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Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.

Identifieur interne : 001A32 ( PubMed/Corpus ); précédent : 001A31; suivant : 001A33

Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.

Auteurs : Chris Planque ; Fatemeh Rajabi ; Fanny Grillet ; Pascal Finetti ; François Bertucci ; Meritxell Gironella ; Juan José Lozano ; Bertrand Beucher ; Julie Giraud ; Véronique Garambois ; Charles Vincent ; Daniel Brown ; Ludovic Caillo ; Jovana Kantar ; André Pelegrin ; Michel Prudhomme ; Jérémie Ripoche ; Jean François Bourgaux ; Christophe Ginestier ; Antoni Castells ; Frédéric Hollande ; Julie Pannequin ; Jean Marc Pascussi

Source :

RBID : pubmed:27448961

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.

DOI: 10.18632/oncotarget.10646
PubMed: 27448961

Links to Exploration step

pubmed:27448961

Le document en format XML

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<nlm:affiliation>Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.</nlm:affiliation>
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<name sortKey="Brown, Daniel" sort="Brown, Daniel" uniqKey="Brown D" first="Daniel" last="Brown">Daniel Brown</name>
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<nlm:affiliation>Department of Pathology, University of Melbourne, Parkville, Australia.</nlm:affiliation>
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<name sortKey="Caillo, Ludovic" sort="Caillo, Ludovic" uniqKey="Caillo L" first="Ludovic" last="Caillo">Ludovic Caillo</name>
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<nlm:affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</nlm:affiliation>
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<name sortKey="Kantar, Jovana" sort="Kantar, Jovana" uniqKey="Kantar J" first="Jovana" last="Kantar">Jovana Kantar</name>
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<nlm:affiliation>Laboratoire de Biochimie, CHU Carémeau, Nîmes, France.</nlm:affiliation>
</affiliation>
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<name sortKey="Pelegrin, Andre" sort="Pelegrin, Andre" uniqKey="Pelegrin A" first="André" last="Pelegrin">André Pelegrin</name>
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<nlm:affiliation>Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.</nlm:affiliation>
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<name sortKey="Prudhomme, Michel" sort="Prudhomme, Michel" uniqKey="Prudhomme M" first="Michel" last="Prudhomme">Michel Prudhomme</name>
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<nlm:affiliation>Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.</nlm:affiliation>
</affiliation>
</author>
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<name sortKey="Ripoche, Jeremie" sort="Ripoche, Jeremie" uniqKey="Ripoche J" first="Jérémie" last="Ripoche">Jérémie Ripoche</name>
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<nlm:affiliation>Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.</nlm:affiliation>
</affiliation>
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<name sortKey="Bourgaux, Jean Francois" sort="Bourgaux, Jean Francois" uniqKey="Bourgaux J" first="Jean François" last="Bourgaux">Jean François Bourgaux</name>
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<nlm:affiliation>Service d'Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France.</nlm:affiliation>
</affiliation>
</author>
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</affiliation>
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<name sortKey="Castells, Antoni" sort="Castells, Antoni" uniqKey="Castells A" first="Antoni" last="Castells">Antoni Castells</name>
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<div type="abstract" xml:lang="en">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.</div>
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<AffiliationInfo>
<Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
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