Research Papers:
Pregnane Xreceptor promotes stem cellmediated colon cancer relapse
PDF | Full Text | How to cite
Chris Planque1,2,3,*, Fatemeh Rajabi1,2,3,*, Fanny Grillet1,2,3, Pascal Finetti4, François Bertucci4, Meritxell Gironella5, Juan José Lozano5, Bertrand Beucher1,2,3, Julie Giraud1,2,3, Véronique Garambois6, Charles Vincent6, Daniel Brown7, Ludovic Caillo1,2,3, Jovana Kantar8, André Pelegrin6, Michel Prudhomme9, Jérémie Ripoche9, Jean François Bourgaux10, Christophe Ginestier11, Antoni Castells5, Frédéric Hollande1,2,3,7,#, Julie Pannequin1,2,3,#, Jean Marc Pascussi1,2,3,#
1CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France
2INSERM U1191, Montpellier, France
3Université Montpellier, Montpellier, France
4Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Marseille, France
5Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
6Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
7Department of Pathology, University of Melbourne, Parkville, Australia
8Laboratoire de Biochimie, CHU Carémeau, Nîmes, France
9Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France
10Service d’Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France
11Centre de Recherche en Cancérologie de Marseille, U1068 Inserm, Marseille, France
*These authors have contributed equally to this work
#These authors jointly supervised the work
Correspondence to:
Frédéric Hollande, email: [email protected]
Jean Marc Pascussi, email: [email protected]
Keywords: PXR, colorectal cancer, cancer stem cell, tumor recurrence
Received: March 23, 2016 Accepted: May 29, 2016 Published: July 18, 2016
ABSTRACT
Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy.