Oncotarget

Research Papers:

SOX9 is an atypical intestinal tumor suppressor controlling the oncogenic Wnt/ß-catenin signaling

Corinne Prévostel, Cyrine Rammah-Bouazza, Hélène Trauchessec, Lucile Canterel-Thouennon, Muriel Busson, Marc Ychou and Philippe Blache _

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Oncotarget. 2016; 7:82228-82243. https://doi.org/10.18632/oncotarget.10573

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Abstract

Corinne Prévostel1,2,3,4, Cyrine Rammah-Bouazza5, Hélène Trauchessec5, Lucile Canterel-Thouennon1,2,3,4, Muriel Busson1,2,3,4, Marc Ychou1,2,3,4,6,7, Philippe Blache1,2,3,4

1IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France

2INSERM, U1194, Montpellier, France

3Université de Montpellier, Montpellier, France

4Institut régional du Cancer de Montpellier, Montpellier, France

5Université de Montpellier, UMR 5237, Centre de Recherche de Biochimie Macromoléculaire, CNRS, Montpellier, France

6Centre Hospitalier Régional Universitaire (CHU) de Montpellier, Montpellier, France

7Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France

Correspondence to:

Corinne Prévostel, email: corinne.prevostel@inserm.fr

Philippe Blache, email: philippe.blache@inserm.fr

Keywords: SOX9, colorectal cancer, tumor suppressor, Wnt/ß-catenin inhibition, c-myc inhibition

Received: December 09, 2015     Accepted: June 26, 2016     Published: July 13, 2016

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.


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