Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1
We previously demonstrated that expression of Notch-1 is associated with poor prognosis in lung adenocarcinoma (LAD) patients. The aim of this study is to reveal whether Notch-1 was associated with Taxanes-resistant LAD and, the underlying mechanisms. We collected 39 patients of advanced LAD treated...
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| Format: | Article |
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Elsevier
2016-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253117301014 |
| _version_ | 1818050663033077760 |
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| author | Jiayuan Huang Yitian Chen Junyang Li Kai Zhang Jing Chen Dongqin Chen Bing Feng Haizhu Song Jifeng Feng Rui Wang Longbang Chen |
| author_facet | Jiayuan Huang Yitian Chen Junyang Li Kai Zhang Jing Chen Dongqin Chen Bing Feng Haizhu Song Jifeng Feng Rui Wang Longbang Chen |
| author_sort | Jiayuan Huang |
| collection | DOAJ |
| description | We previously demonstrated that expression of Notch-1 is associated with poor prognosis in lung adenocarcinoma (LAD) patients. The aim of this study is to reveal whether Notch-1 was associated with Taxanes-resistant LAD and, the underlying mechanisms. We collected 39 patients of advanced LAD treated with Taxanes and found that positive Notch-1 expression is closely related to LAD lymph node metastasis, recurrence and poorer prognosis, and Notch-1 acts as an independent poor prognostic factor in LAD by multivariate analysis with Cox regression model. Then, by using the Docetaxel (DTX)-resistant LAD cell lines that we established previously, we found that Notch-1 contributes to resistance of LAD cells to DTX in vitro, and inhibition of Notch-1 sensitizes LAD to DTX in vivo. We further demonstrated that Notch-1 mediates chemoresistance response and strengthens proliferation capacity in LAD cells partially through negative regulation of miR-451 by transcription factor AP-1. Moreover, we found that MDR-1 is a direct target of miR-451 and influences chemoresistance of LAD cells. Taken together, our data revealed a novel Notch-1/AP-1/miR-451/MDR-1 signaling axis, and suggested a new therapeutic strategy of combining DTX with Notch inhibitors to treat DTX-resistant LAD. |
| first_indexed | 2024-12-10T10:57:03Z |
| format | Article |
| id | doaj.art-9d837bbc9f87489c8963c71d1896011c |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-10T10:57:03Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
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| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-9d837bbc9f87489c8963c71d1896011c2022-12-22T01:51:49ZengElsevierMolecular Therapy: Nucleic Acids2162-25312016-01-015C10.1038/mtna.2016.82Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1Jiayuan Huang0Yitian Chen1Junyang Li2Kai Zhang3Jing Chen4Dongqin Chen5Bing Feng6Haizhu Song7Jifeng Feng8Rui Wang9Longbang Chen10Department of Medical Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Jiangsu Institute of Cancer Research, Jiangsu, ChinaDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Medical Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Jiangsu Institute of Cancer Research, Jiangsu, ChinaDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, ChinaWe previously demonstrated that expression of Notch-1 is associated with poor prognosis in lung adenocarcinoma (LAD) patients. The aim of this study is to reveal whether Notch-1 was associated with Taxanes-resistant LAD and, the underlying mechanisms. We collected 39 patients of advanced LAD treated with Taxanes and found that positive Notch-1 expression is closely related to LAD lymph node metastasis, recurrence and poorer prognosis, and Notch-1 acts as an independent poor prognostic factor in LAD by multivariate analysis with Cox regression model. Then, by using the Docetaxel (DTX)-resistant LAD cell lines that we established previously, we found that Notch-1 contributes to resistance of LAD cells to DTX in vitro, and inhibition of Notch-1 sensitizes LAD to DTX in vivo. We further demonstrated that Notch-1 mediates chemoresistance response and strengthens proliferation capacity in LAD cells partially through negative regulation of miR-451 by transcription factor AP-1. Moreover, we found that MDR-1 is a direct target of miR-451 and influences chemoresistance of LAD cells. Taken together, our data revealed a novel Notch-1/AP-1/miR-451/MDR-1 signaling axis, and suggested a new therapeutic strategy of combining DTX with Notch inhibitors to treat DTX-resistant LAD.http://www.sciencedirect.com/science/article/pii/S2162253117301014activator protein-1chemoresistancelung adenocarcinomamicroRNAnotch signaling pathway |
| spellingShingle | Jiayuan Huang Yitian Chen Junyang Li Kai Zhang Jing Chen Dongqin Chen Bing Feng Haizhu Song Jifeng Feng Rui Wang Longbang Chen Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1 Molecular Therapy: Nucleic Acids activator protein-1 chemoresistance lung adenocarcinoma microRNA notch signaling pathway |
| title | Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1 |
| title_full | Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1 |
| title_fullStr | Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1 |
| title_full_unstemmed | Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1 |
| title_short | Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1 |
| title_sort | notch 1 confers chemoresistance in lung adenocarcinoma to taxanes through ap 1 microrna 451 mediated regulation of mdr 1 |
| topic | activator protein-1 chemoresistance lung adenocarcinoma microRNA notch signaling pathway |
| url | http://www.sciencedirect.com/science/article/pii/S2162253117301014 |
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