, UMR 5237, Centre de Recherche de Biochimie Macromoléculaire, CNRS, Montpellier, France.
authors.forename: Cyrine
authors.initials: C
authors.lastname: Rammah-Bouazza
authors.affiliation: Université de Montpellier, UMR 5237, Centre de Recherche de Biochimie Macromoléculaire, CNRS, Montpellier, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Trauchessec
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Institut régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Canterel-Thouennon
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Institut régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Busson
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Institut régional du Cancer de Montpellier, Montpellier, France.|Centre Hospitalier Régional Universitaire (CHU) de Montpellier, Montpellier, France.|Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Ychou
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Institut régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Blache
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006579:Heterozygote; D006801:Humans; D008807:Mice, Inbred BALB C; D009154:Mutation; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000556:secondary; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D051176:beta Catenin
keywords: SOX9; Wnt/ß-catenin inhibition; c-myc inhibition; colorectal cancer; tumor suppressor