MicroRNA-181d-5p-Containing Exosomes Derived from CAFs Promote EMT by Regulating CDX2/HOXA5 in Breast Cancer
Recently, novel mechanisms underlying the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified in several cancers, including breast cancer. CAFs can secrete exosomes that are loaded with proteins, lipids, and RNAs to affect tumor microenvironment. Herein, we identify...
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Veröffentlicht in: | Molecular therapy. Nucleic acids 2020-03, Vol.19, p.654-667 |
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description | Recently, novel mechanisms underlying the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified in several cancers, including breast cancer. CAFs can secrete exosomes that are loaded with proteins, lipids, and RNAs to affect tumor microenvironment. Herein, we identify CAF-derived exosomes that can transfer miR-181d-5p to enhance the aggressiveness of breast cancer. Cancerous tissues and matched paracancerous tissues were surgically resected from 122 patients with breast cancer. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were employed to identify interaction between homeobox A5 (HOXA5) and caudal-related homeobox 2 (CDX2), as well as between CDX2 and miR-181d-5p, respectively. Human breast cancer Michigan Cancer Foundation-7 (MCF-7) cells were cocultured with CAF-derived exosomes. 5-Ethynyl-2′-deoxyuridine (EdU) assay, TUNEL staining, Transwell invasion assays, and scratch tests were carried out to evaluate MCF-7 cell functions. Nude mice bearing xenografted MCF-7 cells were injected with CAF-derived exosomes, and the tumor formation was evaluated. HOXA5 expressed at a poor level in breast cancer tissues, and its overexpression retarded MCF-7 cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) and facilitated its apoptosis in vitro. miR-181d-5p targets CDX2, a transcription factor binding to HOXA5 promoter. Coculture of CAFs and MCF-7 cells showed that CAFs prolonged proliferation and antagonized apoptosis of MCF-7 cells via release of exosomes. Coculture of MCF-7 cells and exosomes derived from CAFs identified miR-181d-5p as a mediator of the exosomal effects on MCF-7 cells, in part, via downregulation of CDX2 and HOXA5. CAF-derived exosomes containing miR-181d-5p promoted the tumor growth of nude mice bearing xenografted MCF-7 cells. In conclusion, exosomal miR-181d-5p plays a key role in CAF-mediated effects on tumor environment in breast cancer, likely via CDX2 and HOXA5. |
doi_str_mv | 10.1016/j.omtn.2019.11.024 |
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CAFs can secrete exosomes that are loaded with proteins, lipids, and RNAs to affect tumor microenvironment. Herein, we identify CAF-derived exosomes that can transfer miR-181d-5p to enhance the aggressiveness of breast cancer. Cancerous tissues and matched paracancerous tissues were surgically resected from 122 patients with breast cancer. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were employed to identify interaction between homeobox A5 (HOXA5) and caudal-related homeobox 2 (CDX2), as well as between CDX2 and miR-181d-5p, respectively. Human breast cancer Michigan Cancer Foundation-7 (MCF-7) cells were cocultured with CAF-derived exosomes. 5-Ethynyl-2′-deoxyuridine (EdU) assay, TUNEL staining, Transwell invasion assays, and scratch tests were carried out to evaluate MCF-7 cell functions. Nude mice bearing xenografted MCF-7 cells were injected with CAF-derived exosomes, and the tumor formation was evaluated. HOXA5 expressed at a poor level in breast cancer tissues, and its overexpression retarded MCF-7 cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) and facilitated its apoptosis in vitro. miR-181d-5p targets CDX2, a transcription factor binding to HOXA5 promoter. Coculture of CAFs and MCF-7 cells showed that CAFs prolonged proliferation and antagonized apoptosis of MCF-7 cells via release of exosomes. Coculture of MCF-7 cells and exosomes derived from CAFs identified miR-181d-5p as a mediator of the exosomal effects on MCF-7 cells, in part, via downregulation of CDX2 and HOXA5. CAF-derived exosomes containing miR-181d-5p promoted the tumor growth of nude mice bearing xenografted MCF-7 cells. In conclusion, exosomal miR-181d-5p plays a key role in CAF-mediated effects on tumor environment in breast cancer, likely via CDX2 and HOXA5.</description><identifier>ISSN: 2162-2531</identifier><identifier>EISSN: 2162-2531</identifier><identifier>DOI: 10.1016/j.omtn.2019.11.024</identifier><identifier>PMID: 31955007</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>breast cancer ; cancer-associated fibroblasts ; CDX2 ; epithelial-mesenchymal transition ; exosome ; HOXA5 ; microRNA-181d-5p</subject><ispartof>Molecular therapy. Nucleic acids, 2020-03, Vol.19, p.654-667</ispartof><rights>2019</rights><rights>Copyright © 2019. Published by Elsevier Inc.</rights><rights>2019. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c521t-5d144dfea7040574834f6fced4a199b01d450a5680af767867d36438dfd41d353</citedby><cites>FETCH-LOGICAL-c521t-5d144dfea7040574834f6fced4a199b01d450a5680af767867d36438dfd41d353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970169/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970169/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31955007$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Hongbin</creatorcontrib><creatorcontrib>Wei, Hong</creatorcontrib><creatorcontrib>Wang, Jingsong</creatorcontrib><creatorcontrib>Li, Lin</creatorcontrib><creatorcontrib>Chen, Anyue</creatorcontrib><creatorcontrib>Li, Zhigao</creatorcontrib><title>MicroRNA-181d-5p-Containing Exosomes Derived from CAFs Promote EMT by Regulating CDX2/HOXA5 in Breast Cancer</title><title>Molecular therapy. Nucleic acids</title><addtitle>Mol Ther Nucleic Acids</addtitle><description>Recently, novel mechanisms underlying the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified in several cancers, including breast cancer. CAFs can secrete exosomes that are loaded with proteins, lipids, and RNAs to affect tumor microenvironment. Herein, we identify CAF-derived exosomes that can transfer miR-181d-5p to enhance the aggressiveness of breast cancer. Cancerous tissues and matched paracancerous tissues were surgically resected from 122 patients with breast cancer. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were employed to identify interaction between homeobox A5 (HOXA5) and caudal-related homeobox 2 (CDX2), as well as between CDX2 and miR-181d-5p, respectively. Human breast cancer Michigan Cancer Foundation-7 (MCF-7) cells were cocultured with CAF-derived exosomes. 5-Ethynyl-2′-deoxyuridine (EdU) assay, TUNEL staining, Transwell invasion assays, and scratch tests were carried out to evaluate MCF-7 cell functions. Nude mice bearing xenografted MCF-7 cells were injected with CAF-derived exosomes, and the tumor formation was evaluated. HOXA5 expressed at a poor level in breast cancer tissues, and its overexpression retarded MCF-7 cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) and facilitated its apoptosis in vitro. miR-181d-5p targets CDX2, a transcription factor binding to HOXA5 promoter. Coculture of CAFs and MCF-7 cells showed that CAFs prolonged proliferation and antagonized apoptosis of MCF-7 cells via release of exosomes. Coculture of MCF-7 cells and exosomes derived from CAFs identified miR-181d-5p as a mediator of the exosomal effects on MCF-7 cells, in part, via downregulation of CDX2 and HOXA5. CAF-derived exosomes containing miR-181d-5p promoted the tumor growth of nude mice bearing xenografted MCF-7 cells. In conclusion, exosomal miR-181d-5p plays a key role in CAF-mediated effects on tumor environment in breast cancer, likely via CDX2 and HOXA5.</description><subject>breast cancer</subject><subject>cancer-associated fibroblasts</subject><subject>CDX2</subject><subject>epithelial-mesenchymal transition</subject><subject>exosome</subject><subject>HOXA5</subject><subject>microRNA-181d-5p</subject><issn>2162-2531</issn><issn>2162-2531</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kc1q3DAUhU1paUKSF-iiaNmNHV1Zkm0ohakzaQL5I6SQndBY11MNtjWRNEPz9tUwaUg31UYXdM654nxZ9gloARTk6apwY5wKRqEpAArK-LvskIFkORMlvH8zH2QnIaxoOpICk-xjdlBCIwSl1WE2XNvOu_ubWQ41mFys89ZNUdvJTksy_-2CGzGQM_R2i4b03o2knZ0HcpcmF5HMrx_I4pnc43Iz6LgztWeP7PTi9nEmiJ3Id486RNLqqUN_nH3o9RDw5OU-yn6ezx_ai_zq9sdlO7vKO8Eg5sIA56ZHXVFORcXrkvey79BwDU2zoGC4oFrImuq-klUtK1NKXtamNxxMKcqj7Ns-d71ZjGg6nKLXg1p7O2r_rJy26t-Xyf5SS7dVsqlSt00K-PIS4N3TBkNUow0dDoOe0G2CYiVnpZCUQZKyvTTVGILH_nUNULUjpVZqR0rtSCkAlUgl0-e3H3y1_OWSBF_3Akw1bS16FTqLqUNjPXZRGWf_l_8HDniivA</recordid><startdate>20200306</startdate><enddate>20200306</enddate><creator>Wang, Hongbin</creator><creator>Wei, Hong</creator><creator>Wang, Jingsong</creator><creator>Li, Lin</creator><creator>Chen, Anyue</creator><creator>Li, Zhigao</creator><general>Elsevier Inc</general><general>American Society of Gene & Cell Therapy</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200306</creationdate><title>MicroRNA-181d-5p-Containing Exosomes Derived from CAFs Promote EMT by Regulating CDX2/HOXA5 in Breast Cancer</title><author>Wang, Hongbin ; Wei, Hong ; Wang, Jingsong ; Li, Lin ; Chen, Anyue ; Li, Zhigao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c521t-5d144dfea7040574834f6fced4a199b01d450a5680af767867d36438dfd41d353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>breast cancer</topic><topic>cancer-associated fibroblasts</topic><topic>CDX2</topic><topic>epithelial-mesenchymal transition</topic><topic>exosome</topic><topic>HOXA5</topic><topic>microRNA-181d-5p</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Hongbin</creatorcontrib><creatorcontrib>Wei, Hong</creatorcontrib><creatorcontrib>Wang, Jingsong</creatorcontrib><creatorcontrib>Li, Lin</creatorcontrib><creatorcontrib>Chen, Anyue</creatorcontrib><creatorcontrib>Li, Zhigao</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy. Nucleic acids</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Hongbin</au><au>Wei, Hong</au><au>Wang, Jingsong</au><au>Li, Lin</au><au>Chen, Anyue</au><au>Li, Zhigao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MicroRNA-181d-5p-Containing Exosomes Derived from CAFs Promote EMT by Regulating CDX2/HOXA5 in Breast Cancer</atitle><jtitle>Molecular therapy. Nucleic acids</jtitle><addtitle>Mol Ther Nucleic Acids</addtitle><date>2020-03-06</date><risdate>2020</risdate><volume>19</volume><spage>654</spage><epage>667</epage><pages>654-667</pages><issn>2162-2531</issn><eissn>2162-2531</eissn><abstract>Recently, novel mechanisms underlying the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified in several cancers, including breast cancer. CAFs can secrete exosomes that are loaded with proteins, lipids, and RNAs to affect tumor microenvironment. Herein, we identify CAF-derived exosomes that can transfer miR-181d-5p to enhance the aggressiveness of breast cancer. Cancerous tissues and matched paracancerous tissues were surgically resected from 122 patients with breast cancer. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were employed to identify interaction between homeobox A5 (HOXA5) and caudal-related homeobox 2 (CDX2), as well as between CDX2 and miR-181d-5p, respectively. Human breast cancer Michigan Cancer Foundation-7 (MCF-7) cells were cocultured with CAF-derived exosomes. 5-Ethynyl-2′-deoxyuridine (EdU) assay, TUNEL staining, Transwell invasion assays, and scratch tests were carried out to evaluate MCF-7 cell functions. Nude mice bearing xenografted MCF-7 cells were injected with CAF-derived exosomes, and the tumor formation was evaluated. HOXA5 expressed at a poor level in breast cancer tissues, and its overexpression retarded MCF-7 cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) and facilitated its apoptosis in vitro. miR-181d-5p targets CDX2, a transcription factor binding to HOXA5 promoter. Coculture of CAFs and MCF-7 cells showed that CAFs prolonged proliferation and antagonized apoptosis of MCF-7 cells via release of exosomes. Coculture of MCF-7 cells and exosomes derived from CAFs identified miR-181d-5p as a mediator of the exosomal effects on MCF-7 cells, in part, via downregulation of CDX2 and HOXA5. CAF-derived exosomes containing miR-181d-5p promoted the tumor growth of nude mice bearing xenografted MCF-7 cells. In conclusion, exosomal miR-181d-5p plays a key role in CAF-mediated effects on tumor environment in breast cancer, likely via CDX2 and HOXA5.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>31955007</pmid><doi>10.1016/j.omtn.2019.11.024</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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subjects | breast cancer cancer-associated fibroblasts CDX2 epithelial-mesenchymal transition exosome HOXA5 microRNA-181d-5p |
title | MicroRNA-181d-5p-Containing Exosomes Derived from CAFs Promote EMT by Regulating CDX2/HOXA5 in Breast Cancer |
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