The failure of DAC to induce OCT2 expression and its remission by hemoglobin-based nanocarriers under hypoxia in renal cell carcinoma
Identifieur interne : 000018 ( Pmc/Checkpoint ); précédent : 000017; suivant : 000019The failure of DAC to induce OCT2 expression and its remission by hemoglobin-based nanocarriers under hypoxia in renal cell carcinoma
Auteurs : Lu Chen [République populaire de Chine] ; Zeyang Wang [République populaire de Chine] ; Qingwen Xu [République populaire de Chine] ; Yuxi Liu [République populaire de Chine] ; Le Chen [République populaire de Chine] ; Suhang Guo [République populaire de Chine] ; Hua Wang [République populaire de Chine] ; Kui Zeng [République populaire de Chine] ; Junqing Liu [République populaire de Chine] ; Su Zeng [République populaire de Chine] ; Lushan Yu [République populaire de Chine]Source :
- Theranostics [ 1838-7640 ] ; 2020.
Abstract
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DOI: 10.7150/thno.39944
PubMed: NONE
PubMed Central: 7069078
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The failure of DAC to induce OCT2 expression and its remission by hemoglobin-based nanocarriers under hypoxia in renal cell carcinoma</title><author><name sortKey="Chen, Lu" sort="Chen, Lu" uniqKey="Chen L" first="Lu" last="Chen">Lu Chen</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Wang, Zeyang" sort="Wang, Zeyang" uniqKey="Wang Z" first="Zeyang" last="Wang">Zeyang Wang</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Xu, Qingwen" sort="Xu, Qingwen" uniqKey="Xu Q" first="Qingwen" last="Xu">Qingwen Xu</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Liu, Yuxi" sort="Liu, Yuxi" uniqKey="Liu Y" first="Yuxi" last="Liu">Yuxi Liu</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Chen, Le" sort="Chen, Le" uniqKey="Chen L" first="Le" last="Chen">Le Chen</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Guo, Suhang" sort="Guo, Suhang" uniqKey="Guo S" first="Suhang" last="Guo">Suhang Guo</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Wang, Hua" sort="Wang, Hua" uniqKey="Wang H" first="Hua" last="Wang">Hua Wang</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou 310022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou 310022</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Zeng, Kui" sort="Zeng, Kui" uniqKey="Zeng K" first="Kui" last="Zeng">Kui Zeng</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Liu, Junqing" sort="Liu, Junqing" uniqKey="Liu J" first="Junqing" last="Liu">Junqing Liu</name><affiliation wicri:level="4"><nlm:aff id="A3">The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310022</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Zeng, Su" sort="Zeng, Su" uniqKey="Zeng S" first="Su" last="Zeng">Su Zeng</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Yu, Lushan" sort="Yu, Lushan" uniqKey="Yu L" first="Lushan" last="Yu">Lushan Yu</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7069078</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069078</idno><idno type="RBID">PMC:7069078</idno><idno type="doi">10.7150/thno.39944</idno><idno type="pmid">NONE</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000815</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000815</idno><idno type="wicri:Area/Pmc/Curation">000815</idno><idno type="wicri:explorRef" wicri:stream="Pmc" 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Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Wang, Zeyang" sort="Wang, Zeyang" uniqKey="Wang Z" first="Zeyang" last="Wang">Zeyang Wang</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Xu, Qingwen" sort="Xu, Qingwen" uniqKey="Xu Q" first="Qingwen" last="Xu">Qingwen Xu</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Liu, Yuxi" sort="Liu, Yuxi" uniqKey="Liu Y" first="Yuxi" last="Liu">Yuxi Liu</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Chen, Le" sort="Chen, Le" uniqKey="Chen L" first="Le" last="Chen">Le Chen</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Guo, Suhang" sort="Guo, Suhang" uniqKey="Guo S" first="Suhang" last="Guo">Suhang Guo</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Wang, Hua" sort="Wang, Hua" uniqKey="Wang H" first="Hua" last="Wang">Hua Wang</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou 310022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou 310022</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Zeng, Kui" sort="Zeng, Kui" uniqKey="Zeng K" first="Kui" last="Zeng">Kui Zeng</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Liu, Junqing" sort="Liu, Junqing" uniqKey="Liu J" first="Junqing" last="Liu">Junqing Liu</name><affiliation wicri:level="4"><nlm:aff id="A3">The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310022</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Zeng, Su" sort="Zeng, Su" uniqKey="Zeng S" first="Su" last="Zeng">Su Zeng</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName></affiliation></author><author><name sortKey="Yu, Lushan" sort="Yu, Lushan" uniqKey="Yu L" first="Lushan" last="Yu">Lushan Yu</name><affiliation wicri:level="4"><nlm:aff id="A1">Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058</wicri:regionArea><placeName><settlement type="city">Hangzhou</settlement><region type="province">Zhejiang</region></placeName><orgName type="university">Université de Zhejiang</orgName><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><bold>Background:</bold> Human organic cation transporter 2 (OCT2) is the most abundant and important uptake transporter involved in the renal excretion of cationic drugs. Abnormal hypermethylation- mediated silencing of OCT2 results in oxaliplatin resistance in renal cell carcinoma (RCC). The epigenetic activation of OCT2 by decitabine (DAC) reversed this resistance in normoxic conditions. Given the hypoxic characteristic of RCC, it is still unclear whether hypoxia promotes DAC resistance and is involved in the regulation of OCT2.</p><p><bold>Methods:</bold> The mRNA and protein expression of OCT2 was determined by qRT-PCR and Western blotting. MSRE-qPCR and BSP were used to examine methylation modifications at the OCT2 promoter. The ChIP-qPCR analysis was performed to detect the abundance of histone modification and HIF-1α. The accumulation of DAC and 5-mC were detected using LC-MS, and the amount of 5-hmC was determined by dot blot analysis. To understand the role of hypoxia in the regulation of equilibrative nucleoside transporter 1 (ENT1) expression, the HIF-1α KO cell model was constructed. The re-emulsion method was used for the construction of H-NPs, an oxygen nanocarrier based on hemoglobin, to alleviate the drug resistance of DAC under hypoxia.</p><p><bold>Results:</bold> DAC was unable to upregulate OCT2 expression in hypoxic conditions because of the hypermethylation and low H3K4me3 modification in its promoter region. Hypoxia-mediated repression of human ENT1, which was markedly suppressed in RCC, resulted in a decrease in the cellular accumulation of DAC. Besides, hypoxia-induced upregulation of histone deacetylase HDAC9, which impaired the enrichment of H3K27ac modification in the OCT2 promoter, led to the transcriptional repression of OCT2. H-NPs could attenuate the hypoxia-induced loss of DAC activity and sensitize RCC cells to the sequential combination therapy of DAC and oxaliplatin.</p><p><bold>Conclusions:</bold> Hypoxia-mediated repression of ENT1 led to the inability of DAC to upregulate the expression of OCT2 under hypoxia. H-NPs could alleviate resistance to oxaliplatin and DAC in RCC cells under hypoxia and may have potential clinical applications.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Choueiri, Tk" uniqKey="Choueiri T">TK Choueiri</name></author><author><name sortKey="Motzer, Rj" uniqKey="Motzer R">RJ Motzer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nickerson, Ml" uniqKey="Nickerson M">ML Nickerson</name></author><author><name sortKey="Jaeger, E" uniqKey="Jaeger E">E Jaeger</name></author><author><name sortKey="Shi, Y" uniqKey="Shi Y">Y Shi</name></author><author><name sortKey="Durocher, Ja" uniqKey="Durocher J">JA Durocher</name></author><author><name sortKey="Mahurkar, S" uniqKey="Mahurkar S">S Mahurkar</name></author><author><name sortKey="Zaridze, D" uniqKey="Zaridze D">D Zaridze</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singer, Ea" uniqKey="Singer 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article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<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="pmc">7069078</article-id><article-id pub-id-type="doi">10.7150/thno.39944</article-id><article-id pub-id-type="publisher-id">thnov10p3562</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>The failure of DAC to induce OCT2 expression and its remission by hemoglobin-based nanocarriers under hypoxia in renal cell carcinoma</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Lu</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>Wang</surname><given-names>Zeyang</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>Xu</surname><given-names>Qingwen</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Yuxi</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Le</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>Suhang</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Hua</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Zeng</surname><given-names>Kui</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Junqing</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Zeng</surname><given-names>Su</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>Yu</surname><given-names>Lushan</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>Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.</aff><aff id="A2"><label>2</label>Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou 310022, China</aff><aff id="A3"><label>3</label>The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310022, China</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding authors: Tel: +86 571 88208407; Fax: +86 571 88208407; Email: <email>yuls@zju.edu.cn</email> or Tel: +86 571 88208405; Fax: +86 571 88208405; Email: <email>zengsu@zju.edu.cn</email></corresp><fn fn-type="equal" id="FNA_star"><p>*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>18</day><month>2</month><year>2020</year></pub-date><volume>10</volume><issue>8</issue><fpage>3562</fpage><lpage>3578</lpage><history><date date-type="received"><day>3</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>8</day><month>1</month><year>2020</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><bold>Background:</bold> Human organic cation transporter 2 (OCT2) is the most abundant and important uptake transporter involved in the renal excretion of cationic drugs. Abnormal hypermethylation- mediated silencing of OCT2 results in oxaliplatin resistance in renal cell carcinoma (RCC). The epigenetic activation of OCT2 by decitabine (DAC) reversed this resistance in normoxic conditions. Given the hypoxic characteristic of RCC, it is still unclear whether hypoxia promotes DAC resistance and is involved in the regulation of OCT2.</p><p><bold>Methods:</bold> The mRNA and protein expression of OCT2 was determined by qRT-PCR and Western blotting. MSRE-qPCR and BSP were used to examine methylation modifications at the OCT2 promoter. The ChIP-qPCR analysis was performed to detect the abundance of histone modification and HIF-1α. The accumulation of DAC and 5-mC were detected using LC-MS, and the amount of 5-hmC was determined by dot blot analysis. To understand the role of hypoxia in the regulation of equilibrative nucleoside transporter 1 (ENT1) expression, the HIF-1α KO cell model was constructed. The re-emulsion method was used for the construction of H-NPs, an oxygen nanocarrier based on hemoglobin, to alleviate the drug resistance of DAC under hypoxia.</p><p><bold>Results:</bold> DAC was unable to upregulate OCT2 expression in hypoxic conditions because of the hypermethylation and low H3K4me3 modification in its promoter region. Hypoxia-mediated repression of human ENT1, which was markedly suppressed in RCC, resulted in a decrease in the cellular accumulation of DAC. Besides, hypoxia-induced upregulation of histone deacetylase HDAC9, which impaired the enrichment of H3K27ac modification in the OCT2 promoter, led to the transcriptional repression of OCT2. H-NPs could attenuate the hypoxia-induced loss of DAC activity and sensitize RCC cells to the sequential combination therapy of DAC and oxaliplatin.</p><p><bold>Conclusions:</bold> Hypoxia-mediated repression of ENT1 led to the inability of DAC to upregulate the expression of OCT2 under hypoxia. H-NPs could alleviate resistance to oxaliplatin and DAC in RCC cells under hypoxia and may have potential clinical applications.</p></abstract><kwd-group><kwd>renal cell carcinoma</kwd><kwd>hypoxia</kwd><kwd>OCT2</kwd><kwd>ENT1</kwd><kwd>nanoparticles</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold> The demethylation effect of DAC was blocked under hypoxia.</bold> (A) Quantitative RT-PCR analysis of <italic>SLC22A2</italic> mRNA transcripts in 3 RCC cell lines (786-O, 769-P, Caki-1) after being treated with 2.5 μmol/L DAC for 72 h in normoxia and hypoxia. (B) Immunoblotting of OCT2 in 786-O and 769-P at 72 h after DAC treatment, membrane protein was extracted to determine the protein expression of OCT2. ATP2A2 was used as a loading control of membrane extracts. (C) Schematic diagram of CpG island, bisulfite sequencing region and E-BOX motif in the upstream of <italic>SLC22A2</italic> TSS. TSS, transcription start site. (D) MSRE-qPCR analysis of E-BOX methylation frequency in 786-O and 769-P cell lines, treated with DAC for 72 h in normoxia and hypoxia separately. (E) BSP analysis of each CpG site's methylation probability at the promoter of<italic> SLC22A2</italic> gene in 786-O and 769-P cell lines under normoxia or hypoxia, in the presence or absence of DAC for 72 h. The results of each group derives from at least 10 sequenced clones. Solid black dots indicate that the CpG site is methylated, while hollow dots indicate non-methylation. N, normoxia; H, hypoxia.</p></caption><graphic xlink:href="thnov10p3562g001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p><bold> Hypoxia mediated regulation of key factors in the process of DNA dynamic methylation.</bold> (A) Proportion of 5-methylcytosine (5-mC) in total cytosine (Cyt) in 786-O and 769-P was detected after being treated with DAC for 72 h, in normoxia or hypoxia. The mRNA expression level of <italic>DNMT1</italic>, <italic>DNMT3</italic>, <italic>DNMT3b</italic> (B)and <italic>TETs</italic> (C)was significantly decreased during hypoxia in 786-O and 769-P compared with normoxia. Comparison of TET1 protein expression (D) and 5-hmC abundance (E) in 786-O, 769-P, Caki-1 and ACHN cell lines under hypoxia or normoxia by westernblot and dotblot separately. (F) The expression level of TET1 and OCT2 in 786-O and 769-P was detected by RT-PCR after TET1 knock-down and 72 h DAC treatment. (H) The expression level of <italic>OCT2</italic> were assayed in 786-O and 769-P cell lines transfected with TET1 catalytic domain expression vector or empty vector. The mRNA expression level of <italic>TET1</italic> (H) and the density of 5-hmC (G) were detected to ensure successful overexpression of TET1. TET1-CD, TET1 catalytic domain; N, normoxia; H, hypoxia.</p></caption><graphic xlink:href="thnov10p3562g002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p><bold> Repression of ENT1 expression and uptake of substrate entecavir under hypoxia.</bold> Four RCC cell lines (786-O, 769-P, Caki-1, ACHN) were exposed to normoxia or hypoxia for 48 h. Total RNA was isolated to determine <italic>ENT1</italic> mRNA levels by real-time PCR (A) and membrane protein was extracted to determine the protein expression of ENT1 (B). ATP2A2 was used as a loading control of membrane extracts. (C) Accumulation of entecavir, a substrates of ENT1, in 786-O and 769-P was detected by LC-MS after exposure under hypoxia for 48 h. The protein expression of ENT1 (D, F) and uptake of entecavir (E, G) were detected in 786-O and 769-P cell lines, exposed to indicated periods (24, 48 or 72 h) of hypoxia or indicated oxygen concentration (8%, 4% or 1%) for 48 h.</p></caption><graphic xlink:href="thnov10p3562g003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p><bold> Hypoxia-mediated reduction of DAC accumulation in RCC cells.</bold> The mRNA expression level of <italic>SLC22A2</italic> was detected in 786-O and 769-P, treated with 2.5 μmol/L DAC for 72 h under normoxia , in the presence of 1, 10 , 100 μM NBTI (A) or after being transfected with 3 sequence specific ENT1 siRNAs separately or synchronously (B). (C) DAC accumulation was analyzed by LC-MS in 3 RCC cell lines (786-O, 769-P, Caki-1), incubated with 500 μM DAC at 37 °C for 3 min, in the presence of ENT1 inhibitor or pre-transfected with ENT1 specific siRNAs. The mRNA(D) and protein (E) expression level of ENT1 were deteced in 786-O and 769-P cell lines to verify siRNA knockdown inefficiency. (F) ENT1 uptake capacity of DAC was analyzed in 786-O, 769-P and Caki-1, exposed under hypoxia (1% oxygen concentration) for 48 h. (G) Schematic diagram of reduced DAC accumulation mediated by repressed ENT1 expression under hypoxia.</p></caption><graphic xlink:href="thnov10p3562g004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p><bold> The expresssion of ENT1 and ENT2 are downregulated in RCC.</bold> (A, C) Comparison of <italic>SLC29A1</italic> (n=40) and <italic>SLC29A2</italic> (n=20) mRNA expression separately in human matched renal normal-tumor samples. The expression level was normalized to GAPDH. Results are expressed as mean ± SEM, Wilcoxon signed-rank test was used. **<italic>P</italic><0.01. (B) Comparison of ENT1 protein expression in human matched renal normal-tumor samples (n=5). The blot of β-actin was probed as a control for protein loading. (D) Representative images of immunohistochemistry staining for ENT1 in adjacent non-tumor tissue and paired ccRCC tumor tissue at different TNM stages. Scale bar, 20 μm. The antibody 11337-1-AP (proteintech) against ENT1 was used in the immunohistochemistry assays.</p></caption><graphic xlink:href="thnov10p3562g005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p><bold> HIF-1α-mediated repression of ENT1 expression in Caki-1 cells under hypoxia.</bold> Comparison of HIF-1α and HIF-2α protein expression in human matched renal normal-tumor samples (n=11) (A) and 3 RCC cell lines (786-O, 769-P, Caki-1) under normoxia or hypoxia for 6 h (B). (C) Schematic diagram of two hypoxia response elements (HRE) in the promoter of ENT1. (D) CHIP-qPCR analysis of HIF-1α at the promoter of ENT1 in Caki-1 cells, exposed under normoxia or hypoxia for 48 h. Two different HIF-1α antibodies (610958, BD Biosciences; NB100-105, Novus) were used to pull down HIF-1α. The protein expression level of HIF-1α (E) and mRNA expression level of <italic>SLC29A1</italic> (F) in Caki-1 under normoxia or hypoxia and HIF-1α knockout-Caki-1 cells. (G) The expression level of ARNT1 (HIF-1β) was detected in Caki-1, transfected with ARNT1 specific siRNAs or NC. Student's <italic>t</italic> test (two-tailed) was used. (H, I) The expression level of ENT1 in Caki-1, transfected with ARNT1 specific siRNAs or NC, under normoxia or hypoxia. Oneway-ANOVA analysis was used. The results are expressed as mean ± SEM (n=3). ***<italic>P</italic><0.001.</p></caption><graphic xlink:href="thnov10p3562g006"></graphic></fig><fig id="F7" position="float"><label>Figure 7</label><caption><p><bold> Effects of re-oxygenation on hypoxia-induced DAC resistance.</bold> (A) Quantitative RT-PCR analysis of <italic>SLC22A2</italic> mRNA in 786-O and 769-P, treated with 2.5μmol/L DAC for 72h in normoxia, after exposed under hypoxia for 24 or 48 h and The protein expression level of ENT1 in 786-O, 769-P and Caki-1, exposed under normoxia for indicated time, after exposed under hypoxia for 24 h. (B) Schematic of Hemoglobin-based nanocarrier preparation and structure. (C) Western blotting of ENT1 treated by H-NPs in 769-P under hypoxia. (D) MSRE-qPCR analysis of E-BOX methylation frequency in 769-P cell lines, treated with DAC, in the presence or absence of H-NPs, for 72 h in hypoxia separately. The mRNA (E) and protein (F) level expression of OCT2 and oxaliplatin uptake (G) in 769-P cell lines, treated with DAC, in the presence or absence of H-NPs, for 72 h in hypoxia separately. (H) Representative <italic>in-vivo</italic> and <italic>ex-vivo</italic> fluorescence images of nude mice treated with saline, Free ICG and ICG-H-NPs 5 h post injection. (I) The z-stacking images of the 769-P spheroid at different sections from 1 to 55 μm, sections from 20-40 μm had high fluorescence intensity and confocal microscope images of spheroid core and 3D graphics constructed by Imaris 9.3.1. The high fluorescence intensity at the core of 769-P spheroid which arrowed in 3D-plot indicated the H-NPs could alleviate hypoxic core of the solid tumor <italic>in vivo</italic>.</p></caption><graphic xlink:href="thnov10p3562g007"></graphic></fig><fig id="F8" position="float"><label>Figure 8</label><caption><p><bold> Hypoxia-mediated modification of histone acetylation for the regulation of OCT2 expression.</bold> (A) Four RCC cell lines (786-O, 769-P, Caki-1 and ACHN) were exposed to normoxia or hypoxia for 48 h. Membrane protein was extracted to determine the protein expression of OCT2. ATP2A2 was used as a loading control of membrane extracts. N, normoxia; H, hypoxia. (B) Quantitative RT-PCR analysis of <italic>HDAC9</italic> mRNA expression level in 3 RCC cell lines (786-O, 769-P, Caki-1), exposed under normoxia or hypoxia for 48 h. (C) Quantitative RT-PCR analysis of <italic>SLC22A2</italic> mRNA transcript in 3 RCC cell lines (786-O, 769-P, Caki-1) after being treated with 2 μmol/L SAHA for 48 h in hypoxia. (D) The enrichment of H3K27ac modification level at the OCT2 promoter region in 786-O and 769-P was detected by CHIP-qPCR analysis after exposed to normoxia or hypoxia for 48 h.</p></caption><graphic xlink:href="thnov10p3562g008"></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><orgName><li>Université de Zhejiang</li></orgName></list><tree><country name="République populaire de Chine"><region name="Zhejiang"><name sortKey="Chen, Lu" sort="Chen, Lu" uniqKey="Chen L" first="Lu" last="Chen">Lu Chen</name></region><name sortKey="Chen, Le" sort="Chen, Le" uniqKey="Chen L" first="Le" last="Chen">Le Chen</name><name sortKey="Guo, Suhang" sort="Guo, Suhang" uniqKey="Guo S" first="Suhang" last="Guo">Suhang Guo</name><name sortKey="Liu, Junqing" sort="Liu, Junqing" uniqKey="Liu J" first="Junqing" last="Liu">Junqing Liu</name><name sortKey="Liu, Yuxi" sort="Liu, Yuxi" uniqKey="Liu Y" first="Yuxi" last="Liu">Yuxi Liu</name><name sortKey="Wang, Hua" sort="Wang, Hua" uniqKey="Wang H" first="Hua" last="Wang">Hua Wang</name><name sortKey="Wang, Zeyang" sort="Wang, Zeyang" uniqKey="Wang Z" first="Zeyang" last="Wang">Zeyang Wang</name><name sortKey="Xu, Qingwen" sort="Xu, Qingwen" uniqKey="Xu Q" first="Qingwen" last="Xu">Qingwen Xu</name><name sortKey="Yu, Lushan" sort="Yu, Lushan" uniqKey="Yu L" first="Lushan" last="Yu">Lushan Yu</name><name sortKey="Zeng, Kui" sort="Zeng, Kui" uniqKey="Zeng K" first="Kui" last="Zeng">Kui Zeng</name><name sortKey="Zeng, Su" sort="Zeng, Su" uniqKey="Zeng S" first="Su" last="Zeng">Su Zeng</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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