Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling
Abstract Background Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chem...
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| Format: | Article |
| Language: | English |
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BMC
2021-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-021-01901-1 |
| _version_ | 1818849774015610880 |
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| author | Qianxi Yang Shaorong Zhao Zhendong Shi Lixia Cao Jingjing Liu Teng Pan Dongdong Zhou Jin Zhang |
| author_facet | Qianxi Yang Shaorong Zhao Zhendong Shi Lixia Cao Jingjing Liu Teng Pan Dongdong Zhou Jin Zhang |
| author_sort | Qianxi Yang |
| collection | DOAJ |
| description | Abstract Background Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemotherapy-elicited exosomes in regulating chemoresistance is poorly understood. Methods Using commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs. Results Here, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome-induced drug resistance in a nude mouse tumor xenograft model. Conclusion This study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of the WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect. |
| first_indexed | 2024-12-19T06:38:34Z |
| format | Article |
| id | doaj.art-8bb07536940c4478864ded371d7f4118 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-19T06:38:34Z |
| publishDate | 2021-04-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-8bb07536940c4478864ded371d7f41182022-12-21T20:32:10ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662021-04-0140111810.1186/s13046-021-01901-1Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signalingQianxi Yang0Shaorong Zhao1Zhendong Shi2Lixia Cao3Jingjing Liu4Teng Pan5Dongdong Zhou6Jin Zhang7Third Department of Breast Surgery, Tianjin Medical University Cancer Institute and HospitalThird Department of Breast Surgery, Tianjin Medical University Cancer Institute and HospitalThird Department of Breast Surgery, Tianjin Medical University Cancer Institute and HospitalThird Department of Breast Surgery, Tianjin Medical University Cancer Institute and HospitalThird Department of Breast Surgery, Tianjin Medical University Cancer Institute and HospitalThird Department of Breast Surgery, Tianjin Medical University Cancer Institute and HospitalThird Department of Breast Surgery, Tianjin Medical University Cancer Institute and HospitalThird Department of Breast Surgery, Tianjin Medical University Cancer Institute and HospitalAbstract Background Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemotherapy-elicited exosomes in regulating chemoresistance is poorly understood. Methods Using commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs. Results Here, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome-induced drug resistance in a nude mouse tumor xenograft model. Conclusion This study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of the WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect.https://doi.org/10.1186/s13046-021-01901-1Chemotherapy-elicited exosomesmiR-378a-3pmiR-378dChemotherapy resistanceCancer stemness |
| spellingShingle | Qianxi Yang Shaorong Zhao Zhendong Shi Lixia Cao Jingjing Liu Teng Pan Dongdong Zhou Jin Zhang Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling Journal of Experimental & Clinical Cancer Research Chemotherapy-elicited exosomes miR-378a-3p miR-378d Chemotherapy resistance Cancer stemness |
| title | Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling |
| title_full | Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling |
| title_fullStr | Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling |
| title_full_unstemmed | Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling |
| title_short | Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling |
| title_sort | chemotherapy elicited exosomal mir 378a 3p and mir 378d promote breast cancer stemness and chemoresistance via the activation of ezh2 stat3 signaling |
| topic | Chemotherapy-elicited exosomes miR-378a-3p miR-378d Chemotherapy resistance Cancer stemness |
| url | https://doi.org/10.1186/s13046-021-01901-1 |
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