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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression</title><author><name sortKey="Martin, Alberto" sort="Martin, Alberto" uniqKey="Martin A" first="Alberto" last="Martin">Alberto Martin</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Salvador, Fernando" sort="Salvador, Fernando" uniqKey="Salvador F" first="Fernando" last="Salvador">Fernando Salvador</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Moreno Bueno, Gema" sort="Moreno Bueno, Gema" uniqKey="Moreno Bueno G" first="Gema" last="Moreno-Bueno">Gema Moreno-Bueno</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Fundación MD Anderson International Madrid</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Floristan, Alfredo" sort="Floristan, Alfredo" uniqKey="Floristan A" first="Alfredo" last="Floristán">Alfredo Floristán</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ruiz Herguido, Cristina" sort="Ruiz Herguido, Cristina" uniqKey="Ruiz Herguido C" first="Cristina" last="Ruiz-Herguido">Cristina Ruiz-Herguido</name><affiliation><nlm:aff id="au3"><institution>Institut Hospital del Mar d'Investigacions Médiques (IMIM)</institution><addr-line>Barcelona, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cuevas, Eva P" sort="Cuevas, Eva P" uniqKey="Cuevas E" first="Eva P" last="Cuevas">Eva P. Cuevas</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Morales, Saleta" sort="Morales, Saleta" uniqKey="Morales S" first="Saleta" last="Morales">Saleta Morales</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Santos, Vanesa" sort="Santos, Vanesa" uniqKey="Santos V" first="Vanesa" last="Santos">Vanesa Santos</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Csiszar, Katalin" sort="Csiszar, Katalin" uniqKey="Csiszar K" first="Katalin" last="Csiszar">Katalin Csiszar</name><affiliation><nlm:aff id="au4"><institution>John A Burns School of Medicine, University of Hawaii</institution><addr-line>Honolulu, HI, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dubus, Pierre" sort="Dubus, Pierre" uniqKey="Dubus P" first="Pierre" last="Dubus">Pierre Dubus</name><affiliation><nlm:aff id="au5"><institution>Histologie et pathologie moléculaire des tumeurs, Universitie Bordeaux</institution><addr-line>Bordeaux, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J" last="Haigh">Jody J. Haigh</name><affiliation><nlm:aff id="au6"><institution>Australian Centre for Blood Diseases, Monash University</institution><addr-line>Melbourne, Vic., Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bigas, Anna" sort="Bigas, Anna" uniqKey="Bigas A" first="Anna" last="Bigas">Anna Bigas</name><affiliation><nlm:aff id="au3"><institution>Institut Hospital del Mar d'Investigacions Médiques (IMIM)</institution><addr-line>Barcelona, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Portillo, Francisco" sort="Portillo, Francisco" uniqKey="Portillo F" first="Francisco" last="Portillo">Francisco Portillo</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cano, Amparo" sort="Cano, Amparo" uniqKey="Cano A" first="Amparo" last="Cano">Amparo Cano</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25759215</idno><idno type="pmc">4406654</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406654</idno><idno type="RBID">PMC:4406654</idno><idno type="doi">10.15252/embj.201489975</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">001836</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001836</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression</title><author><name sortKey="Martin, Alberto" sort="Martin, Alberto" uniqKey="Martin A" first="Alberto" last="Martin">Alberto Martin</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Salvador, Fernando" sort="Salvador, Fernando" uniqKey="Salvador F" first="Fernando" last="Salvador">Fernando Salvador</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Moreno Bueno, Gema" sort="Moreno Bueno, Gema" uniqKey="Moreno Bueno G" first="Gema" last="Moreno-Bueno">Gema Moreno-Bueno</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Fundación MD Anderson International Madrid</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Floristan, Alfredo" sort="Floristan, Alfredo" uniqKey="Floristan A" first="Alfredo" last="Floristán">Alfredo Floristán</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ruiz Herguido, Cristina" sort="Ruiz Herguido, Cristina" uniqKey="Ruiz Herguido C" first="Cristina" last="Ruiz-Herguido">Cristina Ruiz-Herguido</name><affiliation><nlm:aff id="au3"><institution>Institut Hospital del Mar d'Investigacions Médiques (IMIM)</institution><addr-line>Barcelona, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cuevas, Eva P" sort="Cuevas, Eva P" uniqKey="Cuevas E" first="Eva P" last="Cuevas">Eva P. Cuevas</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Morales, Saleta" sort="Morales, Saleta" uniqKey="Morales S" first="Saleta" last="Morales">Saleta Morales</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Santos, Vanesa" sort="Santos, Vanesa" uniqKey="Santos V" first="Vanesa" last="Santos">Vanesa Santos</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Csiszar, Katalin" sort="Csiszar, Katalin" uniqKey="Csiszar K" first="Katalin" last="Csiszar">Katalin Csiszar</name><affiliation><nlm:aff id="au4"><institution>John A Burns School of Medicine, University of Hawaii</institution><addr-line>Honolulu, HI, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dubus, Pierre" sort="Dubus, Pierre" uniqKey="Dubus P" first="Pierre" last="Dubus">Pierre Dubus</name><affiliation><nlm:aff id="au5"><institution>Histologie et pathologie moléculaire des tumeurs, Universitie Bordeaux</institution><addr-line>Bordeaux, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J" last="Haigh">Jody J. Haigh</name><affiliation><nlm:aff id="au6"><institution>Australian Centre for Blood Diseases, Monash University</institution><addr-line>Melbourne, Vic., Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bigas, Anna" sort="Bigas, Anna" uniqKey="Bigas A" first="Anna" last="Bigas">Anna Bigas</name><affiliation><nlm:aff id="au3"><institution>Institut Hospital del Mar d'Investigacions Médiques (IMIM)</institution><addr-line>Barcelona, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Portillo, Francisco" sort="Portillo, Francisco" uniqKey="Portillo F" first="Francisco" last="Portillo">Francisco Portillo</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cano, Amparo" sort="Cano, Amparo" uniqKey="Cano A" first="Amparo" last="Cano">Amparo Cano</name><affiliation><nlm:aff id="au1"><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">The EMBO Journal</title><idno type="ISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Lysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific <italic>in vivo</italic> role of LOXL2 in physiological and tumor contexts, we generated conditional gain- and loss-of-function mouse models. Germ-line deletion of <italic>Loxl2</italic> promotes lethality in half of newborn mice mainly associated to congenital heart defects, while <italic>Loxl2</italic> overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, <italic>Loxl2-</italic>overexpressing mice increased tumor burden and malignant progression, while <italic>Loxl2</italic>-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of <italic>NOTCH1</italic>. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">EMBO J</journal-id><journal-id journal-id-type="iso-abbrev">EMBO J</journal-id><journal-id journal-id-type="publisher-id">embj</journal-id><journal-title-group><journal-title>The EMBO Journal</journal-title></journal-title-group><issn pub-type="ppub">0261-4189</issn><issn pub-type="epub">1460-2075</issn><publisher><publisher-name>BlackWell Publishing Ltd</publisher-name><publisher-loc>Oxford, UK</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25759215</article-id><article-id pub-id-type="pmc">4406654</article-id><article-id pub-id-type="doi">10.15252/embj.201489975</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Martin</surname><given-names>Alberto</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="author-notes" rid="fn1">†</xref></contrib><contrib contrib-type="author"><name><surname>Salvador</surname><given-names>Fernando</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="author-notes" rid="fn1">†</xref></contrib><contrib contrib-type="author"><name><surname>Moreno-Bueno</surname><given-names>Gema</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref></contrib><contrib contrib-type="author"><name><surname>Floristán</surname><given-names>Alfredo</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ruiz-Herguido</surname><given-names>Cristina</given-names></name><xref ref-type="aff" rid="au3">3</xref></contrib><contrib contrib-type="author"><name><surname>Cuevas</surname><given-names>Eva P</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Morales</surname><given-names>Saleta</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Santos</surname><given-names>Vanesa</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Csiszar</surname><given-names>Katalin</given-names></name><xref ref-type="aff" rid="au4">4</xref></contrib><contrib contrib-type="author"><name><surname>Dubus</surname><given-names>Pierre</given-names></name><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Haigh</surname><given-names>Jody J</given-names></name><xref ref-type="aff" rid="au6">6</xref></contrib><contrib contrib-type="author"><name><surname>Bigas</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="au3">3</xref></contrib><contrib contrib-type="author"><name><surname>Portillo</surname><given-names>Francisco</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Cano</surname><given-names>Amparo</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="corresp" rid="cor2">**</xref></contrib><aff id="au1"><label>1</label><institution>Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ</institution><addr-line>Madrid, Spain</addr-line></aff><aff id="au2"><label>2</label><institution>Fundación MD Anderson International Madrid</institution><addr-line>Madrid, Spain</addr-line></aff><aff id="au3"><label>3</label><institution>Institut Hospital del Mar d'Investigacions Médiques (IMIM)</institution><addr-line>Barcelona, Spain</addr-line></aff><aff id="au4"><label>4</label><institution>John A Burns School of Medicine, University of Hawaii</institution><addr-line>Honolulu, HI, USA</addr-line></aff><aff id="au5"><label>5</label><institution>Histologie et pathologie moléculaire des tumeurs, Universitie Bordeaux</institution><addr-line>Bordeaux, France</addr-line></aff><aff id="au6"><label>6</label><institution>Australian Centre for Blood Diseases, Monash University</institution><addr-line>Melbourne, Vic., Australia</addr-line></aff></contrib-group><author-notes><corresp id="cor1">* Corresponding author. Tel: +34 91 4972732; Fax: +34 91 5854401; E-mail: <email>fportillo@iib.uam.es</email></corresp><corresp id="cor2">** Corresponding author. Tel: +34 91 4975400; Fax: +34 91 5854401; E-mail: <email>acano@iib.uam.es</email></corresp><fn><p><bold>Subject Categories</bold> Development & Differentiation; Cancer</p></fn><fn id="fn1"><label>†</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>15</day><month>4</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>10</day><month>3</month><year>2015</year></pub-date><volume>34</volume><issue>8</issue><fpage>1090</fpage><lpage>1109</lpage><history><date date-type="received"><day>02</day><month>9</month><year>2014</year></date><date date-type="rev-recd"><day>02</day><month>2</month><year>2015</year></date><date date-type="accepted"><day>05</day><month>2</month><year>2015</year></date></history><permissions><copyright-statement>© 2015 The Authors</copyright-statement><copyright-year>2015</copyright-year></permissions><abstract><p>Lysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific <italic>in vivo</italic> role of LOXL2 in physiological and tumor contexts, we generated conditional gain- and loss-of-function mouse models. Germ-line deletion of <italic>Loxl2</italic> promotes lethality in half of newborn mice mainly associated to congenital heart defects, while <italic>Loxl2</italic> overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, <italic>Loxl2-</italic>overexpressing mice increased tumor burden and malignant progression, while <italic>Loxl2</italic>-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of <italic>NOTCH1</italic>. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy.</p></abstract><kwd-group><kwd>epidermal differentiation</kwd><kwd>Loxl2 mouse models</kwd><kwd>male sterility</kwd><kwd>Notch1</kwd><kwd>squamous cell carcinoma</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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