Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer
Identifieur interne : 000687 ( Pmc/Checkpoint ); précédent : 000686; suivant : 000688Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer
Auteurs : Liyuan Zhu [République populaire de Chine] ; Yiran Zhu [République populaire de Chine] ; Shuting Han [République populaire de Chine] ; Miaoqin Chen [République populaire de Chine] ; Ping Song [République populaire de Chine] ; Dongjun Dai [République populaire de Chine] ; Wenxia Xu [République populaire de Chine] ; Tingting Jiang [République populaire de Chine] ; Lifeng Feng [République populaire de Chine] ; Vivian Y. Shin [République populaire de Chine] ; Xian Wang [République populaire de Chine] ; Hongchuan Jin [République populaire de Chine]Source :
- Cell Death & Disease [ 2041-4889 ] ; 2019.
Abstract
Chemoresistance remains the uppermost disincentive for cancer treatment on account of many genetic and epigenetic alterations. Long non-coding RNAs (lncRNAs) are emerging players in promoting cancer initiation and progression. However, the regulation and function in chemoresistance are largely unknown. Herein, we identified ARHGAP5-AS1 as a lncRNA upregulated in chemoresistant gastric cancer cells and its knockdown reversed chemoresistance. Meanwhile, high ARHGAP5-AS1 expression was associated with poor prognosis of gastric cancer patients. Intriguingly, its abundance is affected by autophagy and SQSTM1 is responsible for transporting ARHGAP5-AS1 to autophagosomes. Inhibition of autophagy in chemoresistant cells, thus, resulted in the upregulation of ARHGAP5-AS1. In turn, it activated the transcription of ARHGAP5 in the nucleus by directly interacting with ARHGAP5 promoter. Interestingly, ARHGAP5-AS1 also stabilized ARHGAP5 mRNA in the cytoplasm by recruiting METTL3 to stimulate m6A modification of ARHGAP5 mRNA. As a result, ARHGAP5 was upregulated to promote chemoresistance and its upregulation was also associated with poor prognosis in gastric cancer. In summary, impaired autophagic degradation of lncRNA ARHGAP5-AS1 in chemoresistant cancer cells promoted chemoresistance. It can activate the transcription of ARHGAP5 in the nucleus and stimulate m6A modification of ARHGAP5 mRNA to stabilize ARHGAP5 mRNA in the cytoplasm by recruiting METTL3. Therefore, targeting ARHGAP5-AS1/ARHGAP5 axis might be a promising strategy to overcome chemoresistance in gastric cancer.
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DOI: 10.1038/s41419-019-1585-2
PubMed: 31097692
PubMed Central: 6522595
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wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Zhu, Yiran" sort="Zhu, Yiran" uniqKey="Zhu Y" first="Yiran" last="Zhu">Yiran Zhu</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Han, Shuting" sort="Han, Shuting" uniqKey="Han S" first="Shuting" last="Han">Shuting Han</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Department of Medical Oncology, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Miaoqin" sort="Chen, Miaoqin" uniqKey="Chen M" first="Miaoqin" last="Chen">Miaoqin Chen</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Song, Ping" sort="Song, Ping" uniqKey="Song P" first="Ping" last="Song">Ping Song</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Department of Medical Oncology, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Dai, Dongjun" sort="Dai, Dongjun" uniqKey="Dai D" first="Dongjun" last="Dai">Dongjun Dai</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Department of Medical Oncology, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Xu, Wenxia" sort="Xu, Wenxia" uniqKey="Xu W" first="Wenxia" last="Xu">Wenxia Xu</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Jiang, Tingting" sort="Jiang, Tingting" uniqKey="Jiang T" first="Tingting" last="Jiang">Tingting Jiang</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Department of Medical Oncology, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Feng, Lifeng" sort="Feng, Lifeng" uniqKey="Feng L" first="Lifeng" last="Feng">Lifeng Feng</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Shin, Vivian Y" sort="Shin, Vivian Y" uniqKey="Shin V" first="Vivian Y." last="Shin">Vivian Y. Shin</name><affiliation wicri:level="1"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000000121742757</institution-id><institution-id institution-id-type="GRID">grid.194645.b</institution-id><institution>Department of Surgery,</institution><institution>the University of Hong Kong,</institution></institution-wrap>Hong Kong SAR, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hong Kong SAR</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Xian" sort="Wang, Xian" uniqKey="Wang X" first="Xian" last="Wang">Xian Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Department of Medical Oncology, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Jin, Hongchuan" sort="Jin, Hongchuan" uniqKey="Jin H" first="Hongchuan" last="Jin">Hongchuan Jin</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author></analytic><series><title level="j">Cell Death & Disease</title><idno type="eISSN">2041-4889</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Chemoresistance remains the uppermost disincentive for cancer treatment on account of many genetic and epigenetic alterations. Long non-coding RNAs (lncRNAs) are emerging players in promoting cancer initiation and progression. However, the regulation and function in chemoresistance are largely unknown. Herein, we identified ARHGAP5-AS1 as a lncRNA upregulated in chemoresistant gastric cancer cells and its knockdown reversed chemoresistance. Meanwhile, high ARHGAP5-AS1 expression was associated with poor prognosis of gastric cancer patients. Intriguingly, its abundance is affected by autophagy and SQSTM1 is responsible for transporting ARHGAP5-AS1 to autophagosomes. Inhibition of autophagy in chemoresistant cells, thus, resulted in the upregulation of ARHGAP5-AS1. In turn, it activated the transcription of ARHGAP5 in the nucleus by directly interacting with ARHGAP5 promoter. Interestingly, ARHGAP5-AS1 also stabilized ARHGAP5 mRNA in the cytoplasm by recruiting METTL3 to stimulate m<sup>6</sup>A modification of ARHGAP5 mRNA. As a result, ARHGAP5 was upregulated to promote chemoresistance and its upregulation was also associated with poor prognosis in gastric cancer. In summary, impaired autophagic degradation of lncRNA ARHGAP5-AS1 in chemoresistant cancer cells promoted chemoresistance. It can activate the transcription of ARHGAP5 in the nucleus and stimulate m<sup>6</sup>A modification of ARHGAP5 mRNA to stabilize ARHGAP5 mRNA in the cytoplasm by recruiting METTL3. Therefore, targeting ARHGAP5-AS1/ARHGAP5 axis might be a promising strategy to overcome chemoresistance in gastric cancer.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, W" uniqKey="Chen W">W Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sun, W" uniqKey="Sun W">W Sun</name></author><author><name sortKey="Yan, L" uniqKey="Yan L">L Yan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Holohan, C" uniqKey="Holohan C">C Holohan</name></author><author><name sortKey="Van Schaeybroeck, S" uniqKey="Van Schaeybroeck S">S Van Schaeybroeck</name></author><author><name sortKey="Longley, Db" uniqKey="Longley D">DB Longley</name></author><author><name sortKey="Johnston, Pg" uniqKey="Johnston P">PG 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Death Dis</journal-id><journal-id journal-id-type="iso-abbrev">Cell Death Dis</journal-id><journal-title-group><journal-title>Cell Death & Disease</journal-title></journal-title-group><issn pub-type="epub">2041-4889</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31097692</article-id><article-id pub-id-type="pmc">6522595</article-id><article-id pub-id-type="publisher-id">1585</article-id><article-id pub-id-type="doi">10.1038/s41419-019-1585-2</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zhu</surname><given-names>Liyuan</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhu</surname><given-names>Yiran</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Han</surname><given-names>Shuting</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Miaoqin</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Song</surname><given-names>Ping</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Dai</surname><given-names>Dongjun</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Wenxia</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Tingting</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4506-1213</contrib-id><name><surname>Feng</surname><given-names>Lifeng</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Shin</surname><given-names>Vivian Y.</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Xian</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Jin</surname><given-names>Hongchuan</given-names></name><address><phone>+86 057186006366</phone><email>jinhc@zju.edu.cn</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Department of Medical Oncology, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000000121742757</institution-id><institution-id institution-id-type="GRID">grid.194645.b</institution-id><institution>Department of Surgery,</institution><institution>the University of Hong Kong,</institution></institution-wrap>Hong Kong SAR, China</aff></contrib-group><pub-date pub-type="epub"><day>16</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>16</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>6</month><year>2019</year></pub-date><volume>10</volume><issue>6</issue><elocation-id>383</elocation-id><history><date date-type="received"><day>18</day><month>12</month><year>2018</year></date><date date-type="rev-recd"><day>18</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>8</day><month>4</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Chemoresistance remains the uppermost disincentive for cancer treatment on account of many genetic and epigenetic alterations. Long non-coding RNAs (lncRNAs) are emerging players in promoting cancer initiation and progression. However, the regulation and function in chemoresistance are largely unknown. Herein, we identified ARHGAP5-AS1 as a lncRNA upregulated in chemoresistant gastric cancer cells and its knockdown reversed chemoresistance. Meanwhile, high ARHGAP5-AS1 expression was associated with poor prognosis of gastric cancer patients. Intriguingly, its abundance is affected by autophagy and SQSTM1 is responsible for transporting ARHGAP5-AS1 to autophagosomes. Inhibition of autophagy in chemoresistant cells, thus, resulted in the upregulation of ARHGAP5-AS1. In turn, it activated the transcription of ARHGAP5 in the nucleus by directly interacting with ARHGAP5 promoter. Interestingly, ARHGAP5-AS1 also stabilized ARHGAP5 mRNA in the cytoplasm by recruiting METTL3 to stimulate m<sup>6</sup>A modification of ARHGAP5 mRNA. As a result, ARHGAP5 was upregulated to promote chemoresistance and its upregulation was also associated with poor prognosis in gastric cancer. In summary, impaired autophagic degradation of lncRNA ARHGAP5-AS1 in chemoresistant cancer cells promoted chemoresistance. It can activate the transcription of ARHGAP5 in the nucleus and stimulate m<sup>6</sup>A modification of ARHGAP5 mRNA to stabilize ARHGAP5 mRNA in the cytoplasm by recruiting METTL3. Therefore, targeting ARHGAP5-AS1/ARHGAP5 axis might be a promising strategy to overcome chemoresistance in gastric cancer.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Cancer therapy</kwd><kwd>Cancer therapy</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China (National Science Foundation of China)</institution></institution-wrap></funding-source><award-id>91740106</award-id><award-id>81761138047</award-id><principal-award-recipient><name><surname>Wang</surname><given-names>Xian</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Zhu, Liyuan" sort="Zhu, Liyuan" uniqKey="Zhu L" first="Liyuan" last="Zhu">Liyuan Zhu</name></noRegion><name sortKey="Chen, Miaoqin" sort="Chen, Miaoqin" uniqKey="Chen M" first="Miaoqin" last="Chen">Miaoqin Chen</name><name sortKey="Dai, Dongjun" sort="Dai, Dongjun" uniqKey="Dai D" first="Dongjun" last="Dai">Dongjun Dai</name><name sortKey="Feng, Lifeng" sort="Feng, Lifeng" uniqKey="Feng L" first="Lifeng" last="Feng">Lifeng Feng</name><name sortKey="Han, Shuting" sort="Han, Shuting" uniqKey="Han S" first="Shuting" last="Han">Shuting Han</name><name sortKey="Jiang, Tingting" sort="Jiang, Tingting" uniqKey="Jiang T" first="Tingting" last="Jiang">Tingting Jiang</name><name sortKey="Jin, Hongchuan" sort="Jin, Hongchuan" uniqKey="Jin H" first="Hongchuan" last="Jin">Hongchuan Jin</name><name sortKey="Shin, Vivian Y" sort="Shin, Vivian Y" uniqKey="Shin V" first="Vivian Y." last="Shin">Vivian Y. Shin</name><name sortKey="Song, Ping" sort="Song, Ping" uniqKey="Song P" first="Ping" last="Song">Ping Song</name><name sortKey="Wang, Xian" sort="Wang, Xian" uniqKey="Wang X" first="Xian" last="Wang">Xian Wang</name><name sortKey="Xu, Wenxia" sort="Xu, Wenxia" uniqKey="Xu W" first="Wenxia" last="Xu">Wenxia Xu</name><name sortKey="Zhu, Yiran" sort="Zhu, Yiran" uniqKey="Zhu Y" first="Yiran" last="Zhu">Yiran Zhu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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