Symplekin promotes tumorigenicity by up-regulating claudin-2 expression
Identifieur interne : 002461 ( Pmc/Checkpoint ); précédent : 002460; suivant : 002462Symplekin promotes tumorigenicity by up-regulating claudin-2 expression
Auteurs : Michael Buchert [France] ; Marina Papin [France] ; Caroline Bonnans [France] ; Charbel Darido [France] ; Warren S. Raye [Australie] ; Véronique Garambois [France] ; André Pélegrin [France] ; Jean-François Bourgaux [France] ; Julie Pannequin [France] ; Dominique Joubert [France] ; Frédéric Hollande [France, Australie]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2010.
Abstract
Symplekin is a ubiquitously expressed protein involved in cytoplasmic RNA polyadenylation and transcriptional regulation and is localized at tight junctions (TJs) in epithelial cells. Nuclear symplekin cooperates with the Y-box transcription factor zonula occludens 1-associated nucleic acid-binding protein (ZONAB) to increase the transcription of cell cycle-related genes and also inhibits differentiation of intestinal cells. We detected high levels of nuclear symplekin in 8 of 12 human colorectal cancer (CRC) samples. shRNA-mediated reduction of symplekin expression was sufficient to decrease significantly the anchorage-independent growth and proliferation of HT-29 CRC cells as well as their tumorigenicity when injected into immunodeficient animals. Symplekin down-regulation also was found to alter ion transport through TJs, to promote the localization of ZONAB in the membrane rather than the nucleus, and strongly to enhance cell polarization in a 3D matrix, leading to the formation of spheroids organized around a central lumen. Claudin-2 expression was reduced following symplekin down-regulation, an effect mimicked when ZONAB expression was down-regulated using selective siRNA. Virus-mediated restoration of claudin-2 expression was found to restore nuclear expression of ZONAB in HT29ΔSym cells and to rescue the phenotypic alterations induced by symplekin down-regulation of cell polarity, paracellular transport, ZONAB localization, cyclin D1 expression, proliferation, and anchorage-independent growth. Finally, siRNA-mediated claudin-2 down-regulation increased the transepithelial resistance and decreased cyclin D1 expression and ZONAB nuclear localization, similar to observations in symplekin-depleted cells. Our results suggest that nuclear overexpression of symplekin promotes tumorigenesis in the human colon and that the regulation of claudin-2 expression is instrumental in this effect.
Url:
DOI: 10.1073/pnas.0903747107
PubMed: 20133805
PubMed Central: 2823888
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Val d’Aurelle Paul Lamarque, Montpellier F-34093,<country>France</country>
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<front><div type="abstract" xml:lang="en"><p>Symplekin is a ubiquitously expressed protein involved in cytoplasmic RNA polyadenylation and transcriptional regulation and is localized at tight junctions (TJs) in epithelial cells. Nuclear symplekin cooperates with the Y-box transcription factor zonula occludens 1-associated nucleic acid-binding protein (ZONAB) to increase the transcription of cell cycle-related genes and also inhibits differentiation of intestinal cells. We detected high levels of nuclear symplekin in 8 of 12 human colorectal cancer (CRC) samples. shRNA-mediated reduction of symplekin expression was sufficient to decrease significantly the anchorage-independent growth and proliferation of HT-29 CRC cells as well as their tumorigenicity when injected into immunodeficient animals. Symplekin down-regulation also was found to alter ion transport through TJs, to promote the localization of ZONAB in the membrane rather than the nucleus, and strongly to enhance cell polarization in a 3D matrix, leading to the formation of spheroids organized around a central lumen. Claudin-2 expression was reduced following symplekin down-regulation, an effect mimicked when ZONAB expression was down-regulated using selective siRNA. Virus-mediated restoration of claudin-2 expression was found to restore nuclear expression of ZONAB in HT29ΔSym cells and to rescue the phenotypic alterations induced by symplekin down-regulation of cell polarity, paracellular transport, ZONAB localization, cyclin D1 expression, proliferation, and anchorage-independent growth. Finally, siRNA-mediated claudin-2 down-regulation increased the transepithelial resistance and decreased cyclin D1 expression and ZONAB nuclear localization, similar to observations in symplekin-depleted cells. Our results suggest that nuclear overexpression of symplekin promotes tumorigenesis in the human colon and that the regulation of claudin-2 expression is instrumental in this effect.</p>
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<title-group><article-title>Symplekin promotes tumorigenicity by up-regulating claudin-2 expression</article-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Buchert</surname>
<given-names>Michael</given-names>
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<xref ref-type="aff" rid="aff1"><sup>a</sup>
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<xref ref-type="aff" rid="aff2"><sup>b</sup>
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<xref ref-type="aff" rid="aff3"><sup>c</sup>
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<xref ref-type="author-notes" rid="fn1"><sup>1</sup>
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<contrib contrib-type="author"><name><surname>Papin</surname>
<given-names>Marina</given-names>
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<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bonnans</surname>
<given-names>Caroline</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Darido</surname>
<given-names>Charbel</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
<xref ref-type="author-notes" rid="fn2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Raye</surname>
<given-names>Warren S.</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Garambois</surname>
<given-names>Véronique</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pélegrin</surname>
<given-names>André</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bourgaux</surname>
<given-names>Jean-François</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>f</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pannequin</surname>
<given-names>Julie</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>f</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Joubert</surname>
<given-names>Dominique</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hollande</surname>
<given-names>Frédéric</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>d</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>3</sup>
</xref>
</contrib>
<aff id="aff1"><sup>a</sup>
Institut de Génomique Fonctionnelle,<institution>Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche</institution>
5203,</aff>
<aff id="aff2"><sup>b</sup>
<institution>Institut National de la Santé et de la Recherche Médicale</institution>
(INSERM) U661, and</aff>
<aff id="aff3"><sup>c</sup>
<institution>Université Montpellier 1 and 2</institution>
, Montpellier F-34094,<country>France</country>
;</aff>
<aff id="aff4"><sup>d</sup>
Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, Parkville, Victoria 3052,<country>Australia</country>
;</aff>
<aff id="aff5"><sup>e</sup>
Institut National de la Santé et de la Recherche Médicale EMI0227,<institution>Centre Régional de Lutte Contre le Cancer</institution>
Val d’Aurelle Paul Lamarque, Montpellier F-34093,<country>France</country>
; and</aff>
<aff id="aff6"><sup>f</sup>
Service d’Hépato-Gastroentérologie,<institution>Centre Hospitalier Universitaire Carémeau</institution>
, Nimes F-30000,<country>France</country>
</aff>
</contrib-group>
<author-notes><corresp id="cor1"><sup>3</sup>
To whom correspondence should be addressed. E-mail: <email>fhollande@univ-montp1.fr</email>
.</corresp>
<fn fn-type="edited-by"><p>Edited by Valera Vasioukhin, Fred Hutchinson Cancer Research Center, Seattle, WA, and accepted by the Editorial Board December 30, 2009 (received for review April 4, 2009)</p>
</fn>
<fn fn-type="con"><p>Author contributions: M.B., D.J., and F.H. designed research; M.B., M.P., C.B., C.D., W.S.R., V.G., and J.P. performed research; A.P. and J-F.B. contributed new reagents/analytic tools; M.B., M.P., C.B., J.P., and F.H. analyzed data; and D.J. and F.H. wrote the paper.</p>
</fn>
<fn fn-type="present-address" id="fn1"><p><sup>1</sup>
Present address: Ludwig institute for Cancer Research, Parkville, VIC3052, Australia.</p>
</fn>
<fn fn-type="present-address" id="fn2"><p><sup>2</sup>
Present address: Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Parkville, VIC3052, Australia .</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>25</day>
<month>1</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="ppub"><day>9</day>
<month>2</month>
<year>2010</year>
</pub-date>
<volume>107</volume>
<issue>6</issue>
<fpage>2628</fpage>
<lpage>2633</lpage>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.200903747.pdf"></self-uri>
<abstract><p>Symplekin is a ubiquitously expressed protein involved in cytoplasmic RNA polyadenylation and transcriptional regulation and is localized at tight junctions (TJs) in epithelial cells. Nuclear symplekin cooperates with the Y-box transcription factor zonula occludens 1-associated nucleic acid-binding protein (ZONAB) to increase the transcription of cell cycle-related genes and also inhibits differentiation of intestinal cells. We detected high levels of nuclear symplekin in 8 of 12 human colorectal cancer (CRC) samples. shRNA-mediated reduction of symplekin expression was sufficient to decrease significantly the anchorage-independent growth and proliferation of HT-29 CRC cells as well as their tumorigenicity when injected into immunodeficient animals. Symplekin down-regulation also was found to alter ion transport through TJs, to promote the localization of ZONAB in the membrane rather than the nucleus, and strongly to enhance cell polarization in a 3D matrix, leading to the formation of spheroids organized around a central lumen. Claudin-2 expression was reduced following symplekin down-regulation, an effect mimicked when ZONAB expression was down-regulated using selective siRNA. Virus-mediated restoration of claudin-2 expression was found to restore nuclear expression of ZONAB in HT29ΔSym cells and to rescue the phenotypic alterations induced by symplekin down-regulation of cell polarity, paracellular transport, ZONAB localization, cyclin D1 expression, proliferation, and anchorage-independent growth. Finally, siRNA-mediated claudin-2 down-regulation increased the transepithelial resistance and decreased cyclin D1 expression and ZONAB nuclear localization, similar to observations in symplekin-depleted cells. Our results suggest that nuclear overexpression of symplekin promotes tumorigenesis in the human colon and that the regulation of claudin-2 expression is instrumental in this effect.</p>
</abstract>
<kwd-group><kwd>polarity</kwd>
<kwd>transcription</kwd>
<kwd>tumorigenesis</kwd>
<kwd>colorectal</kwd>
<kwd>tight junctions</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>France</li>
</country>
</list>
<tree><country name="France"><noRegion><name sortKey="Buchert, Michael" sort="Buchert, Michael" uniqKey="Buchert M" first="Michael" last="Buchert">Michael Buchert</name>
</noRegion>
<name sortKey="Bonnans, Caroline" sort="Bonnans, Caroline" uniqKey="Bonnans C" first="Caroline" last="Bonnans">Caroline Bonnans</name>
<name sortKey="Bourgaux, Jean Francois" sort="Bourgaux, Jean Francois" uniqKey="Bourgaux J" first="Jean-François" last="Bourgaux">Jean-François Bourgaux</name>
<name sortKey="Darido, Charbel" sort="Darido, Charbel" uniqKey="Darido C" first="Charbel" last="Darido">Charbel Darido</name>
<name sortKey="Garambois, Veronique" sort="Garambois, Veronique" uniqKey="Garambois V" first="Véronique" last="Garambois">Véronique Garambois</name>
<name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
<name sortKey="Joubert, Dominique" sort="Joubert, Dominique" uniqKey="Joubert D" first="Dominique" last="Joubert">Dominique Joubert</name>
<name sortKey="Pannequin, Julie" sort="Pannequin, Julie" uniqKey="Pannequin J" first="Julie" last="Pannequin">Julie Pannequin</name>
<name sortKey="Papin, Marina" sort="Papin, Marina" uniqKey="Papin M" first="Marina" last="Papin">Marina Papin</name>
<name sortKey="Pelegrin, Andre" sort="Pelegrin, Andre" uniqKey="Pelegrin A" first="André" last="Pélegrin">André Pélegrin</name>
</country>
<country name="Australie"><noRegion><name sortKey="Raye, Warren S" sort="Raye, Warren S" uniqKey="Raye W" first="Warren S." last="Raye">Warren S. Raye</name>
</noRegion>
<name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name>
</country>
</tree>
</affiliations>
</record>
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