Zhiyong Yang, Ning Zhao, Jing Cui, Heshui Wu, Jiongxin Xiong, Tao Peng
{"title":"来自吉西他滨耐药胰腺癌干细胞的外泌体通过递送miR-210增强耐药。","authors":"Zhiyong Yang, Ning Zhao, Jing Cui, Heshui Wu, Jiongxin Xiong, Tao Peng","doi":"10.1007/s13402-019-00476-6","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance.</p><p><strong>Methods: </strong>GEM-sensitive BxPC-3-derived Bx<sub>S</sub> and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived Bx<sub>R</sub> cells (Bx<sub>R</sub>-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in Bx<sub>S</sub> and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo.</p><p><strong>Results: </strong>Bx<sub>R</sub>-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in Bx<sub>S</sub> and PANC-1 cells. Elevated miR-210 expression levels were detected in Bx<sub>R</sub>-CSCs and Bx<sub>R</sub>-CSC-derived exosomes compared to those in Bx<sub>S</sub>-CSCs and Bx<sub>S</sub>-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in Bx<sub>S</sub> and PANC-1 cells cultured with Bx<sub>R</sub>-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in Bx<sub>S</sub> cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by Bx<sub>R</sub>-CSC-derived exosomes.</p><p><strong>Conclusions: </strong>Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"11 1","pages":"123-136"},"PeriodicalIF":4.8000,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210.\",\"authors\":\"Zhiyong Yang, Ning Zhao, Jing Cui, Heshui Wu, Jiongxin Xiong, Tao Peng\",\"doi\":\"10.1007/s13402-019-00476-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance.</p><p><strong>Methods: </strong>GEM-sensitive BxPC-3-derived Bx<sub>S</sub> and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived Bx<sub>R</sub> cells (Bx<sub>R</sub>-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in Bx<sub>S</sub> and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo.</p><p><strong>Results: </strong>Bx<sub>R</sub>-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in Bx<sub>S</sub> and PANC-1 cells. Elevated miR-210 expression levels were detected in Bx<sub>R</sub>-CSCs and Bx<sub>R</sub>-CSC-derived exosomes compared to those in Bx<sub>S</sub>-CSCs and Bx<sub>S</sub>-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in Bx<sub>S</sub> and PANC-1 cells cultured with Bx<sub>R</sub>-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in Bx<sub>S</sub> cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by Bx<sub>R</sub>-CSC-derived exosomes.</p><p><strong>Conclusions: </strong>Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.</p>\",\"PeriodicalId\":9690,\"journal\":{\"name\":\"Cellular Oncology\",\"volume\":\"11 1\",\"pages\":\"123-136\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2020-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cellular Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s13402-019-00476-6\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2019/11/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13402-019-00476-6","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2019/11/12 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210.
Purpose: Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance.
Methods: GEM-sensitive BxPC-3-derived BxS and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived BxR cells (BxR-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in BxS and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo.
Results: BxR-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in BxS and PANC-1 cells. Elevated miR-210 expression levels were detected in BxR-CSCs and BxR-CSC-derived exosomes compared to those in BxS-CSCs and BxS-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in BxS and PANC-1 cells cultured with BxR-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in BxS cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by BxR-CSC-derived exosomes.
Conclusions: Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.
Cellular OncologyBiochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍：
The Official Journal of the International Society for Cellular Oncology
Focuses on translational research
Addresses the conversion of cell biology to clinical applications
Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions.
A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients.
In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
