miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells
Identifieur interne : 000258 ( Main/Exploration ); précédent : 000257; suivant : 000259miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells
Auteurs : Yue Zhou ; Enjiang Chen ; Yuexiao Tang ; Jiayan Mao ; Jian Shen ; Xiaoxiao Zheng ; Shangzhi Xie ; Shufen Zhang ; Ying Wu ; Hao Liu [États-Unis] ; Xiao Zhi ; Tao Ma ; Haibin Ni ; Jiabin Chen ; Kequn Chai ; Wei ChenSource :
- Cell Death & Disease [ 2041-4889 ] ; 2019.
Abstract
Doxorubicin is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. Autophagy, a conserved catabolic process for cellular self-protection and adaptation to the changing environment, is regarded as a potential clinical target to overcome doxorubicin resistance. In this study, the potential role of miR-223 in modulating doxorubicin-induced autophagy and sensitivity were evaluated in four transfected human HCC cell lines, and the in vivo relevance was assessed using a mouse xenograft model of HCC. We found that the well-defined miR-223 is expressed at low levels in doxorubicin treated HCC cells and that miR-223 overexpression inhibits the doxorubicin-induced autophagy that contributes to chemoresistance. Blockade of autophagic flux by chloroquine resulted in the failure of miR-223 inhibitor to suppress doxorubicin sensitivity of HCC cells. We further identified FOXO3a as a direct downstream target of miR-223 and primary mediator of the regulatory effect of miR-223 on doxorubicin-induced autophagy and chemoresistance in HCC cells. Finally, we confirmed the enhancement of doxorubicin sensitivity by agomiR-223 in xenograft models of HCC. These findings establish a novel miRNA-based approach for autophagy interference to reverse doxorubicin resistance in future chemotherapy regimens against human HCC.
Url:
DOI: 10.1038/s41419-019-2053-8
PubMed: 31695022
PubMed Central: 6834650
Affiliations:
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sortKey="Chen, Enjiang" sort="Chen, Enjiang" uniqKey="Chen E" first="Enjiang" last="Chen">Enjiang Chen</name><affiliation><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>The Second Affiliated Hospital of Zhejiang University,</institution><institution>School of Medicine,</institution></institution-wrap>310009 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation></author><author><name sortKey="Tang, Yuexiao" sort="Tang, Yuexiao" uniqKey="Tang Y" first="Yuexiao" last="Tang">Yuexiao Tang</name><affiliation><nlm:aff id="Aff3"><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 Genetics, Research Center for Molecular Medicine, Institute of Cell Biology, Key Laboratory of Reproductive Genetics, Ministry of Education,</institution><institution>Zhejiang University School of Medicine,</institution></institution-wrap>310058 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8744 8924</institution-id><institution-id institution-id-type="GRID">grid.268505.c</institution-id><institution>Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine,</institution><institution>Zhejiang Academy of Traditional Chinese Medicine,</institution></institution-wrap>310012 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation></author><author><name sortKey="Mao, Jiayan" sort="Mao, Jiayan" uniqKey="Mao J" 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institution-id-type="GRID">grid.13402.34</institution-id><institution>Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University,</institution><institution>School of Medicine,</institution></institution-wrap>310009 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation></author><author><name sortKey="Ni, Haibin" sort="Ni, Haibin" uniqKey="Ni H" first="Haibin" last="Ni">Haibin Ni</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4666 9789</institution-id><institution-id institution-id-type="GRID">grid.417168.d</institution-id><institution>Department of Gastrointestinal Surgery,</institution><institution>Tongde Hospital of Zhejiang Province,</institution></institution-wrap>310012 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation></author><author><name sortKey="Chen, Jiabin" sort="Chen, Jiabin" uniqKey="Chen J" first="Jiabin" last="Chen">Jiabin Chen</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4666 9789</institution-id><institution-id institution-id-type="GRID">grid.417168.d</institution-id><institution>Department of Medical Oncology,</institution><institution>Tongde Hospital of Zhejiang Province,</institution></institution-wrap>310012 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation></author><author><name sortKey="Chai, Kequn" sort="Chai, Kequn" uniqKey="Chai K" first="Kequn" last="Chai">Kequn Chai</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8744 8924</institution-id><institution-id institution-id-type="GRID">grid.268505.c</institution-id><institution>Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine,</institution><institution>Zhejiang Academy of Traditional Chinese Medicine,</institution></institution-wrap>310012 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4666 9789</institution-id><institution-id institution-id-type="GRID">grid.417168.d</institution-id><institution>Department of Medical Oncology,</institution><institution>Tongde Hospital of Zhejiang Province,</institution></institution-wrap>310012 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation></author><author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8744 8924</institution-id><institution-id institution-id-type="GRID">grid.268505.c</institution-id><institution>Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine,</institution><institution>Zhejiang Academy of Traditional Chinese Medicine,</institution></institution-wrap>310012 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4666 9789</institution-id><institution-id institution-id-type="GRID">grid.417168.d</institution-id><institution>Department of Medical Oncology,</institution><institution>Tongde Hospital of Zhejiang Province,</institution></institution-wrap>310012 Hangzhou, Zhejiang China</nlm:aff><wicri:noCountry code="subfield">Zhejiang China</wicri:noCountry></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">Doxorubicin is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. Autophagy, a conserved catabolic process for cellular self-protection and adaptation to the changing environment, is regarded as a potential clinical target to overcome doxorubicin resistance. In this study, the potential role of miR-223 in modulating doxorubicin-induced autophagy and sensitivity were evaluated in four transfected human HCC cell lines, and the in vivo relevance was assessed using a mouse xenograft model of HCC. We found that the well-defined miR-223 is expressed at low levels in doxorubicin treated HCC cells and that miR-223 overexpression inhibits the doxorubicin-induced autophagy that contributes to chemoresistance. Blockade of autophagic flux by chloroquine resulted in the failure of miR-223 inhibitor to suppress doxorubicin sensitivity of HCC cells. We further identified FOXO3a as a direct downstream target of miR-223 and primary mediator of the regulatory effect of miR-223 on doxorubicin-induced autophagy and chemoresistance in HCC cells. Finally, we confirmed the enhancement of doxorubicin sensitivity by agomiR-223 in xenograft models of HCC. These findings establish a novel miRNA-based approach for autophagy interference to reverse doxorubicin resistance in future chemotherapy regimens against human HCC.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Forner, A" uniqKey="Forner A">A Forner</name></author><author><name sortKey="Reig, M" uniqKey="Reig M">M Reig</name></author><author><name sortKey="Bruix, J" uniqKey="Bruix J">J Bruix</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Forner, A" uniqKey="Forner A">A Forner</name></author><author><name sortKey="Gilabert, M" uniqKey="Gilabert M">M Gilabert</name></author><author><name sortKey="Bruix, J" uniqKey="Bruix J">J Bruix</name></author><author><name sortKey="Raoul, Jl" uniqKey="Raoul J">JL Raoul</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Asghar, U" uniqKey="Asghar U">U Asghar</name></author><author><name sortKey="Meyer, T" uniqKey="Meyer T">T Meyer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheng, By" uniqKey="Cheng B">BY Cheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karkampouna, S" uniqKey="Karkampouna S">S Karkampouna</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Dikic, I" uniqKey="Dikic I">I Dikic</name></author><author><name sortKey="Elazar, Z" uniqKey="Elazar Z">Z Elazar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, W" uniqKey="Chen W">W Chen</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Salcher, S" uniqKey="Salcher S">S Salcher</name></author><author><name sortKey="Hermann, M" uniqKey="Hermann M">M Hermann</name></author><author><name sortKey="Kiechl Kohlendorfer, U" uniqKey="Kiechl Kohlendorfer U">U Kiechl-Kohlendorfer</name></author><author><name sortKey="Ausserlechner, Mj" uniqKey="Ausserlechner M">MJ Ausserlechner</name></author><author><name sortKey="Obexer, P" uniqKey="Obexer P">P Obexer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gade, Tpf" uniqKey="Gade T">TPF Gade</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, N" uniqKey="Zhang N">N Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sun, H" uniqKey="Sun H">H Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rupaimoole, R" uniqKey="Rupaimoole R">R Rupaimoole</name></author><author><name sortKey="Slack, Fj" uniqKey="Slack F">FJ Slack</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, M" uniqKey="Chen M">M Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chowdhury, Sm" uniqKey="Chowdhury S">SM Chowdhury</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, P" uniqKey="Zhao P">P Zhao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ji, J" uniqKey="Ji J">J Ji</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dong, Yw" uniqKey="Dong Y">YW Dong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, J" uniqKey="Zhou J">J Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wong, Qw" uniqKey="Wong Q">QW Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zheng, H" uniqKey="Zheng H">H Zheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, T" uniqKey="Yang T">T Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, X" uniqKey="Liu X">X Liu</name></author><author><name sortKey="Deng, Y" uniqKey="Deng Y">Y Deng</name></author><author><name sortKey="Xu, Y" uniqKey="Xu Y">Y Xu</name></author><author><name sortKey="Jin, W" uniqKey="Jin W">W Jin</name></author><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shin, Hj" uniqKey="Shin H">HJ Shin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cai, J" uniqKey="Cai J">J Cai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fitzwalter, Be" uniqKey="Fitzwalter B">BE Fitzwalter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, G" uniqKey="Liu G">G Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Olivieri, F" uniqKey="Olivieri F">F Olivieri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, Y" uniqKey="Zhou Y">Y Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jin, F" uniqKey="Jin F">F Jin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xu, L" uniqKey="Xu L">L Xu</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Colorado</li></region></list><tree><noCountry><name sortKey="Chai, Kequn" sort="Chai, Kequn" uniqKey="Chai K" first="Kequn" last="Chai">Kequn Chai</name><name sortKey="Chen, Enjiang" sort="Chen, Enjiang" uniqKey="Chen E" first="Enjiang" last="Chen">Enjiang Chen</name><name sortKey="Chen, Jiabin" sort="Chen, Jiabin" uniqKey="Chen J" first="Jiabin" last="Chen">Jiabin Chen</name><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><name sortKey="Ma, Tao" sort="Ma, Tao" uniqKey="Ma T" first="Tao" last="Ma">Tao Ma</name><name sortKey="Mao, Jiayan" sort="Mao, Jiayan" uniqKey="Mao J" first="Jiayan" last="Mao">Jiayan Mao</name><name sortKey="Ni, Haibin" sort="Ni, Haibin" uniqKey="Ni H" first="Haibin" last="Ni">Haibin Ni</name><name sortKey="Shen, Jian" sort="Shen, Jian" uniqKey="Shen J" first="Jian" last="Shen">Jian Shen</name><name sortKey="Tang, Yuexiao" sort="Tang, Yuexiao" uniqKey="Tang Y" first="Yuexiao" last="Tang">Yuexiao Tang</name><name sortKey="Wu, Ying" sort="Wu, Ying" uniqKey="Wu Y" first="Ying" last="Wu">Ying Wu</name><name sortKey="Xie, Shangzhi" sort="Xie, Shangzhi" uniqKey="Xie S" first="Shangzhi" last="Xie">Shangzhi Xie</name><name sortKey="Zhang, Shufen" sort="Zhang, Shufen" uniqKey="Zhang S" first="Shufen" last="Zhang">Shufen Zhang</name><name sortKey="Zheng, Xiaoxiao" sort="Zheng, Xiaoxiao" uniqKey="Zheng X" first="Xiaoxiao" last="Zheng">Xiaoxiao Zheng</name><name sortKey="Zhi, Xiao" sort="Zhi, Xiao" uniqKey="Zhi X" first="Xiao" last="Zhi">Xiao Zhi</name><name sortKey="Zhou, Yue" sort="Zhou, Yue" uniqKey="Zhou Y" first="Yue" last="Zhou">Yue Zhou</name></noCountry><country name="États-Unis"><region name="Colorado"><name sortKey="Liu, Hao" sort="Liu, Hao" uniqKey="Liu H" first="Hao" last="Liu">Hao Liu</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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