Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer
Identifieur interne : 000176 ( Pmc/Checkpoint ); précédent : 000175; suivant : 000177Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer
Auteurs : Ying Wu [République populaire de Chine] ; Yuexiao Tang [République populaire de Chine] ; Shangzhi Xie [République populaire de Chine] ; Xiaoxiao Zheng [République populaire de Chine] ; Shufen Zhang [République populaire de Chine] ; Jiayan Mao [République populaire de Chine] ; Baoming Wang [République populaire de Chine] ; Yuerou Hou [République populaire de Chine] ; Liqiang Hu [République populaire de Chine] ; Kequn Chai [République populaire de Chine] ; Wei Chen [République populaire de Chine]Source :
- Theranostics [ 1838-7640 ] ; 2020.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis. Insights into the roles of MicroRNAs (miRNAs) in diseases, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches.
Url:
DOI: 10.7150/thno.38327
PubMed: 31938057
PubMed Central: 6956805
Affiliations:
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Y" first="Yuexiao" last="Tang">Yuexiao Tang</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Genetics, Institute of Genetics, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Genetics, Institute of Genetics, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang 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Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Hou, Yuerou" sort="Hou, Yuerou" uniqKey="Hou Y" first="Yuerou" last="Hou">Yuerou Hou</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Hu, Liqiang" sort="Hu, Liqiang" uniqKey="Hu L" first="Liqiang" last="Hu">Liqiang Hu</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Chai, Kequn" sort="Chai, Kequn" uniqKey="Chai K" first="Kequn" last="Chai">Kequn Chai</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 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xml:lang="en" level="a" type="main">Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer</title><author><name sortKey="Wu, Ying" sort="Wu, Ying" uniqKey="Wu Y" first="Ying" last="Wu">Ying Wu</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Tang, Yuexiao" sort="Tang, Yuexiao" uniqKey="Tang Y" first="Yuexiao" last="Tang">Yuexiao Tang</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Genetics, Institute of Genetics, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Genetics, Institute of Genetics, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Xie, Shangzhi" sort="Xie, Shangzhi" uniqKey="Xie S" first="Shangzhi" last="Xie">Shangzhi Xie</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Zheng, Xiaoxiao" sort="Zheng, Xiaoxiao" uniqKey="Zheng X" first="Xiaoxiao" last="Zheng">Xiaoxiao Zheng</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Zhang, Shufen" sort="Zhang, Shufen" uniqKey="Zhang S" first="Shufen" last="Zhang">Shufen Zhang</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Mao, Jiayan" sort="Mao, Jiayan" uniqKey="Mao J" first="Jiayan" last="Mao">Jiayan Mao</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Wang, Baoming" sort="Wang, Baoming" uniqKey="Wang B" first="Baoming" last="Wang">Baoming Wang</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Hou, Yuerou" sort="Hou, Yuerou" uniqKey="Hou Y" first="Yuerou" last="Hou">Yuerou Hou</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Hu, Liqiang" sort="Hu, Liqiang" uniqKey="Hu L" first="Liqiang" last="Hu">Liqiang Hu</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Chai, Kequn" sort="Chai, Kequn" uniqKey="Chai K" first="Kequn" last="Chai">Kequn Chai</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author></analytic><series><title level="j">Theranostics</title><idno type="eISSN">1838-7640</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis. Insights into the roles of MicroRNAs (miRNAs) in diseases, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches.</p><p><bold>Methods:</bold> Here, we employed a novel chimeric peptide supramolecular nanoparticle delivery system for plectin-1 (PL-1)-targeted PDAC-specific miR-9 delivery <italic>in vitro</italic> and in pancreatic cancer patient-derived xenograft (PDX) model. RT-PCR and immunohistochemistry (IHC) were conducted to detect the expression pattern of eIF5A2. mRFP-GFP-LC3 fluorescence microscopy and Western blot were carried out to determine autophagy. Luciferase reporter assays were performed to elucidate the regulatory role of miR-9/eIF5A2 axis.</p><p><bold>Results:</bold> PL-1/miR-9 nanocomplexes dramatically improve the anticancer effect of doxorubicin through downregulating eIF5A2 expression to inhibit autophagy and induce apoptosis in PDAC therapy<italic> in vivo</italic>. Mechanistically, miR-9 directly targets the <italic>eIF5A2</italic> transcript by binding to its 3'-untranslated region (3'-UTR) to reduce the expression levels and the secreted protein of eIF5A2 in PDAC cells.</p><p><bold>Conclusion:</bold> PL-1/miR-9 nanoparticles can be used as a novel promising anti-cancer strategy with tumor targeting and miR-9/eIF5A2 may serve as a new potential therapeutic target for future synergic therapy against human PDAC.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Miller, Kd" uniqKey="Miller K">KD Miller</name></author><author><name sortKey="Siegel, Rl" uniqKey="Siegel R">RL Siegel</name></author><author><name sortKey="Lin, Cc" uniqKey="Lin C">CC Lin</name></author><author><name sortKey="Mariotto, Ab" uniqKey="Mariotto A">AB Mariotto</name></author><author><name sortKey="Kramer, Jl" uniqKey="Kramer J">JL Kramer</name></author><author><name sortKey="Rowland, Jh" uniqKey="Rowland J">JH 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Theranostics</journal-id><journal-id journal-id-type="iso-abbrev">Theranostics</journal-id><journal-id journal-id-type="publisher-id">thno</journal-id><journal-title-group><journal-title>Theranostics</journal-title></journal-title-group><issn pub-type="epub">1838-7640</issn><publisher><publisher-name>Ivyspring International Publisher</publisher-name><publisher-loc>Sydney</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31938057</article-id><article-id pub-id-type="pmc">6956805</article-id><article-id pub-id-type="doi">10.7150/thno.38327</article-id><article-id pub-id-type="publisher-id">thnov10p1151</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Ying</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Yuexiao</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Xie</surname><given-names>Shangzhi</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Zheng</surname><given-names>Xiaoxiao</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Shufen</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mao</surname><given-names>Jiayan</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Baoming</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hou</surname><given-names>Yuerou</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Liqiang</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chai</surname><given-names>Kequn</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib></contrib-group><aff id="A1"><label>1</label>Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province, Hangzhou 310012, China</aff><aff id="A2"><label>2</label>Department of Genetics, Institute of Genetics, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding author: Wei Chen (<email>wei_chen@zju.edu.cn</email>) E-mail: <email>wei_chen@zju.edu.cn</email> Telephone: +86-0571-89975968 and/or Kequn Chai (<email>ckq3301@aliyun.com</email>) E-mail: <email>ckq3301@aliyun.com</email> Telephone: +86-0571-89972001 Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang province 234 Gucui Road, Hangzhou, Zhejiang province, 310012, China</corresp><fn fn-type="equal" id="FNA_star"><p><sup>*</sup>These authors contributed equally to this work</p></fn><fn fn-type="COI-statement"><p>Competing Interests: The authors have declared that no competing interest exists.</p></fn></author-notes><pub-date pub-type="collection"><year>2020</year></pub-date><pub-date pub-type="epub"><day>1</day><month>1</month><year>2020</year></pub-date><volume>10</volume><issue>3</issue><fpage>1151</fpage><lpage>1165</lpage><history><date date-type="received"><day>11</day><month>7</month><year>2019</year></date><date date-type="accepted"><day>6</day><month>11</month><year>2019</year></date></history><permissions><copyright-statement>© The author(s)</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>). See <ext-link ext-link-type="uri" xlink:href="http://ivyspring.com/terms">http://ivyspring.com/terms</ext-link> for full terms and conditions.</license-p></license></permissions><abstract><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis. Insights into the roles of MicroRNAs (miRNAs) in diseases, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches.</p><p><bold>Methods:</bold> Here, we employed a novel chimeric peptide supramolecular nanoparticle delivery system for plectin-1 (PL-1)-targeted PDAC-specific miR-9 delivery <italic>in vitro</italic> and in pancreatic cancer patient-derived xenograft (PDX) model. RT-PCR and immunohistochemistry (IHC) were conducted to detect the expression pattern of eIF5A2. mRFP-GFP-LC3 fluorescence microscopy and Western blot were carried out to determine autophagy. Luciferase reporter assays were performed to elucidate the regulatory role of miR-9/eIF5A2 axis.</p><p><bold>Results:</bold> PL-1/miR-9 nanocomplexes dramatically improve the anticancer effect of doxorubicin through downregulating eIF5A2 expression to inhibit autophagy and induce apoptosis in PDAC therapy<italic> in vivo</italic>. Mechanistically, miR-9 directly targets the <italic>eIF5A2</italic> transcript by binding to its 3'-untranslated region (3'-UTR) to reduce the expression levels and the secreted protein of eIF5A2 in PDAC cells.</p><p><bold>Conclusion:</bold> PL-1/miR-9 nanoparticles can be used as a novel promising anti-cancer strategy with tumor targeting and miR-9/eIF5A2 may serve as a new potential therapeutic target for future synergic therapy against human PDAC.</p></abstract><kwd-group><kwd>PDAC</kwd><kwd>miR-9</kwd><kwd>nanoparticle</kwd><kwd>eIF5A2</kwd><kwd>autophagy</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold> miR-9 enhances doxorubicin sensitivity in PDAC cells. (A)</bold> PDAC cells were incubated with indicated concentration (0, 0.125, 0.25, 0.5, 1, 2 μg/ml) of doxorubicin for 48 hr. Cell viability was assessed using Cell Counting Kit-8 assay. <bold>(B)</bold> Quantitative IC50 analysis of doxorubicin and quantitative RT-PCR analysis of miR-9 abundance in PDAC cells (n=3 independent experiments). <bold>(C)</bold> The correlation between miR-9 expression and IC50 value of PDAC cell lines for doxorubicin. <bold>(D)</bold> Quantitative RT-PCR analysis of miR-9 abundance in paired Adjacent and Tumor from PDAC patients (n=16). <bold>(E)</bold> PDAC cells were treated with 0.5 μg/ml doxorubicin for 48 hr. Shown are quantitative RT-PCR analysis of miR-9 abundance. <bold>(F-H)</bold> PDAC cells were treated with indicated concentration of doxorubicin for 48 hr after lipofectamine 2000 (Lipo) mediated miR-9 or control transfection in PANC-1 cells and CFPAC-1 cells. Quantitative RT-PCR analysis of miR-9 abundance (F). Cell viability was assessed using Cell Counting Kit-8 assay (G). Shown are quantitative IC50 analysis of doxorubicin (n=3 independent experiments) (H). <bold>(I)</bold> EdU analysis of proliferation in PDAC cells. Cells were treated with doxorubicin after lipofectamine mediated miR-9 or control transfection in PANC-1 cells and CFPAC-1 cells. Shown are representative EdU labeling images (left) and quantifications of EdU-positive cells in percentages (right), respectively. Scale bars, 50 μm. Data are presented as the mean ± SD, and analyzed with Student's <italic>t</italic>-test or one-way ANOVA. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01</p></caption><graphic xlink:href="thnov10p1151g001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p><bold> miR-9 ameliorates doxorubicin sensitivity though inhibiting autophagy in PDAC cells. (A)</bold> PDAC cells were incubated with 0.5 μg/ml doxorubicin for 48 hr along with or without 10 μΜ Chloroquine. LC3 and P62 protein expression were assessed using Western blot. β-actin was used as the loading control. <bold>(B)</bold> PDAC cells with lipofectamine mediated miR-9 or control transfection, treated with or without 0.5 μg/ml doxorubicin for 48 hr. LC3 and P62 protein expression were assessed using Western blot. β-actin was used as the loading control.<bold> (C)</bold> mRFP-GFP-LC3 stable PANC-1 and CFPAC-1 cells with different treatment were visualized by confocal microscopy. The numbers of GFP<sup>+</sup>/mRFP<sup>+</sup>-LC3 (yellow) and GFP<sup>-</sup>/mRFP<sup>+</sup>-LC3 (red) dots were recorded at least in 50-100 cells. Scale bars, 10 μm. <bold>(D-G)</bold> PDAC cells were transfected with Lipo mediated miR-9 or control, then cells were incubated with indicated concentration of doxorubicin for 48 hr along with 10 μΜ Chloroquine (D, E) or 100 nM Rapamycin (F, G). Cell viability was assessed using Cell Counting Kit-8 assay (D, F). LC3 and P62 protein expression were assessed using Western blot (E, G). β-actin was used as the loading control. Data are presented as the mean ± SD, and analyzed with Student's <italic>t</italic>-test, one-way or two-way ANOVA. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01.</p></caption><graphic xlink:href="thnov10p1151g002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p><bold> miR-9 sensitizes PDAC cells to doxorubicin chemotherapy via directly targeting the eIF5A2 transcript. (A-B)</bold> PDAC cells were transfected with miR-9 or control for 48 hr. Quantitative RT-PCR analysis of the mRNA abundance of eIF5A2 (A). eIF5A2 protein expression was assessed using Western blot (B). <bold>(C)</bold> miR-9 and its supposed binding sequence of eIF5A2, and the construct of eIF5A2-luciferase reporter plasmids (eIF5A2 WT and eIF5A2 Mut). <bold>(D)</bold> HEK293T cells were co-transfected for 48 h with the eIF5A2-luciferase reporter plasmids (eIF5A2 WT and eIF5A2 Mut) along with miR-9 mimics, miR-9 inhibitor or a negative control. eIF5A2 activity was determined by the luciferase assay. Shown are relative luciferase activities after normalization to Renilla that was used as the internal control. <bold>(E)</bold> PDAC cells with miR-9 or control transfection, treated with 0.5 μg/ml doxorubicin for 48 hr. eIF5A2 protein expression was assessed using Western blot. β-actin was used as the loading control. <bold>(F)</bold> Quantitative RT-PCR analysis of eIF5A2 abundance in paired Adjacent and Tumor from PDAC patients (n=16). <bold>(G)</bold> PDAC cells with siRNA directed against eIF5A2 or control transfection, treated with 0.5 μg/ml doxorubicin for 48 hr. eIF5A2, LC3 and P62 protein expression were assessed using Western blot. β-actin was used as the loading control. <bold>(H)</bold> PDAC cells with sieIF5A2 or control transfection were incubated with indicated concentration of doxorubicin for 48 hr. Cell viability was assessed using Cell Counting Kit-8 assay.<bold> (I)</bold> PDAC cells with miR-9 or sieIF5A2 transfection were incubated with 0.5 μg/ml doxorubicin for 48 hr. LC3 and P62 protein expression were assessed using Western blot. β-actin was used as the loading control. <bold>(J)</bold> PDAC cells with sieIF5A2 or miR-9 co-transfection were incubated with indicated concentration of doxorubicin for 48 hr. Cell viability was assessed using Cell Counting Kit-8 assay. <bold>(K)</bold> PDAC cells with miR-9 or eIF5A2 overexpression plasmid (OE eIF5A2) transfection were incubated with 0.5 μg/ml doxorubicin for 48 hr. eIF5A2, LC3 and P62 protein expression were assessed using Western blot. β-actin was used as the loading control. <bold>(L)</bold> PDAC cells with eIF5A2 overexpression plasmid (OE eIF5A2) or miR-9 co-transfection were incubated with indicated concentration of doxorubicin for 48 hr. Cell viability was assessed using Cell Counting Kit-8 assay. Experiments were repeated in three times. Data are presented as the mean ± SD, and analyzed with Student's <italic>t</italic>-test or one-way ANOVA. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.001.</p></caption><graphic xlink:href="thnov10p1151g003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p><bold> PL-1 motif-functionalized nanoparticles are more stable and deliver miR-9 to PDAC cells with high specificity. (A)</bold> Self-assembly of PL-1 polypeptides with miR-9 payloads to form nanocomplexes. The PDAC-specific peptide PTP was fused to the N-terminus of nine D-arginine residues via a four-glycine linker. <bold>(B)</bold> Agarose gel (3%) retardation assay at different molar ratios of PL-1 to miR-9.<bold> (C)</bold> The average hydrodynamic diameter of the nanoparticles in ddH<sub>2</sub>O, as assessed by DLS, was 180 ± 17 nm. <bold>(D)</bold> Stability of naked miR-9 and miR-9 complexed with PL-1 at a molar ratio of 20:1, after incubation with RNase A (upper). Serum stability after incubation in 50% mouse-serum solution (lower). <bold>(E)</bold> Representative confocal fluorescence microscopy images of PANC-1 and CFPAC-1 cells treated with Cy3 (red)-labeled miR-9 (50 nM)/PL-1 peptide complex. Nuclei and endosomes/lysosomes were stained with Hoechst (blue) and FITC-labeled Dextran (green, endo/lysosome tracker). Scale bars, 10 μm. <bold>(F-G)</bold> PDAC cells were transfected with miR-9 using PL-1 or Lipo for 48 hr. Quantitative RT-PCR analysis of the mRNA abundance of miR-9 and eIF5A2 (F). eIF5A2 protein expression was assessed using Western blot (G). Experiments were repeated in three times. Data are presented as the mean ± SD, and analyzed with Student's <italic>t</italic>-test or one-way ANOVA. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.001.</p></caption><graphic xlink:href="thnov10p1151g004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p><bold> PL-1/miR-9 nanoparticles effectively reverse the sensitivity of PDAC cells to doxorubicin. (A)</bold> PDAC cells were incubated with indicated concentration of doxorubicin for 48 hr with PL-1/NC or PL-1/miR-9 nanoparticles pretransfection. Cell viability was assessed using Cell Counting Kit-8 assay.<bold> (B)</bold> mRFP-GFP-LC3 stable PANC-1 and CFPAC-1 cells with different treatment were visualized by confocal microscopy. The numbers of GFP<sup>+</sup>/mRFP<sup>+</sup>-LC3 (yellow) and GFP<sup>-</sup>/mRFP<sup>+</sup>-LC3 (red) dots were recorded at least in 50-100 cells. Scale bars, 10 μm. <bold>(C)</bold> PDAC cells with PL-1 mediated miR-9 or control transfection, treated with 0.5 μg/ml doxorubicin for 48 hr. eIF5A2, LC3 and P62 protein expression were assessed using Western blot. β-actin was used as the loading control. Experiments were repeated in three times. Data are presented as the mean ± SD, and analyzed with Student's <italic>t</italic>-test or two-way ANOVA. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01</p></caption><graphic xlink:href="thnov10p1151g005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p><bold> miR-9 intervention enhances doxorubicin efficacy in xenografts growth from PDXs. (A)</bold> Xenografts dissected from mice of different groups after two weeks of various treatments. <bold>(B)</bold> Body weight. <bold>(C)</bold> Tumor volume. <bold>(D)</bold> Tumor regression rates. <bold>(E)</bold> eIF5A2, LC3 and P62 protein expression in tumors were assessed using Western blot. β-actin was used as the loading control.<bold> (F)</bold> Representative TUNEL labeling images and immunohistochemistry (IHC) images of tumors stained with anti-Ki-67 or anti-eIF5A2 antibody. Scale bars, 50 μm or 100 μm. <bold>(G)</bold> Ki-67-positive, TUNEL-positive and eIF5A2-positive cells were quantified and are shown in percentages, respectively.<bold> (H)</bold> Representative <italic>ex vivo</italic> NIRF image of xenografts in the PDXs-bearing mice at 24 hr after intravenous injection of Vehicle (equal volume of PBS), PL-1-Cy5/miR-9 or SP-94dr-Cy5/miR-9 nanoparticles. Data are presented as the mean ± SD, and analyzed with Student's <italic>t</italic>-test or one-way ANOVA. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01.</p></caption><graphic xlink:href="thnov10p1151g006"></graphic></fig></floats-group></pmc><affiliations><list><country><li>République populaire de Chine</li></country><region><li>Zhejiang</li></region><settlement><li>Hangzhou</li></settlement></list><tree><country name="République populaire de Chine"><region name="Zhejiang"><name sortKey="Wu, Ying" sort="Wu, Ying" uniqKey="Wu Y" first="Ying" last="Wu">Ying Wu</name></region><name sortKey="Chai, Kequn" sort="Chai, Kequn" uniqKey="Chai K" first="Kequn" last="Chai">Kequn Chai</name><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><name sortKey="Hou, Yuerou" sort="Hou, Yuerou" uniqKey="Hou Y" first="Yuerou" last="Hou">Yuerou Hou</name><name sortKey="Hu, Liqiang" sort="Hu, Liqiang" uniqKey="Hu L" first="Liqiang" last="Hu">Liqiang Hu</name><name sortKey="Mao, Jiayan" sort="Mao, Jiayan" uniqKey="Mao J" first="Jiayan" last="Mao">Jiayan Mao</name><name sortKey="Tang, Yuexiao" sort="Tang, Yuexiao" uniqKey="Tang Y" first="Yuexiao" last="Tang">Yuexiao Tang</name><name sortKey="Tang, Yuexiao" sort="Tang, Yuexiao" uniqKey="Tang Y" first="Yuexiao" last="Tang">Yuexiao Tang</name><name sortKey="Wang, Baoming" sort="Wang, Baoming" uniqKey="Wang B" first="Baoming" last="Wang">Baoming Wang</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></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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