miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles
Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray ana...
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| Veröffentlicht in: | Cell death & disease 2020-10, Vol.11 (10), p.899-899, Article 899 |
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| creator | Bier, Ariel Hong, Xin Cazacu, Simona Goldstein, Hodaya Rand, Daniel Xiang, Cunli Jiang, Wei Ben-Asher, Hiba Waldman Attia, Moshe Brodie, Aharon She, Ruicong Poisson, Laila M. Brodie, Chaya |
| description | Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-β signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs. |
| doi_str_mv | 10.1038/s41419-020-03088-3 |
| format | Article |
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A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-β signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-020-03088-3</identifier><identifier>PMID: 33093452</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/100 ; 13/106 ; 13/31 ; 38 ; 38/61 ; 38/77 ; 38/89 ; 631/67 ; 631/67/1922 ; 64 ; 64/60 ; Animals ; Antibodies ; Antitumor activity ; Axon guidance ; Biochemistry ; Biomedical and Life Sciences ; Brain Neoplasms - genetics ; Brain Neoplasms - metabolism ; Cell Biology ; Cell Culture ; Cell self-renewal ; DNA microarrays ; Extracellular vesicles ; Extracellular Vesicles - physiology ; Gene clusters ; Gene Expression Regulation, Neoplastic ; Glioblastoma ; Glioblastoma - genetics ; Glioblastoma - metabolism ; Glioma ; Glioma cells ; GRB10 Adaptor Protein - physiology ; Humans ; Immunology ; Invasiveness ; Life Sciences ; Medical prognosis ; Mesenchyme ; Mice ; Mice, Nude ; Microarray Analysis ; Microglia ; Microglia - cytology ; MicroRNAs - physiology ; miRNA ; Neoplastic Stem Cells - cytology ; Neural stem cells ; Neural Stem Cells - cytology ; Polarization ; Stem cell transplantation ; Stem cells ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Cell death & disease, 2020-10, Vol.11 (10), p.899-899, Article 899</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-991317bc98e89d12d51f3213d9f6446abc6c7ffe337f3fdf325568e55575b4db3</citedby><cites>FETCH-LOGICAL-c474t-991317bc98e89d12d51f3213d9f6446abc6c7ffe337f3fdf325568e55575b4db3</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/PMC7581800/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581800/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33093452$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bier, Ariel</creatorcontrib><creatorcontrib>Hong, Xin</creatorcontrib><creatorcontrib>Cazacu, Simona</creatorcontrib><creatorcontrib>Goldstein, Hodaya</creatorcontrib><creatorcontrib>Rand, Daniel</creatorcontrib><creatorcontrib>Xiang, Cunli</creatorcontrib><creatorcontrib>Jiang, Wei</creatorcontrib><creatorcontrib>Ben-Asher, Hiba Waldman</creatorcontrib><creatorcontrib>Attia, Moshe</creatorcontrib><creatorcontrib>Brodie, Aharon</creatorcontrib><creatorcontrib>She, Ruicong</creatorcontrib><creatorcontrib>Poisson, Laila M.</creatorcontrib><creatorcontrib>Brodie, Chaya</creatorcontrib><title>miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-β signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs.</description><subject>13</subject><subject>13/100</subject><subject>13/106</subject><subject>13/31</subject><subject>38</subject><subject>38/61</subject><subject>38/77</subject><subject>38/89</subject><subject>631/67</subject><subject>631/67/1922</subject><subject>64</subject><subject>64/60</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antitumor activity</subject><subject>Axon guidance</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - metabolism</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell self-renewal</subject><subject>DNA microarrays</subject><subject>Extracellular vesicles</subject><subject>Extracellular Vesicles - physiology</subject><subject>Gene clusters</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glioblastoma</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - metabolism</subject><subject>Glioma</subject><subject>Glioma cells</subject><subject>GRB10 Adaptor Protein - physiology</subject><subject>Humans</subject><subject>Immunology</subject><subject>Invasiveness</subject><subject>Life Sciences</subject><subject>Medical prognosis</subject><subject>Mesenchyme</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Microarray Analysis</subject><subject>Microglia</subject><subject>Microglia - cytology</subject><subject>MicroRNAs - physiology</subject><subject>miRNA</subject><subject>Neoplastic Stem Cells - cytology</subject><subject>Neural stem cells</subject><subject>Neural Stem Cells - cytology</subject><subject>Polarization</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU2LFDEQhoMo7jLuH_AgAS9eWvPZSV8EWfyCBUH0HNLp6pksnWRNukfnr_hrzUyv6-rBQEhBPfWmql6EnlLykhKuXxVBBe0awkhDONG64Q_QOSOCNkLr7uG9-AxdlHJN6uGcMNk-Rmc16LiQ7Bz9DP5zI4nAIQ3LZGcoeN4BLjOECKVgGwccoEB0u0OwE56zjcXPPkWcRrydfAr2RGMH07TyVcBn7OMM2boT-t3POxy8y6lWWLyvd4DJ7yEfcH_A8KPKHutrBxnvoXg3QXmCHo12KnBx-27Q13dvv1x-aK4-vf94-eaqcUKJuek6yqnqXadBdwNlg6QjZ5QP3dgK0dretU6NI3CuRj4ONSdlq0FKqWQvhp5v0OtV92bpAwwOYu1mMjfZB5sPJllv_s5EvzPbtDdKaqrrVjfoxa1ATt8WKLMJvhzHsRHSUgwTUlDGiVIVff4Pep2WHOt4lVJUkrZVbaXYStWFlZJhvGuGEnN036zum-q-OblveC16dn-Mu5LfXleAr0CpqbiF_Ofv_8j-AirDviM</recordid><startdate>20201022</startdate><enddate>20201022</enddate><creator>Bier, Ariel</creator><creator>Hong, Xin</creator><creator>Cazacu, Simona</creator><creator>Goldstein, Hodaya</creator><creator>Rand, Daniel</creator><creator>Xiang, Cunli</creator><creator>Jiang, Wei</creator><creator>Ben-Asher, Hiba Waldman</creator><creator>Attia, Moshe</creator><creator>Brodie, Aharon</creator><creator>She, Ruicong</creator><creator>Poisson, Laila M.</creator><creator>Brodie, Chaya</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20201022</creationdate><title>miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles</title><author>Bier, Ariel ; Hong, Xin ; Cazacu, Simona ; Goldstein, Hodaya ; Rand, Daniel ; Xiang, Cunli ; Jiang, Wei ; Ben-Asher, Hiba Waldman ; Attia, Moshe ; Brodie, Aharon ; She, Ruicong ; Poisson, Laila M. ; Brodie, Chaya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-991317bc98e89d12d51f3213d9f6446abc6c7ffe337f3fdf325568e55575b4db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13</topic><topic>13/100</topic><topic>13/106</topic><topic>13/31</topic><topic>38</topic><topic>38/61</topic><topic>38/77</topic><topic>38/89</topic><topic>631/67</topic><topic>631/67/1922</topic><topic>64</topic><topic>64/60</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antitumor activity</topic><topic>Axon guidance</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Brain Neoplasms - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bier, Ariel</au><au>Hong, Xin</au><au>Cazacu, Simona</au><au>Goldstein, Hodaya</au><au>Rand, Daniel</au><au>Xiang, Cunli</au><au>Jiang, Wei</au><au>Ben-Asher, Hiba Waldman</au><au>Attia, Moshe</au><au>Brodie, Aharon</au><au>She, Ruicong</au><au>Poisson, Laila M.</au><au>Brodie, Chaya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2020-10-22</date><risdate>2020</risdate><volume>11</volume><issue>10</issue><spage>899</spage><epage>899</epage><pages>899-899</pages><artnum>899</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-β signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33093452</pmid><doi>10.1038/s41419-020-03088-3</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/100 13/106 13/31 38 38/61 38/77 38/89 631/67 631/67/1922 64 64/60 Animals Antibodies Antitumor activity Axon guidance Biochemistry Biomedical and Life Sciences Brain Neoplasms - genetics Brain Neoplasms - metabolism Cell Biology Cell Culture Cell self-renewal DNA microarrays Extracellular vesicles Extracellular Vesicles - physiology Gene clusters Gene Expression Regulation, Neoplastic Glioblastoma Glioblastoma - genetics Glioblastoma - metabolism Glioma Glioma cells GRB10 Adaptor Protein - physiology Humans Immunology Invasiveness Life Sciences Medical prognosis Mesenchyme Mice Mice, Nude Microarray Analysis Microglia Microglia - cytology MicroRNAs - physiology miRNA Neoplastic Stem Cells - cytology Neural stem cells Neural Stem Cells - cytology Polarization Stem cell transplantation Stem cells Tumor Cells, Cultured Xenograft Model Antitumor Assays Xenografts |
| title | miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles |
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