Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.
Identifieur interne : 001A32 ( PubMed/Corpus ); précédent : 001A31; suivant : 001A33Pregnane 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 PascussiSource :
- Oncotarget [ 1949-2553 ] ; 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.
DOI: 10.18632/oncotarget.10646
PubMed: 27448961
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pubmed:27448961Le document en format XML
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<author><name sortKey="Gironella, Meritxell" sort="Gironella, Meritxell" uniqKey="Gironella M" first="Meritxell" last="Gironella">Meritxell Gironella</name>
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<author><name sortKey="Kantar, Jovana" sort="Kantar, Jovana" uniqKey="Kantar J" first="Jovana" last="Kantar">Jovana Kantar</name>
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<author><name sortKey="Ripoche, Jeremie" sort="Ripoche, Jeremie" uniqKey="Ripoche J" first="Jérémie" last="Ripoche">Jérémie Ripoche</name>
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<author><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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<author><name sortKey="Ginestier, Christophe" sort="Ginestier, Christophe" uniqKey="Ginestier C" first="Christophe" last="Ginestier">Christophe Ginestier</name>
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<author><name sortKey="Castells, Antoni" sort="Castells, Antoni" uniqKey="Castells A" first="Antoni" last="Castells">Antoni Castells</name>
<affiliation><nlm:affiliation>Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.</title>
<author><name sortKey="Planque, Chris" sort="Planque, Chris" uniqKey="Planque C" first="Chris" last="Planque">Chris Planque</name>
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<author><name sortKey="Rajabi, Fatemeh" sort="Rajabi, Fatemeh" uniqKey="Rajabi F" first="Fatemeh" last="Rajabi">Fatemeh Rajabi</name>
<affiliation><nlm:affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Grillet, Fanny" sort="Grillet, Fanny" uniqKey="Grillet F" first="Fanny" last="Grillet">Fanny Grillet</name>
<affiliation><nlm:affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Finetti, Pascal" sort="Finetti, Pascal" uniqKey="Finetti P" first="Pascal" last="Finetti">Pascal Finetti</name>
<affiliation><nlm:affiliation>Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Marseille, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Bertucci, Francois" sort="Bertucci, Francois" uniqKey="Bertucci F" first="François" last="Bertucci">François Bertucci</name>
<affiliation><nlm:affiliation>Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Marseille, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Gironella, Meritxell" sort="Gironella, Meritxell" uniqKey="Gironella M" first="Meritxell" last="Gironella">Meritxell Gironella</name>
<affiliation><nlm:affiliation>Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Lozano, Juan Jose" sort="Lozano, Juan Jose" uniqKey="Lozano J" first="Juan José" last="Lozano">Juan José Lozano</name>
<affiliation><nlm:affiliation>Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.</nlm:affiliation>
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<author><name sortKey="Giraud, Julie" sort="Giraud, Julie" uniqKey="Giraud J" first="Julie" last="Giraud">Julie Giraud</name>
<affiliation><nlm:affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Garambois, Veronique" sort="Garambois, Veronique" uniqKey="Garambois V" first="Véronique" last="Garambois">Véronique Garambois</name>
<affiliation><nlm:affiliation>Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Vincent, Charles" sort="Vincent, Charles" uniqKey="Vincent C" first="Charles" last="Vincent">Charles Vincent</name>
<affiliation><nlm:affiliation>Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Brown, Daniel" sort="Brown, Daniel" uniqKey="Brown D" first="Daniel" last="Brown">Daniel Brown</name>
<affiliation><nlm:affiliation>Department of Pathology, University of Melbourne, Parkville, Australia.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Caillo, Ludovic" sort="Caillo, Ludovic" uniqKey="Caillo L" first="Ludovic" last="Caillo">Ludovic Caillo</name>
<affiliation><nlm:affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Kantar, Jovana" sort="Kantar, Jovana" uniqKey="Kantar J" first="Jovana" last="Kantar">Jovana Kantar</name>
<affiliation><nlm:affiliation>Laboratoire de Biochimie, CHU Carémeau, Nîmes, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Pelegrin, Andre" sort="Pelegrin, Andre" uniqKey="Pelegrin A" first="André" last="Pelegrin">André Pelegrin</name>
<affiliation><nlm:affiliation>Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Prudhomme, Michel" sort="Prudhomme, Michel" uniqKey="Prudhomme M" first="Michel" last="Prudhomme">Michel Prudhomme</name>
<affiliation><nlm:affiliation>Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Ripoche, Jeremie" sort="Ripoche, Jeremie" uniqKey="Ripoche J" first="Jérémie" last="Ripoche">Jérémie Ripoche</name>
<affiliation><nlm:affiliation>Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Bourgaux, Jean Francois" sort="Bourgaux, Jean Francois" uniqKey="Bourgaux J" first="Jean François" last="Bourgaux">Jean François Bourgaux</name>
<affiliation><nlm:affiliation>Service d'Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Ginestier, Christophe" sort="Ginestier, Christophe" uniqKey="Ginestier C" first="Christophe" last="Ginestier">Christophe Ginestier</name>
<affiliation><nlm:affiliation>Centre de Recherche en Cancérologie de Marseille, U1068 Inserm, Marseille, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Castells, Antoni" sort="Castells, Antoni" uniqKey="Castells A" first="Antoni" last="Castells">Antoni Castells</name>
<affiliation><nlm:affiliation>Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
<affiliation><nlm:affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Pannequin, Julie" sort="Pannequin, Julie" uniqKey="Pannequin J" first="Julie" last="Pannequin">Julie Pannequin</name>
<affiliation><nlm:affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Pascussi, Jean Marc" sort="Pascussi, Jean Marc" uniqKey="Pascussi J" first="Jean Marc" last="Pascussi">Jean Marc Pascussi</name>
<affiliation><nlm:affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</nlm:affiliation>
</affiliation>
</author>
</analytic>
<series><title level="j">Oncotarget</title>
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<imprint><date when="2016" type="published">2016</date>
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<front><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>
</front>
</TEI>
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<DateCreated><Year>2016</Year>
<Month>07</Month>
<Day>24</Day>
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<Month>02</Month>
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<Month>Aug</Month>
<Day>30</Day>
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<Title>Oncotarget</Title>
<ISOAbbreviation>Oncotarget</ISOAbbreviation>
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<ArticleTitle>Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.</ArticleTitle>
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<Abstract><AbstractText>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.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Planque</LastName>
<ForeName>Chris</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Université Montpellier, Montpellier, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rajabi</LastName>
<ForeName>Fatemeh</ForeName>
<Initials>F</Initials>
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</AffiliationInfo>
<AffiliationInfo><Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Université Montpellier, Montpellier, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Grillet</LastName>
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<Initials>F</Initials>
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</AffiliationInfo>
<AffiliationInfo><Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Université Montpellier, Montpellier, France.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Finetti</LastName>
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<Initials>P</Initials>
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</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Bertucci</LastName>
<ForeName>François</ForeName>
<Initials>F</Initials>
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</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gironella</LastName>
<ForeName>Meritxell</ForeName>
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<AffiliationInfo><Affiliation>Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigaciones Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Lozano</LastName>
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<Initials>JJ</Initials>
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</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Beucher</LastName>
<ForeName>Bertrand</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Université Montpellier, Montpellier, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Giraud</LastName>
<ForeName>Julie</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Université Montpellier, Montpellier, France.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Garambois</LastName>
<ForeName>Véronique</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Vincent</LastName>
<ForeName>Charles</ForeName>
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<Initials>J</Initials>
<AffiliationInfo><Affiliation>Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.</Affiliation>
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<Initials>C</Initials>
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<AffiliationInfo><Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Université Montpellier, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Pathology, University of Melbourne, Parkville, Australia.</Affiliation>
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<ForeName>Julie</ForeName>
<Initials>J</Initials>
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<AffiliationInfo><Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Université Montpellier, Montpellier, France.</Affiliation>
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<AffiliationInfo><Affiliation>CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>INSERM U1191, Montpellier, France.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Université Montpellier, Montpellier, France.</Affiliation>
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<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">PXR</Keyword>
<Keyword MajorTopicYN="N">cancer stem cell</Keyword>
<Keyword MajorTopicYN="N">colorectal cancer</Keyword>
<Keyword MajorTopicYN="N">tumor recurrence</Keyword>
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<CoiStatement>Authors have nothing to disclose.</CoiStatement>
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<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year>
<Month>03</Month>
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