The c-Myc/miR-27b-3p/ATG10 regulatory axis regulates chemoresistance in colorectal cancer
Identifieur interne : 000021 ( Pmc/Checkpoint ); précédent : 000020; suivant : 000022The c-Myc/miR-27b-3p/ATG10 regulatory axis regulates chemoresistance in colorectal cancer
Auteurs : Wu Sun [République populaire de Chine] ; Jialu Li [République populaire de Chine] ; Likun Zhou [République populaire de Chine] ; Jiayi Han [République populaire de Chine] ; Rui Liu [République populaire de Chine] ; Haiyang Zhang [République populaire de Chine] ; Tao Ning [République populaire de Chine] ; Zhiying Gao [République populaire de Chine] ; Baorui Liu [République populaire de Chine] ; Xi Chen [République populaire de Chine] ; Yi Ba [République populaire de Chine]Source :
- Theranostics [ 1838-7640 ] ; 2020.
Abstract
Oxaliplatin (OXA) resistance is the major obstacle to the anticancer effects of chemotherapy in colorectal cancer (CRC) patients. MicroRNAs (miRNAs) play an important role in the chemoresistance of various tumors. Our objective is to clarify the underlying mechanism of miRNAs in chemoresistance and provide a potential strategy to improve the response of CRC patients to chemotherapeutics.
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DOI: 10.7150/thno.37621
PubMed: 32104496
PubMed Central: 7019154
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uniqKey="Li J" first="Jialu" last="Li">Jialu Li</name><affiliation wicri:level="1"><nlm:aff id="A2">State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Zhou, Likun" sort="Zhou, Likun" uniqKey="Zhou L" first="Likun" last="Zhou">Likun Zhou</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Han, Jiayi" sort="Han, Jiayi" uniqKey="Han J" first="Jiayi" last="Han">Jiayi Han</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Liu, Rui" sort="Liu, Rui" uniqKey="Liu R" first="Rui" last="Liu">Rui Liu</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Zhang, Haiyang" sort="Zhang, Haiyang" uniqKey="Zhang H" first="Haiyang" last="Zhang">Haiyang Zhang</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Ning, Tao" sort="Ning, Tao" uniqKey="Ning T" first="Tao" last="Ning">Tao Ning</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Gao, Zhiying" sort="Gao, Zhiying" uniqKey="Gao Z" first="Zhiying" last="Gao">Zhiying Gao</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing</wicri:regionArea><wicri:noRegion>Nanjing</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Baorui" sort="Liu, Baorui" uniqKey="Liu B" first="Baorui" last="Liu">Baorui Liu</name><affiliation wicri:level="1"><nlm:aff id="A4">The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing</wicri:regionArea><wicri:noRegion>Nanjing</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Xi" sort="Chen, Xi" uniqKey="Chen X" first="Xi" last="Chen">Xi Chen</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing</wicri:regionArea><wicri:noRegion>Nanjing</wicri:noRegion></affiliation></author><author><name sortKey="Ba, Yi" sort="Ba, Yi" uniqKey="Ba Y" first="Yi" last="Ba">Yi Ba</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32104496</idno><idno type="pmc">7019154</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019154</idno><idno type="RBID">PMC:7019154</idno><idno type="doi">10.7150/thno.37621</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000827</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000827</idno><idno type="wicri:Area/Pmc/Curation">000827</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000827</idno><idno type="wicri:Area/Pmc/Checkpoint">000021</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000021</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The c-Myc/miR-27b-3p/ATG10 regulatory axis regulates chemoresistance in colorectal cancer</title><author><name sortKey="Sun, Wu" sort="Sun, Wu" uniqKey="Sun W" first="Wu" last="Sun">Wu Sun</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Li, Jialu" sort="Li, Jialu" uniqKey="Li J" first="Jialu" last="Li">Jialu Li</name><affiliation wicri:level="1"><nlm:aff id="A2">State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Zhou, Likun" sort="Zhou, Likun" uniqKey="Zhou L" first="Likun" last="Zhou">Likun Zhou</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Han, Jiayi" sort="Han, Jiayi" uniqKey="Han J" first="Jiayi" last="Han">Jiayi Han</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Liu, Rui" sort="Liu, Rui" uniqKey="Liu R" first="Rui" last="Liu">Rui Liu</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Zhang, Haiyang" sort="Zhang, Haiyang" uniqKey="Zhang H" first="Haiyang" last="Zhang">Haiyang Zhang</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Ning, Tao" sort="Ning, Tao" uniqKey="Ning T" first="Tao" last="Ning">Tao Ning</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Gao, Zhiying" sort="Gao, Zhiying" uniqKey="Gao Z" first="Zhiying" last="Gao">Zhiying Gao</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing</wicri:regionArea><wicri:noRegion>Nanjing</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Baorui" sort="Liu, Baorui" uniqKey="Liu B" first="Baorui" last="Liu">Baorui Liu</name><affiliation wicri:level="1"><nlm:aff id="A4">The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing</wicri:regionArea><wicri:noRegion>Nanjing</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Xi" sort="Chen, Xi" uniqKey="Chen X" first="Xi" last="Chen">Xi Chen</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing</wicri:regionArea><wicri:noRegion>Nanjing</wicri:noRegion></affiliation></author><author><name sortKey="Ba, Yi" sort="Ba, Yi" uniqKey="Ba Y" first="Yi" last="Ba">Yi Ba</name><affiliation wicri:level="3"><nlm:aff id="A1">Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></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>Oxaliplatin (OXA) resistance is the major obstacle to the anticancer effects of chemotherapy in colorectal cancer (CRC) patients. MicroRNAs (miRNAs) play an important role in the chemoresistance of various tumors. Our objective is to clarify the underlying mechanism of miRNAs in chemoresistance and provide a potential strategy to improve the response of CRC patients to chemotherapeutics.</p><p><bold>Methods</bold>: MiRNA microarray and Real-time PCR were performed to compare changes in miRNA expression between oxaliplatin-resistant and the parental cells. CCK8, apoptosis assay, immunofluorescence and xenograft studies were used to elucidate the impact of miR-27b-3p on regulating chemoresistance. Luciferase reporter assay and western blot were carried to assess the regulatory role of miR-27b-3p in ATG10 expression. The effects of miR-27b-3p and ATG10 on autophagy were investigated by GFP-LC3 fluorescence microscopy, transmission electron microscopy, and western blot. ChIP assay and luciferase assay were performed to test the c-Myc's occupancy on the miR-27B promoter.</p><p><bold>Results</bold>: We observed that miR-27b-3p expression was significantly downregulated in oxaliplatin-resistant cell lines (SW480-OxR and HCT116-OxR) compared to the corresponding parental cell lines and that miR-27b-3p expression was positively correlated with disease-free survival (DFS) time in colorectal cancer patients. MiR-27b-3p could sensitize colorectal cancer cells to oxaliplatin in vitro and in vivo. Under oxaliplatin treatment, chemoresistant cells showed a higher autophagy level than parental cells. Moreover, we also identified that miR-27b-3p inhibited the expression of ATG10 at the posttranscriptional level, thus inhibiting autophagy. Further study demonstrated that c-Myc can inhibit the expression of miR-27b-3p via binding to the promoter region of miR-27B gene.</p><p><bold>Conclusions</bold>: Our study identifies a novel c-Myc/miR-27b-3p/ATG10 signaling pathway that regulates colorectal cancer chemoresistance. These results suggest that miR-27b-3p is not only a potential indicator for evaluating efficiency of chemotherapy, but also a valuable therapeutic target for CRC, especially for patients with chemoresistance.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Siegel, Rl" uniqKey="Siegel R">RL Siegel</name></author><author><name sortKey="Miller, Kd" uniqKey="Miller K">KD Miller</name></author><author><name sortKey="Fedewa, Sa" uniqKey="Fedewa S">SA Fedewa</name></author><author><name sortKey="Ahnen, Dj" uniqKey="Ahnen D">DJ Ahnen</name></author><author><name sortKey="Meester, R" uniqKey="Meester R">R Meester</name></author><author><name sortKey="Barzi, A" uniqKey="Barzi A">A Barzi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J Ferlay</name></author><author><name sortKey="Soerjomataram, I" 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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">32104496</article-id><article-id pub-id-type="pmc">7019154</article-id><article-id pub-id-type="doi">10.7150/thno.37621</article-id><article-id pub-id-type="publisher-id">thnov10p1981</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>The c-Myc/miR-27b-3p/ATG10 regulatory axis regulates chemoresistance in colorectal cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Wu</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_number">#</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Jialu</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="author-notes" rid="FNA_number">#</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Likun</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_number">#</xref></contrib><contrib contrib-type="author"><name><surname>Han</surname><given-names>Jiayi</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_number">#</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Rui</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_number">#</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Haiyang</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ning</surname><given-names>Tao</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Zhiying</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Baorui</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Xi</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib><contrib contrib-type="author"><name><surname>Ba</surname><given-names>Yi</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>Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.</aff><aff id="A2"><label>2</label>State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.</aff><aff id="A3"><label>3</label>State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, China.</aff><aff id="A4"><label>4</label>The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, China.</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding authors: Yi Ba,Ph.D., Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huan hu xi Road 18, Tianjin, China; 300060; (Tel): 022-2334-0123; Email: <email>bayi@tjmuch.com</email> or Xi Chen, Ph.D., State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Xianlin Road 163, Nanjing, Jiangsu, China; 210046; (Tel): 86-25-89681323; Email: <email>xichen@nju.edu.cn</email> or Baorui Liu, Ph.D., The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Zhognshan Road 321, Nanjing, Jiangsu, China; 210008; (Tel): 025-83304616; Email: <email>baoruiliu07@163.com</email>.</corresp><fn fn-type="equal" id="FNA_number"><p><sup>#</sup>These authors contributed equally to this study.</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>12</day><month>1</month><year>2020</year></pub-date><volume>10</volume><issue>5</issue><fpage>1981</fpage><lpage>1996</lpage><history><date date-type="received"><day>15</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>15</day><month>12</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>Oxaliplatin (OXA) resistance is the major obstacle to the anticancer effects of chemotherapy in colorectal cancer (CRC) patients. MicroRNAs (miRNAs) play an important role in the chemoresistance of various tumors. Our objective is to clarify the underlying mechanism of miRNAs in chemoresistance and provide a potential strategy to improve the response of CRC patients to chemotherapeutics.</p><p><bold>Methods</bold>: MiRNA microarray and Real-time PCR were performed to compare changes in miRNA expression between oxaliplatin-resistant and the parental cells. CCK8, apoptosis assay, immunofluorescence and xenograft studies were used to elucidate the impact of miR-27b-3p on regulating chemoresistance. Luciferase reporter assay and western blot were carried to assess the regulatory role of miR-27b-3p in ATG10 expression. The effects of miR-27b-3p and ATG10 on autophagy were investigated by GFP-LC3 fluorescence microscopy, transmission electron microscopy, and western blot. ChIP assay and luciferase assay were performed to test the c-Myc's occupancy on the miR-27B promoter.</p><p><bold>Results</bold>: We observed that miR-27b-3p expression was significantly downregulated in oxaliplatin-resistant cell lines (SW480-OxR and HCT116-OxR) compared to the corresponding parental cell lines and that miR-27b-3p expression was positively correlated with disease-free survival (DFS) time in colorectal cancer patients. MiR-27b-3p could sensitize colorectal cancer cells to oxaliplatin in vitro and in vivo. Under oxaliplatin treatment, chemoresistant cells showed a higher autophagy level than parental cells. Moreover, we also identified that miR-27b-3p inhibited the expression of ATG10 at the posttranscriptional level, thus inhibiting autophagy. Further study demonstrated that c-Myc can inhibit the expression of miR-27b-3p via binding to the promoter region of miR-27B gene.</p><p><bold>Conclusions</bold>: Our study identifies a novel c-Myc/miR-27b-3p/ATG10 signaling pathway that regulates colorectal cancer chemoresistance. These results suggest that miR-27b-3p is not only a potential indicator for evaluating efficiency of chemotherapy, but also a valuable therapeutic target for CRC, especially for patients with chemoresistance.</p></abstract><kwd-group><kwd>miR-27b-3p</kwd><kwd>ATG10</kwd><kwd>chemoresistance</kwd><kwd>colorectal cancer</kwd><kwd>autophagy</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p>Oxaliplatin-resistant colorectal cancer cells express decreased levels of miR-27b-3p. (A) Different miRNA expressions levels in parental cells (SW480 and HCT116) and chemoresistant cells (SW480-OxR and HCT116-OxR) were determined by using the miRNA microarray. (B) Twenty-two miRNAs were dysregulated in oxaliplatin-resistant cells relative to their expression in the corresponding parental cells. (C) The relative levels of miRNAs in SW480, HCT116, SW480-OxR and HCT116-OxR cell lines were determined using qRT-PCR. (D) The correlation between the expression level of miR-27b-3p and IC<sub>50</sub> for oxaliplatin in 8 CRC cell lines (SW480, HCT116, SW480-OxR, HCT116-OxR, SW620, Caco2, HT-29 and LOVO) was shown. (E) MiR-27b-3p expression levels were decreased in human colorectal cancer samples compared with those in the paired noncancerous tissues (n=20). (F) Representative images of the expression of miR-27b-3p in paired tissues using ISH. Scale bars: 100 μm. (G) Kaplan-Meier plots for investigating the correlation of miR-27b-3p expression level with disease-free survival (DFS). Patients were split into the high- and low-expression groups by the mean expression level of the miR-27b-3p (n=62; log-rank test). *p < 0.05, **p < 0.01, ***p < 0.001.</p></caption><graphic xlink:href="thnov10p1981g001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p>MiR-27b-3p reverses the chemoresistance of colorectal cancer cells. (A) Growth curves of SW480 cells (left) and SW480-OxR cells (right) after transfection as indicated. (B) The CCK8 assay showed a change in cell viability in response to oxaliplatin after transfection of SW480 cells (left) and SW480-OxR cells (right). (C) Cell apoptotic rates of SW480 (left) and SW480-OxR (right) cells were detected by flow cytometry. (D) Cleaved-caspase 3 and PARP expression were observed by western blot in SW480 cells (left) and SW480-OxR cells(right).(E) Formation of γ-H2AX foci was observed in SW480 (left) and SW480-OxR (right) cells. Scale bars: 20 μm. (F) γ-H2AX expression was detected by western blot in SW480 and SW480-OxR cells. **p < 0.01, ***p < 0.001.</p></caption><graphic xlink:href="thnov10p1981g002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p>MiR-27b-3p suppresses tumor growth combined with oxaliplatin in vivo. (A) A schematic outline of the experimental design. (B) Representative images of tumors in nude mice bearing SW480-OxR cells in different groups (n= 5 for each group). Scale bars: 1 cm. (C) Tumor weights were measured in different groups. (D) Representative images of tumors in nude mice bearing SW480 cells in different groups (n= 5 for each group). Scale bars: 1 cm. (E) Tumor weights were measured in different groups, (F) Representative images of tumor samples derived from SW480-OxR group that were stained with H&E (left) and immunohistochemistry of Ki67 (middle) and cleaved-caspase 3 (right). Scale bars: 100 μm; (insets) 25 μm. (G) Statistical analysis of Ki-67 and cleaved-caspase 3 protein levels in (F). (H) Representative images of tumor samples derived from SW480 group that were stained with H&E (left) and immunohistochemistry of Ki67 (middle) and cleaved-caspase 3 (right). Scale bars: 100 μm; (insets) 25 μm. (I) Statistical analysis of Ki-67 and cleaved-caspase 3 protein levels in (H). *p < 0.05, **p < 0.01, ***p < 0.001.</p></caption><graphic xlink:href="thnov10p1981g003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p>MiR-27b-3p inhibits autophagic activity in chemoresistant CRC cells. (A) Autophagy element expression levels were detected by western blot in SW480 and SW480-OxR cells cultured with oxaliplatin. (B and C) Confocal microscopic analysis was performed to observe green fluorescent LC3 puncta in SW480-OxR cells cultured with oxaliplatin. Representative images are shown in (B), and LC3 puncta per cell were quantified in (C). Scale bar: 10 μm. Autophagosomes were observed by transmission electron microscopy (TEM) in SW480-OxR cells cultured with oxaliplatin. Representative images are shown in (D), and autophagosomes per cell were quantified in (E). Scale bar: 1 μm; (insets) 250 nm. (F)Western blot was performed in SW480-OxR cells treated with oxaliplatin in the presence of CQ. (G) IC<sub>50</sub> for oxaliplatin in SW480-OxR cells in the presence or absence of CQ. (H-L) SW480-OxR and SW480 cells were transfected with mimics or inhibitor of miR-27b-3p, respectively. After culturing with oxaliplatin, (H) autophagy element expression levels were detected by western blot, (I) green fluorescent LC3 puncta were observed under confocal microscope, (K) autophagosomes were observed by TEM, respectively. LC3 puncta per cell were quantified in (J). Scale bar: 10 μm. Autophagosomes per cell were quantified in (L). Scale bar: 1 μm; (insets) 250 nm. **p < 0.01.</p></caption><graphic xlink:href="thnov10p1981g004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p>Identification of ATG10 as a direct target of miR-27b-3p. (A)Luciferase assays showing suppression of luciferase activity of candidate genes by miR-27b-3p in SW480-OxR cells. (B) Schematic of the hypothetical duplexes formed by miR-27b-3p and the 3'-UTR of ATG10. (C) Relative luciferase activity in SW480-OxR cells transfected with the miR-27b-3p mimic or inhibitor. (D) Western blot showing the expression levels of ATG10 in four CRC cell lines. (E and F) Western blot analysis was performed to measure the expression level of ATG10 in oxaliplatin-resistant cells transfected with the miR-27b-3p mimic and the corresponding parental cells transfected with the miR-27b-3p inhibitor. (G) Protein levels of ATG10 were measured in 20 pairs of samples using western blot as previously described. (H) The levels of ATG10 protein expression were measured. (I) Representative images of tumor samples that were stained for ATG10 by IHC. Scale bar: 100 μm; (insets) 25 μm. (J) The correction between the fold changes in the expression of miR-27b-3p and the ATG10 protein in human CRC tissue pairs (n=20). *p<0.05, **p<0.01, ***p<0.001.</p></caption><graphic xlink:href="thnov10p1981g005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p>MiR-27b-3p enhances the sensitivity of CRC cells to oxaliplatin by inhibiting ATG10 and thereby inhibiting autophagy. (A and B) Growth curves of SW480 cells (A) and SW480-OxR cells (B) after transfection as indicated. (C and D) The CCK8 assay showed a change in cell viability in response to oxaliplatin after transfection of SW480 cells (C) and SW480-OxR cells (D). (E and F) Apoptosis was detected by flow cytometry in SW480 cells (E) and SW480-OxR cells (F) with the indicated modifications and then were incubated with oxaliplatin, respectively.(G and H) The protein levels of cleaved-caspase 3 and PARP in SW480 cells (G) and SW480-OxR cells (H) after transfection and then were stimulated with oxaliplatin. (I)Western blot analysis for autophagy element expression levels in SW480 cells, after treated as in (G). (J and K) Representative photographs of LC3 puncta (green) in SW480 cells with the indicated modifications (J). Quantification of LC3 puncta in the indicated SW480 cells (K). Scale bar: 10 μm. (L) Western blot analysis for autophagy elements expression levels in SW480-OxR cells, after treated as in (H). (M and N) Representative photographs of LC3 puncta (green) in SW480-OxR cells with the indicated modifications (M). Quantification of LC3 puncta in the indicated SW480-OxR cells (N). Scale bar: 10 μm. *p<0.05, **p<0.01, ***p<0.001.</p></caption><graphic xlink:href="thnov10p1981g006"></graphic></fig><fig id="F7" position="float"><label>Figure 7</label><caption><p>Expression of miR-27b-3p is inhibited by c-Myc. (A) The influence of c-Myc on the expression of miR-27b-3p. (B) Schematic showing the three putative c-Myc-binding motifs in the miR-27B promoter region. (C) ChIP assay for c-Myc occupancy on the miR-27B promoter region. (D) Luciferase reporter assays were performed to confirm the suppression of miR-27B promoter by c-Myc. (E and F) Western blot analysis of the c-Myc and ATG10 protein levels in SW480 cells (E) and SW480-OxR cells (F). (G and H) Western blot analysis of the c-Myc expression level in 20 pairs of CRC tissues and NATs. G: representative images; H: quantitative analysis (n=20). (I) The correction between the fold changes in the expression of miR-27b-3p and the c-Myc protein in CRC tissues as mentioned previously (n = 20). (J) Schematic of the c-Myc/miR-27b-3p/ATG10 axis in CRC. **p<0.01, ***p<0.001.</p></caption><graphic xlink:href="thnov10p1981g007"></graphic></fig></floats-group></pmc><affiliations><list><country><li>République populaire de Chine</li></country><settlement><li>Tianjin</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Sun, Wu" sort="Sun, Wu" uniqKey="Sun W" first="Wu" last="Sun">Wu Sun</name></noRegion><name sortKey="Ba, Yi" sort="Ba, Yi" uniqKey="Ba Y" first="Yi" last="Ba">Yi Ba</name><name sortKey="Chen, Xi" sort="Chen, Xi" uniqKey="Chen X" first="Xi" last="Chen">Xi Chen</name><name sortKey="Gao, Zhiying" sort="Gao, Zhiying" uniqKey="Gao Z" first="Zhiying" last="Gao">Zhiying Gao</name><name sortKey="Han, Jiayi" sort="Han, Jiayi" uniqKey="Han J" first="Jiayi" last="Han">Jiayi Han</name><name sortKey="Li, Jialu" sort="Li, Jialu" uniqKey="Li J" first="Jialu" last="Li">Jialu Li</name><name sortKey="Liu, Baorui" sort="Liu, Baorui" uniqKey="Liu B" first="Baorui" last="Liu">Baorui Liu</name><name sortKey="Liu, Rui" sort="Liu, Rui" uniqKey="Liu R" first="Rui" last="Liu">Rui Liu</name><name sortKey="Ning, Tao" sort="Ning, Tao" uniqKey="Ning T" first="Tao" last="Ning">Tao Ning</name><name sortKey="Zhang, Haiyang" sort="Zhang, Haiyang" uniqKey="Zhang H" first="Haiyang" last="Zhang">Haiyang Zhang</name><name sortKey="Zhou, Likun" sort="Zhou, Likun" uniqKey="Zhou L" first="Likun" last="Zhou">Likun Zhou</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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