The Oncogenic MicroRNA Hsa-miR-155-5p Targets the Transcription Factor ELK3 and Links It to the Hypoxia Response
Identifieur interne : 000093 ( Pmc/Curation ); précédent : 000092; suivant : 000094The Oncogenic MicroRNA Hsa-miR-155-5p Targets the Transcription Factor ELK3 and Links It to the Hypoxia Response
Auteurs : E. Douglas Robertson [France] ; Christine Wasylyk [France] ; Tao Ye [France] ; Alain C. Jung [France] ; Bohdan Wasylyk [France]Source :
- PLoS ONE [ 1932-6203 ] ; 2014.
Abstract
The molecular response to hypoxia is a critical cellular process implicated in cancer, and a target for drug development. The activity of the major player, HIF1α, is regulated at different levels by various factors, including the transcription factor ELK3. The molecular mechanisms of this intimate connection remain largely unknown. Whilst investigating global ELK3-chromatin interactions, we uncovered an unexpected connection that involves the microRNA hsa-miR-155-5p, a hypoxia-inducible oncomir that targets HIF1α. One of the ELK3 chromatin binding sites, detected by Chromatin Immuno-Precipitation Sequencing (ChIP-seq) of normal Human Umbilical Vein Endothelial Cells (HUVEC), is located at the transcription start site of the MIR155HG genes that expresses hsa-miR-155-5p. We confirmed that ELK3 binds to this promoter by ChIP and quantitative polymerase chain reaction (QPCR). We showed that ELK3 and hsa-miR-155-5p form a double-negative regulatory loop, in that ELK3 depletion induced hsa-miR-155-5p expression and hsa-miR-155-5p expression decreased ELK3 expression at the RNA level through a conserved target sequence in its 3′-UTR. We further showed that the activities of hsa-miR-155-5p and ELK3 are functionally linked. Pathway analysis indicates that both factors are implicated in related processes, including cancer and angiogenesis. Hsa-miR-155-5p expression and ELK3 depletion have similar effects on expression of known ELK3 target genes, and on in-vitro angiogenesis and wound closure. Bioinformatic analysis of cancer RNA-seq data shows that hsa-miR-155-5p and ELK3 expression are significantly anti-correlated, as would be expected from hsa-miR-155-5p targeting ELK3 RNA. Finally, hypoxia (0% oxygen) down-regulates ELK3 mRNA in a microRNA and hsa-miR-155-5p dependent manner. These results tie ELK3 into the hypoxia response pathway through an oncogenic microRNA and into a circuit implicated in the dynamics of the hypoxic response. This crosstalk could be important for the development of new treatments for a range of pathologies.
Url:
DOI: 10.1371/journal.pone.0113050
PubMed: 25401928
PubMed Central: 4234625
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: Pour aller vers cette notice dans l'étape Curation :000093
Links to Exploration step
PMC:4234625Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Oncogenic MicroRNA Hsa-miR-155-5p Targets the Transcription Factor ELK3 and Links It to the Hypoxia Response</title><author><name sortKey="Robertson, E Douglas" sort="Robertson, E Douglas" uniqKey="Robertson E" first="E. Douglas" last="Robertson">E. Douglas Robertson</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, UMR7104, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Université de Strasbourg, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Strasbourg, Illkirch</wicri:regionArea></affiliation></author><author><name sortKey="Wasylyk, Christine" sort="Wasylyk, Christine" uniqKey="Wasylyk C" first="Christine" last="Wasylyk">Christine Wasylyk</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, UMR7104, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Université de Strasbourg, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Strasbourg, Illkirch</wicri:regionArea></affiliation></author><author><name sortKey="Ye, Tao" sort="Ye, Tao" uniqKey="Ye T" first="Tao" last="Ye">Tao Ye</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, UMR7104, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Université de Strasbourg, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Strasbourg, Illkirch</wicri:regionArea></affiliation></author><author><name sortKey="Jung, Alain C" sort="Jung, Alain C" uniqKey="Jung A" first="Alain C." last="Jung">Alain C. Jung</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Laboratoire de Biologie Tumorale, Centre Régional de Lutte Contre le Cancer Paul Strauss, EA3430 de l’Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Biologie Tumorale, Centre Régional de Lutte Contre le Cancer Paul Strauss, EA3430 de l’Université de Strasbourg, Strasbourg</wicri:regionArea></affiliation></author><author><name sortKey="Wasylyk, Bohdan" sort="Wasylyk, Bohdan" uniqKey="Wasylyk B" first="Bohdan" last="Wasylyk">Bohdan Wasylyk</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, UMR7104, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Université de Strasbourg, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Strasbourg, Illkirch</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25401928</idno><idno type="pmc">4234625</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234625</idno><idno type="RBID">PMC:4234625</idno><idno type="doi">10.1371/journal.pone.0113050</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000093</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000093</idno><idno type="wicri:Area/Pmc/Curation">000093</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000093</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Oncogenic MicroRNA Hsa-miR-155-5p Targets the Transcription Factor ELK3 and Links It to the Hypoxia Response</title><author><name sortKey="Robertson, E Douglas" sort="Robertson, E Douglas" uniqKey="Robertson E" first="E. Douglas" last="Robertson">E. Douglas Robertson</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, UMR7104, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Université de Strasbourg, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Strasbourg, Illkirch</wicri:regionArea></affiliation></author><author><name sortKey="Wasylyk, Christine" sort="Wasylyk, Christine" uniqKey="Wasylyk C" first="Christine" last="Wasylyk">Christine Wasylyk</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, UMR7104, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Université de Strasbourg, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Strasbourg, Illkirch</wicri:regionArea></affiliation></author><author><name sortKey="Ye, Tao" sort="Ye, Tao" uniqKey="Ye T" first="Tao" last="Ye">Tao Ye</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, UMR7104, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Université de Strasbourg, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Strasbourg, Illkirch</wicri:regionArea></affiliation></author><author><name sortKey="Jung, Alain C" sort="Jung, Alain C" uniqKey="Jung A" first="Alain C." last="Jung">Alain C. Jung</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Laboratoire de Biologie Tumorale, Centre Régional de Lutte Contre le Cancer Paul Strauss, EA3430 de l’Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Biologie Tumorale, Centre Régional de Lutte Contre le Cancer Paul Strauss, EA3430 de l’Université de Strasbourg, Strasbourg</wicri:regionArea></affiliation></author><author><name sortKey="Wasylyk, Bohdan" sort="Wasylyk, Bohdan" uniqKey="Wasylyk B" first="Bohdan" last="Wasylyk">Bohdan Wasylyk</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre National de la Recherche Scientifique, UMR7104, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Université de Strasbourg, Illkirch, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Strasbourg, Illkirch</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The molecular response to hypoxia is a critical cellular process implicated in cancer, and a target for drug development. The activity of the major player, HIF1α, is regulated at different levels by various factors, including the transcription factor ELK3. The molecular mechanisms of this intimate connection remain largely unknown. Whilst investigating global ELK3-chromatin interactions, we uncovered an unexpected connection that involves the microRNA hsa-miR-155-5p, a hypoxia-inducible oncomir that targets HIF1α. One of the ELK3 chromatin binding sites, detected by Chromatin Immuno-Precipitation Sequencing (ChIP-seq) of normal Human Umbilical Vein Endothelial Cells (HUVEC), is located at the transcription start site of the MIR155HG genes that expresses hsa-miR-155-5p. We confirmed that ELK3 binds to this promoter by ChIP and quantitative polymerase chain reaction (QPCR). We showed that ELK3 and hsa-miR-155-5p form a double-negative regulatory loop, in that ELK3 depletion induced hsa-miR-155-5p expression and hsa-miR-155-5p expression decreased ELK3 expression at the RNA level through a conserved target sequence in its 3′-UTR. We further showed that the activities of hsa-miR-155-5p and ELK3 are functionally linked. Pathway analysis indicates that both factors are implicated in related processes, including cancer and angiogenesis. Hsa-miR-155-5p expression and ELK3 depletion have similar effects on expression of known ELK3 target genes, and on in-vitro angiogenesis and wound closure. Bioinformatic analysis of cancer RNA-seq data shows that hsa-miR-155-5p and ELK3 expression are significantly anti-correlated, as would be expected from hsa-miR-155-5p targeting ELK3 RNA. Finally, hypoxia (0% oxygen) down-regulates ELK3 mRNA in a microRNA and hsa-miR-155-5p dependent manner. These results tie ELK3 into the hypoxia response pathway through an oncogenic microRNA and into a circuit implicated in the dynamics of the hypoxic response. This crosstalk could be important for the development of new treatments for a range of pathologies.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Goda, N" uniqKey="Goda N">N Goda</name></author><author><name sortKey="Kanai, M" uniqKey="Kanai M">M Kanai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bertout, Ja" uniqKey="Bertout J">JA Bertout</name></author><author><name sortKey="Patel, Sa" uniqKey="Patel S">SA Patel</name></author><author><name sortKey="Simon, Mc" uniqKey="Simon M">MC Simon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mucaj, V" uniqKey="Mucaj V">V Mucaj</name></author><author><name sortKey="Shay, Jes" uniqKey="Shay J">JES Shay</name></author><author><name sortKey="Simon, Mc" uniqKey="Simon M">MC Simon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ke, Q" uniqKey="Ke Q">Q Ke</name></author><author><name sortKey="Costa, M" uniqKey="Costa M">M Costa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gross, C" uniqKey="Gross C">C Gross</name></author><author><name sortKey="Buchwalter, G" uniqKey="Buchwalter G">G Buchwalter</name></author><author><name sortKey="Dubois Pot, H" uniqKey="Dubois Pot H">H Dubois-Pot</name></author><author><name sortKey="Cler, E" uniqKey="Cler E">E Cler</name></author><author><name sortKey="Zheng, H" uniqKey="Zheng H">H Zheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gross, C" uniqKey="Gross C">C Gross</name></author><author><name sortKey="Dubois Pot, H" uniqKey="Dubois Pot H">H Dubois-Pot</name></author><author><name sortKey="Wasylyk, B" uniqKey="Wasylyk B">B Wasylyk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Buchwalter, G" uniqKey="Buchwalter G">G Buchwalter</name></author><author><name sortKey="Gross, C" uniqKey="Gross C">C Gross</name></author><author><name sortKey="Wasylyk, B" uniqKey="Wasylyk B">B Wasylyk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Giovane, A" uniqKey="Giovane A">A Giovane</name></author><author><name sortKey="Pintzas, A" uniqKey="Pintzas A">A Pintzas</name></author><author><name sortKey="Maira, Sm" uniqKey="Maira S">SM Maira</name></author><author><name sortKey="Sobieszczuk, P" uniqKey="Sobieszczuk P">P Sobieszczuk</name></author><author><name sortKey="Wasylyk, B" uniqKey="Wasylyk B">B Wasylyk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Buchwalter, G" uniqKey="Buchwalter G">G Buchwalter</name></author><author><name sortKey="Gross, C" uniqKey="Gross C">C Gross</name></author><author><name sortKey="Wasylyk, B" uniqKey="Wasylyk B">B Wasylyk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zheng, H" uniqKey="Zheng H">H Zheng</name></author><author><name sortKey="Wasylyk, C" uniqKey="Wasylyk C">C Wasylyk</name></author><author><name sortKey="Ayadi, A" uniqKey="Ayadi A">A Ayadi</name></author><author><name sortKey="Abecassis, J" uniqKey="Abecassis J">J Abecassis</name></author><author><name sortKey="Schalken, Ja" uniqKey="Schalken J">JA Schalken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ayadi, A" uniqKey="Ayadi A">A Ayadi</name></author><author><name sortKey="Zheng, H" uniqKey="Zheng H">H Zheng</name></author><author><name sortKey="Sobieszczuk, P" uniqKey="Sobieszczuk P">P Sobieszczuk</name></author><author><name sortKey="Buchwalter, G" uniqKey="Buchwalter G">G Buchwalter</name></author><author><name sortKey="Moerman, P" uniqKey="Moerman P">P Moerman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Criqui Filipe, P" uniqKey="Criqui Filipe P">P Criqui-Filipe</name></author><author><name sortKey="Ducret, C" uniqKey="Ducret C">C Ducret</name></author><author><name sortKey="Maira, Sm" uniqKey="Maira S">SM Maira</name></author><author><name sortKey="Wasylyk, B" uniqKey="Wasylyk B">B Wasylyk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maira, Sm" uniqKey="Maira S">SM Maira</name></author><author><name sortKey="Wurtz, Jm" uniqKey="Wurtz J">JM Wurtz</name></author><author><name sortKey="Wasylyk, B" uniqKey="Wasylyk B">B Wasylyk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Serchov, T" uniqKey="Serchov T">T Serchov</name></author><author><name sortKey="Dubois Pot Schneider, H" uniqKey="Dubois Pot Schneider H">H Dubois-Pot-Schneider</name></author><author><name sortKey="Charlot, C" uniqKey="Charlot C">C Charlot</name></author><author><name sortKey="Rosl, F" uniqKey="Rosl F">F Rosl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kulshreshtha, R" uniqKey="Kulshreshtha R">R Kulshreshtha</name></author><author><name sortKey="Ferracin, M" uniqKey="Ferracin M">M Ferracin</name></author><author><name sortKey="Wojcik, Se" uniqKey="Wojcik S">SE Wojcik</name></author><author><name sortKey="Garzon, R" uniqKey="Garzon R">R Garzon</name></author><author><name sortKey="Alder, H" uniqKey="Alder H">H Alder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shen, G" uniqKey="Shen G">G Shen</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author><author><name sortKey="Jia, Yf" uniqKey="Jia Y">YF Jia</name></author><author><name sortKey="Piazza, Ga" uniqKey="Piazza G">GA Piazza</name></author><author><name sortKey="Xi, Y" uniqKey="Xi Y">Y Xi</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Peng, H" uniqKey="Peng H">H Peng</name></author><author><name sortKey="Hamanaka, Rb" uniqKey="Hamanaka R">RB Hamanaka</name></author><author><name sortKey="Katsnelson, J" uniqKey="Katsnelson J">J Katsnelson</name></author><author><name sortKey="Hao, Ll" uniqKey="Hao L">LL Hao</name></author><author><name sortKey="Yang, W" uniqKey="Yang W">W Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kong, W" uniqKey="Kong W">W Kong</name></author><author><name sortKey="He, L" uniqKey="He L">L He</name></author><author><name sortKey="Richards, Ej" uniqKey="Richards E">EJ Richards</name></author><author><name sortKey="Challa, S" uniqKey="Challa S">S Challa</name></author><author><name sortKey="Xu, Cx" uniqKey="Xu C">CX Xu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bruning, U" uniqKey="Bruning U">U Bruning</name></author><author><name sortKey="Cerone, L" uniqKey="Cerone L">L Cerone</name></author><author><name sortKey="Neufeld, Z" uniqKey="Neufeld Z">Z Neufeld</name></author><author><name sortKey="Fitzpatrick, Sf" uniqKey="Fitzpatrick S">SF Fitzpatrick</name></author><author><name sortKey="Cheong, A" uniqKey="Cheong A">A Cheong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oda, Y" uniqKey="Oda Y">Y Oda</name></author><author><name sortKey="Nakajima, M" uniqKey="Nakajima M">M Nakajima</name></author><author><name sortKey="Mohri, T" uniqKey="Mohri T">T Mohri</name></author><author><name sortKey="Takamiya, M" uniqKey="Takamiya M">M Takamiya</name></author><author><name sortKey="Aoki, Y" uniqKey="Aoki Y">Y Aoki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huang, X" uniqKey="Huang X">X Huang</name></author><author><name sortKey="Ding, L" uniqKey="Ding L">L Ding</name></author><author><name sortKey="Bennewith, Kl" uniqKey="Bennewith K">KL Bennewith</name></author><author><name sortKey="Tong, Rt" uniqKey="Tong R">RT Tong</name></author><author><name sortKey="Welford, Sm" uniqKey="Welford S">SM Welford</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fasanaro, P" uniqKey="Fasanaro P">P Fasanaro</name></author><author><name sortKey="Greco, S" uniqKey="Greco S">S Greco</name></author><author><name sortKey="Lorenzi, M" uniqKey="Lorenzi M">M Lorenzi</name></author><author><name sortKey="Pescatori, M" uniqKey="Pescatori M">M Pescatori</name></author><author><name sortKey="Brioschi, M" uniqKey="Brioschi M">M Brioschi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Sy" uniqKey="Chan S">SY Chan</name></author><author><name sortKey="Loscalzo, J" uniqKey="Loscalzo J">J Loscalzo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, Jh" uniqKey="Li J">JH Li</name></author><author><name sortKey="Liu, S" uniqKey="Liu S">S Liu</name></author><author><name sortKey="Zhou, H" uniqKey="Zhou H">H Zhou</name></author><author><name sortKey="Qu, Lh" uniqKey="Qu L">LH Qu</name></author><author><name sortKey="Yang, Jh" uniqKey="Yang J">JH Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Jh" uniqKey="Yang J">JH Yang</name></author><author><name sortKey="Li, Jh" uniqKey="Li J">JH Li</name></author><author><name sortKey="Shao, P" uniqKey="Shao P">P Shao</name></author><author><name sortKey="Zhou, H" uniqKey="Zhou H">H Zhou</name></author><author><name sortKey="Chen, Yq" uniqKey="Chen Y">YQ Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Williams, Rl" uniqKey="Williams R">RL Williams</name></author><author><name sortKey="Courtneidge, Sa" uniqKey="Courtneidge S">SA Courtneidge</name></author><author><name sortKey="Wagner, Ef" uniqKey="Wagner E">EF Wagner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van, Beijnumjr" uniqKey="Van B">BeijnumJR van</name></author><author><name sortKey="Van Der Linden, E" uniqKey="Van Der Linden E">E van der Linden</name></author><author><name sortKey="Griffioen, Aw" uniqKey="Griffioen A">AW Griffioen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fontijn, Rd" uniqKey="Fontijn R">RD Fontijn</name></author><author><name sortKey="Volger, Ol" uniqKey="Volger O">OL Volger</name></author><author><name sortKey="Fledderus, Jo" uniqKey="Fledderus J">JO Fledderus</name></author><author><name sortKey="Reijerkerk, A" uniqKey="Reijerkerk A">A Reijerkerk</name></author><author><name sortKey="De Vries, He" uniqKey="De Vries H">HE De Vries</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Goke, J" uniqKey="Goke J">J Göke</name></author><author><name sortKey="Chan, Y S" uniqKey="Chan Y">Y-S Chan</name></author><author><name sortKey="Yan, J" uniqKey="Yan J">J Yan</name></author><author><name sortKey="Vingron, M" uniqKey="Vingron M">M Vingron</name></author><author><name sortKey="Ng, H H" uniqKey="Ng H">H-H Ng</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Babar, Ia" uniqKey="Babar I">IA Babar</name></author><author><name sortKey="Czochor, J" uniqKey="Czochor J">J Czochor</name></author><author><name sortKey="Steinmetz, A" uniqKey="Steinmetz A">A Steinmetz</name></author><author><name sortKey="Weidhaas, Jb" uniqKey="Weidhaas J">JB Weidhaas</name></author><author><name sortKey="Glazer, Pm" uniqKey="Glazer P">PM Glazer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jiang, S" uniqKey="Jiang S">S Jiang</name></author><author><name sortKey="Zhang, Hw" uniqKey="Zhang H">HW Zhang</name></author><author><name sortKey="Lu, Mh" uniqKey="Lu M">MH Lu</name></author><author><name sortKey="He, Xh" uniqKey="He X">XH He</name></author><author><name sortKey="Li, Y" uniqKey="Li Y">Y Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vergoulis, T" uniqKey="Vergoulis T">T Vergoulis</name></author><author><name sortKey="Vlachos, Is" uniqKey="Vlachos I">IS Vlachos</name></author><author><name sortKey="Alexiou, P" uniqKey="Alexiou P">P Alexiou</name></author><author><name sortKey="Georgakilas, G" uniqKey="Georgakilas G">G Georgakilas</name></author><author><name sortKey="Maragkakis, M" uniqKey="Maragkakis M">M Maragkakis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tsuchiya, S" uniqKey="Tsuchiya S">S Tsuchiya</name></author><author><name sortKey="Fujiwara, T" uniqKey="Fujiwara T">T Fujiwara</name></author><author><name sortKey="Sato, F" uniqKey="Sato F">F Sato</name></author><author><name sortKey="Shimada, Y" uniqKey="Shimada Y">Y Shimada</name></author><author><name sortKey="Tanaka, E" uniqKey="Tanaka E">E Tanaka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hammond, Sm" uniqKey="Hammond S">SM Hammond</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ferrajoli, A" uniqKey="Ferrajoli A">A Ferrajoli</name></author><author><name sortKey="Shanafelt, Td" uniqKey="Shanafelt T">TD Shanafelt</name></author><author><name sortKey="Ivan, C" uniqKey="Ivan C">C Ivan</name></author><author><name sortKey="Shimizu, M" uniqKey="Shimizu M">M Shimizu</name></author><author><name sortKey="Rabe, Kg" uniqKey="Rabe K">KG Rabe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Esnault, C" uniqKey="Esnault C">C Esnault</name></author><author><name sortKey="Stewart, A" uniqKey="Stewart A">A Stewart</name></author><author><name sortKey="Gualdrini, F" uniqKey="Gualdrini F">F Gualdrini</name></author><author><name sortKey="East, P" uniqKey="East P">P East</name></author><author><name sortKey="Horswell, S" uniqKey="Horswell S">S Horswell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wozniak, Ma" uniqKey="Wozniak M">MA Wozniak</name></author><author><name sortKey="Cheng, Cq" uniqKey="Cheng C">CQ Cheng</name></author><author><name sortKey="Shen, Cj" uniqKey="Shen C">CJ Shen</name></author><author><name sortKey="Gao, L" uniqKey="Gao L">L Gao</name></author><author><name sortKey="Olarerin George, Ao" uniqKey="Olarerin George A">AO Olarerin-George</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dai, Y" uniqKey="Dai Y">Y Dai</name></author><author><name sortKey="Qiu, Z" uniqKey="Qiu Z">Z Qiu</name></author><author><name sortKey="Diao, Z" uniqKey="Diao Z">Z Diao</name></author><author><name sortKey="Shen, L" uniqKey="Shen L">L Shen</name></author><author><name sortKey="Xue, P" uniqKey="Xue P">P Xue</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, S" uniqKey="Liu S">S Liu</name></author><author><name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name></author><author><name sortKey="Wu, J" uniqKey="Wu J">J Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Elton, Ts" uniqKey="Elton T">TS Elton</name></author><author><name sortKey="Selemon, H" uniqKey="Selemon H">H Selemon</name></author><author><name sortKey="Elton, Sm" uniqKey="Elton S">SM Elton</name></author><author><name sortKey="Parinandi, Nl" uniqKey="Parinandi N">NL Parinandi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name></author><author><name sortKey="Ma, T" uniqKey="Ma T">T Ma</name></author><author><name sortKey="Huang, C" uniqKey="Huang C">C Huang</name></author><author><name sortKey="Hu, T" uniqKey="Hu T">T Hu</name></author><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Higgs, G" uniqKey="Higgs G">G Higgs</name></author><author><name sortKey="Slack, F" uniqKey="Slack F">F Slack</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Czyzyk Krzeska, Mf" uniqKey="Czyzyk Krzeska M">MF Czyzyk-Krzeska</name></author><author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Flynt, As" uniqKey="Flynt A">AS Flynt</name></author><author><name sortKey="Lai, Ec" uniqKey="Lai E">EC Lai</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25401928</article-id><article-id pub-id-type="pmc">4234625</article-id><article-id pub-id-type="publisher-id">PONE-D-14-35394</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0113050</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cell Processes</subject><subject>Hypoxia</subject><subject>Molecular Cell Biology</subject></subj-group></subj-group><subj-group><subject>Computational Biology</subject><subj-group><subject>Gene Regulatory Networks</subject></subj-group></subj-group><subj-group><subject>Genetics</subject><subj-group><subject>Epigenetics</subject><subject>Gene Expression</subject><subject>Genomics</subject></subj-group></subj-group><subj-group><subject>Molecular Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>The Oncogenic MicroRNA Hsa-miR-155-5p Targets the Transcription Factor ELK3 and Links It to the Hypoxia Response</article-title><alt-title alt-title-type="running-head">MicroRNA Hsa-miR-155-5p Links ELK3 and Hypoxia</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Robertson</surname><given-names>E. Douglas</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wasylyk</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ye</surname><given-names>Tao</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jung</surname><given-names>Alain C.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wasylyk</surname><given-names>Bohdan</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Centre National de la Recherche Scientifique, UMR7104, Illkirch, France</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Université de Strasbourg, Illkirch, France</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Laboratoire de Biologie Tumorale, Centre Régional de Lutte Contre le Cancer Paul Strauss, EA3430 de l’Université de Strasbourg, Strasbourg, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Fujii</surname><given-names>Hodaka</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Osaka University, Japan</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>boh@igbmc.fr</email></corresp><fn fn-type="conflict"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: EDR CW TY ACJ BW. Performed the experiments: EDR CW. Analyzed the data: EDR CW TY ACJ BW. Contributed to the writing of the manuscript: EDR CW TY ACJ BW.</p></fn></author-notes><pub-date pub-type="collection"><year>2014</year></pub-date><pub-date pub-type="epub"><day>17</day><month>11</month><year>2014</year></pub-date><volume>9</volume><issue>11</issue><elocation-id>e113050</elocation-id><history><date date-type="received"><day>8</day><month>8</month><year>2014</year></date><date date-type="accepted"><day>18</day><month>10</month><year>2014</year></date></history><permissions><copyright-year>2014</copyright-year><copyright-holder>Robertson et al</copyright-holder><license><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>The molecular response to hypoxia is a critical cellular process implicated in cancer, and a target for drug development. The activity of the major player, HIF1α, is regulated at different levels by various factors, including the transcription factor ELK3. The molecular mechanisms of this intimate connection remain largely unknown. Whilst investigating global ELK3-chromatin interactions, we uncovered an unexpected connection that involves the microRNA hsa-miR-155-5p, a hypoxia-inducible oncomir that targets HIF1α. One of the ELK3 chromatin binding sites, detected by Chromatin Immuno-Precipitation Sequencing (ChIP-seq) of normal Human Umbilical Vein Endothelial Cells (HUVEC), is located at the transcription start site of the MIR155HG genes that expresses hsa-miR-155-5p. We confirmed that ELK3 binds to this promoter by ChIP and quantitative polymerase chain reaction (QPCR). We showed that ELK3 and hsa-miR-155-5p form a double-negative regulatory loop, in that ELK3 depletion induced hsa-miR-155-5p expression and hsa-miR-155-5p expression decreased ELK3 expression at the RNA level through a conserved target sequence in its 3′-UTR. We further showed that the activities of hsa-miR-155-5p and ELK3 are functionally linked. Pathway analysis indicates that both factors are implicated in related processes, including cancer and angiogenesis. Hsa-miR-155-5p expression and ELK3 depletion have similar effects on expression of known ELK3 target genes, and on in-vitro angiogenesis and wound closure. Bioinformatic analysis of cancer RNA-seq data shows that hsa-miR-155-5p and ELK3 expression are significantly anti-correlated, as would be expected from hsa-miR-155-5p targeting ELK3 RNA. Finally, hypoxia (0% oxygen) down-regulates ELK3 mRNA in a microRNA and hsa-miR-155-5p dependent manner. These results tie ELK3 into the hypoxia response pathway through an oncogenic microRNA and into a circuit implicated in the dynamics of the hypoxic response. This crosstalk could be important for the development of new treatments for a range of pathologies.</p></abstract><funding-group><funding-statement>The authors are thankful for financial support from the Institut National du Cancer (INCa; HypoNet, PLBIO2010), the Association pour la Recherche sur le Cancer, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Strasbourg (UdS) and the Conférence de Coordination Interrégionale du Grand Est (CCIR-GE) de la Ligue Contre le Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="13"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>The authors confirm that all data underlying the findings are fully available without restriction. All Chip-seq files are available from the GEO database, assession number GSE60156. Link: <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=mloxmommlfwffyh&acc=GSE60156">http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=mloxmommlfwffyh&acc=GSE60156</ext-link>.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>The authors confirm that all data underlying the findings are fully available without restriction. All Chip-seq files are available from the GEO database, assession number GSE60156. Link: <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=mloxmommlfwffyh&acc=GSE60156">http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=mloxmommlfwffyh&acc=GSE60156</ext-link>.</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonFranceV1/Data/Pmc/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000093 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd -nk 000093 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonFranceV1
|flux= Pmc
|étape= Curation
|type= RBID
|clé= PMC:4234625
|texte= The Oncogenic MicroRNA Hsa-miR-155-5p Targets the Transcription Factor ELK3 and Links It to the Hypoxia Response
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Curation/RBID.i -Sk "pubmed:25401928" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd \
| NlmPubMed2Wicri -a ParkinsonFranceV1
| This area was generated with Dilib version V0.6.29. |  |