Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer
Abstract Background Oxaliplatin resistance is a major challenge for treatment of advanced colorectal cancer (CRC). Both acquisition of epithelial-mesenchymal transition (EMT) and suppressed drug accumulation in cancer cells contributes to development of oxaliplatin resistance. Aberrant expression of...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-03-01
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| Series: | Molecular Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12943-019-0981-7 |
| _version_ | 1818448575094325248 |
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| author | Tong Liu Xin Zhang Lutao Du Yunshan Wang Xiaoming Liu Hui Tian Lili Wang Peilong Li Yinghui Zhao Weili Duan Yujiao Xie Zhaowei Sun Chuanxin Wang |
| author_facet | Tong Liu Xin Zhang Lutao Du Yunshan Wang Xiaoming Liu Hui Tian Lili Wang Peilong Li Yinghui Zhao Weili Duan Yujiao Xie Zhaowei Sun Chuanxin Wang |
| author_sort | Tong Liu |
| collection | DOAJ |
| description | Abstract Background Oxaliplatin resistance is a major challenge for treatment of advanced colorectal cancer (CRC). Both acquisition of epithelial-mesenchymal transition (EMT) and suppressed drug accumulation in cancer cells contributes to development of oxaliplatin resistance. Aberrant expression of small noncoding RNA, miR-128-3p, has been shown to be a key regulator in tumorigenesis and cancer development. However, its roles in the progression of CRC and oxaliplatin-resistance are largely unknown. Methods Oxaliplatin-resistant CRC and normal intestinal FHC cells were transfected with a miR-128-3p expression lentivirus. After transfection, FHC-derived exosomes were isolated and co-cultured with CRC cells. miR-128-3p expression in resistant CRC cells, FHC cells, and exosomes was quantified by quantitative real-time PCR (RT-qPCR). The mRNA and protein levels of miR-128-3p target genes in resistant CRC cells were quantified by RT-qPCR and western blot, respectively. The effects of miR-128-3p on CRC cell viability, apoptosis, EMT, motility and drug efflux were evaluated by CCK8, flow cytometry, Transwell and wound healing assays, immunofluorescence, and atomic absorption spectrophotometry. Xenograft models were used to determine whether miR-128-3p loaded exosomes can re-sensitize CRC cells to oxaliplatin in vivo. Results In our established stable oxaliplatin-resistant CRC cell lines, in vitro and vivo studies revealed miR-128-3p suppressed EMT and increased intracellular oxaliplatin accumulation. Importantly, our results indicated that lower miR-128-3p expression was associated with poor oxaliplatin response in advanced human CRC patients. Moreover, data showed that miR-128-3p-transfected FHC cells effectively packaged miR-128-3p into secreted exosomes and mediated miR-128-3p delivery to oxaliplatin-resistant cells, improving oxaliplatin response in CRC cells both in vitro and in vivo. In addition, miR-128-3p overexpression up-regulated E-cadherin levels and inhibited oxaliplatin-induced EMT by suppressing Bmi1 expression in resistant cells. Meanwhile, it also decreased oxaliplatin efflux through suppressed expression of the drug transporter MRP5. Conclusion Our results demonstrate that miR-128-3p delivery via exosomes represents a novel strategy enhancing chemosensitivity in CRC through negative regulation of Bmi1 and MRP5. Moreover, miR-128-3p may be a promising diagnostic and prognostic marker for oxaliplatin-based chemotherapy. |
| first_indexed | 2024-12-14T20:21:41Z |
| format | Article |
| id | doaj.art-4c3513a465b1451f9205ea47bfcbef29 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-14T20:21:41Z |
| publishDate | 2019-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-4c3513a465b1451f9205ea47bfcbef292022-12-21T22:48:43ZengBMCMolecular Cancer1476-45982019-03-0118111710.1186/s12943-019-0981-7Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancerTong Liu0Xin Zhang1Lutao Du2Yunshan Wang3Xiaoming Liu4Hui Tian5Lili Wang6Peilong Li7Yinghui Zhao8Weili Duan9Yujiao Xie10Zhaowei Sun11Chuanxin Wang12Department of Clinical Laboratory, The Second Hospital of Shandong UniversityDepartment of Clinical Laboratory, Qilu Hospital, Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital of Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital of Shandong UniversityDepartment of Preventive Medicine, Shandong Provincial Traditional Chinese Medical HospitalCancer Center, Qilu Hospital, Shandong UniversityDepartment of Clinical Laboratory, Qilu Hospital, Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital of Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital of Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital of Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital of Shandong UniversityDepartment of Surgery, The Affiliated Hospital of Medical College Qingdao UniversityDepartment of Clinical Laboratory, The Second Hospital of Shandong UniversityAbstract Background Oxaliplatin resistance is a major challenge for treatment of advanced colorectal cancer (CRC). Both acquisition of epithelial-mesenchymal transition (EMT) and suppressed drug accumulation in cancer cells contributes to development of oxaliplatin resistance. Aberrant expression of small noncoding RNA, miR-128-3p, has been shown to be a key regulator in tumorigenesis and cancer development. However, its roles in the progression of CRC and oxaliplatin-resistance are largely unknown. Methods Oxaliplatin-resistant CRC and normal intestinal FHC cells were transfected with a miR-128-3p expression lentivirus. After transfection, FHC-derived exosomes were isolated and co-cultured with CRC cells. miR-128-3p expression in resistant CRC cells, FHC cells, and exosomes was quantified by quantitative real-time PCR (RT-qPCR). The mRNA and protein levels of miR-128-3p target genes in resistant CRC cells were quantified by RT-qPCR and western blot, respectively. The effects of miR-128-3p on CRC cell viability, apoptosis, EMT, motility and drug efflux were evaluated by CCK8, flow cytometry, Transwell and wound healing assays, immunofluorescence, and atomic absorption spectrophotometry. Xenograft models were used to determine whether miR-128-3p loaded exosomes can re-sensitize CRC cells to oxaliplatin in vivo. Results In our established stable oxaliplatin-resistant CRC cell lines, in vitro and vivo studies revealed miR-128-3p suppressed EMT and increased intracellular oxaliplatin accumulation. Importantly, our results indicated that lower miR-128-3p expression was associated with poor oxaliplatin response in advanced human CRC patients. Moreover, data showed that miR-128-3p-transfected FHC cells effectively packaged miR-128-3p into secreted exosomes and mediated miR-128-3p delivery to oxaliplatin-resistant cells, improving oxaliplatin response in CRC cells both in vitro and in vivo. In addition, miR-128-3p overexpression up-regulated E-cadherin levels and inhibited oxaliplatin-induced EMT by suppressing Bmi1 expression in resistant cells. Meanwhile, it also decreased oxaliplatin efflux through suppressed expression of the drug transporter MRP5. Conclusion Our results demonstrate that miR-128-3p delivery via exosomes represents a novel strategy enhancing chemosensitivity in CRC through negative regulation of Bmi1 and MRP5. Moreover, miR-128-3p may be a promising diagnostic and prognostic marker for oxaliplatin-based chemotherapy.http://link.springer.com/article/10.1186/s12943-019-0981-7miR-218-3pExosomeColorectal cancerChemoresistanceEpithelial-mesenchymal transitionDrug efflux |
| spellingShingle | Tong Liu Xin Zhang Lutao Du Yunshan Wang Xiaoming Liu Hui Tian Lili Wang Peilong Li Yinghui Zhao Weili Duan Yujiao Xie Zhaowei Sun Chuanxin Wang Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer Molecular Cancer miR-218-3p Exosome Colorectal cancer Chemoresistance Epithelial-mesenchymal transition Drug efflux |
| title | Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer |
| title_full | Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer |
| title_fullStr | Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer |
| title_full_unstemmed | Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer |
| title_short | Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer |
| title_sort | exosome transmitted mir 128 3p increase chemosensitivity of oxaliplatin resistant colorectal cancer |
| topic | miR-218-3p Exosome Colorectal cancer Chemoresistance Epithelial-mesenchymal transition Drug efflux |
| url | http://link.springer.com/article/10.1186/s12943-019-0981-7 |
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