HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways
Abstract Background Hypoxic tumor microenvironment and maintenance of stemness contribute to drug resistance in breast cancer. However, whether Hypoxia-inducible factor-2α (HIF-2α) in hypoxic tumor microenvironment mediates conversion to a stem cell phenotype and chemoresistance of breast tumors has...
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| Format: | Article |
| Language: | English |
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BMC
2018-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0925-x |
| _version_ | 1818675419564474368 |
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| author | Yuanyuan Yan Fangxiao Liu Li Han Lin Zhao Jianjun Chen Olufunmilayo I Olopade Miao He Minjie Wei |
| author_facet | Yuanyuan Yan Fangxiao Liu Li Han Lin Zhao Jianjun Chen Olufunmilayo I Olopade Miao He Minjie Wei |
| author_sort | Yuanyuan Yan |
| collection | DOAJ |
| description | Abstract Background Hypoxic tumor microenvironment and maintenance of stemness contribute to drug resistance in breast cancer. However, whether Hypoxia-inducible factor-2α (HIF-2α) in hypoxic tumor microenvironment mediates conversion to a stem cell phenotype and chemoresistance of breast tumors has not been elucidated. Methods The mRNA and protein expressions of HIF-1α, HIF-2α, Wnt and Notch pathway were determined using qRT-PCR and western blot. Cell viability and renew ability were assessed by MTT, Flow cytometric analysis and soft agar colony formation. Results In our study, acute hypoxia (6–12 h) briefly increased HIF-1α expression, while chronic hypoxia (48 h) continuously enhanced HIF-2α expression and induced the resistance of breast cancer cells to Paclitaxel (PTX). Furthermore, HIF-2α overexpression induced a stem cell phenotype, the resistance to PTX and enhanced protein expression of stem cell markers, c-Myc, OCT4 and Nanog. Most importantly, Wnt and Notch signaling, but not including Shh, pathways were both activated by HIF-2α overexpression. Dickkopf-1 (DKK-1), a Wnt pathway inhibitor, and L685,458, an inhibitor of the Notch pathway, reversed the resistance to PTX and stem phenotype conversion induced by HIF-2α overexpression. In addition, HIF-2α overexpression enhanced tumorigenicity and resistance of xenograft tumors to PTX, increased activation of the Wnt and Notch pathways and induced a stem cell phenotype in vivo. Conclusion In conclusion, HIF-2α promoted stem phenotype conversion and induced resistance to PTX by activating Wnt and Notch pathways. |
| first_indexed | 2024-12-17T08:27:17Z |
| format | Article |
| id | doaj.art-3db43806472544fcbe4e6db3b29d2a76 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-17T08:27:17Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-3db43806472544fcbe4e6db3b29d2a762022-12-21T21:56:42ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-10-0137111410.1186/s13046-018-0925-xHIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathwaysYuanyuan Yan0Fangxiao Liu1Li Han2Lin Zhao3Jianjun Chen4Olufunmilayo I Olopade5Miao He6Minjie Wei7Department of Pharmacology, School of Pharmacy, China Medical UniversityDepartment of Pharmacology, School of Pharmacy, China Medical UniversityDepartment of Pharmacology, School of Pharmacy, China Medical UniversityDepartment of Pharmacology, School of Pharmacy, China Medical UniversityDepartment of Systems Biology, City of hopeCenter for Clinical Cancer Genetics, Department of Medicine, The University of ChicagoDepartment of Pharmacology, School of Pharmacy, China Medical UniversityDepartment of Pharmacology, School of Pharmacy, China Medical UniversityAbstract Background Hypoxic tumor microenvironment and maintenance of stemness contribute to drug resistance in breast cancer. However, whether Hypoxia-inducible factor-2α (HIF-2α) in hypoxic tumor microenvironment mediates conversion to a stem cell phenotype and chemoresistance of breast tumors has not been elucidated. Methods The mRNA and protein expressions of HIF-1α, HIF-2α, Wnt and Notch pathway were determined using qRT-PCR and western blot. Cell viability and renew ability were assessed by MTT, Flow cytometric analysis and soft agar colony formation. Results In our study, acute hypoxia (6–12 h) briefly increased HIF-1α expression, while chronic hypoxia (48 h) continuously enhanced HIF-2α expression and induced the resistance of breast cancer cells to Paclitaxel (PTX). Furthermore, HIF-2α overexpression induced a stem cell phenotype, the resistance to PTX and enhanced protein expression of stem cell markers, c-Myc, OCT4 and Nanog. Most importantly, Wnt and Notch signaling, but not including Shh, pathways were both activated by HIF-2α overexpression. Dickkopf-1 (DKK-1), a Wnt pathway inhibitor, and L685,458, an inhibitor of the Notch pathway, reversed the resistance to PTX and stem phenotype conversion induced by HIF-2α overexpression. In addition, HIF-2α overexpression enhanced tumorigenicity and resistance of xenograft tumors to PTX, increased activation of the Wnt and Notch pathways and induced a stem cell phenotype in vivo. Conclusion In conclusion, HIF-2α promoted stem phenotype conversion and induced resistance to PTX by activating Wnt and Notch pathways.http://link.springer.com/article/10.1186/s13046-018-0925-xHypoxia-inducible factor-2αStemness phenotypeWnt pathwayNotch pathwayDrug resistance |
| spellingShingle | Yuanyuan Yan Fangxiao Liu Li Han Lin Zhao Jianjun Chen Olufunmilayo I Olopade Miao He Minjie Wei HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways Journal of Experimental & Clinical Cancer Research Hypoxia-inducible factor-2α Stemness phenotype Wnt pathway Notch pathway Drug resistance |
| title | HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways |
| title_full | HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways |
| title_fullStr | HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways |
| title_full_unstemmed | HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways |
| title_short | HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways |
| title_sort | hif 2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating wnt and notch pathways |
| topic | Hypoxia-inducible factor-2α Stemness phenotype Wnt pathway Notch pathway Drug resistance |
| url | http://link.springer.com/article/10.1186/s13046-018-0925-x |
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