{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T01:09:56Z","timestamp":1774314596569,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"3-4","license":[{"start":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T00:00:00Z","timestamp":1610409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["CENTRO-01-0145-FEDER-000008"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Competitiveness and Internationalisation and Portuguese national funds","award":["POCI-01-0145-FEDER-016390"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016390"]}]},{"name":"Competitiveness and Internationalisation and Portuguese national funds","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Despite the intense global efforts towards an effective treatment of glioblastoma (GB), current therapeutic options are unsatisfactory with a median survival time of 12\u201315\u00a0months after diagnosis, which has not improved significantly over more than a decade. The high tumoral heterogeneity confers resistance to therapies, which has hindered a successful clinical outcome, GB remaining among the deadliest cancers. A hallmark of GB is its high recurrence rate, which has been attributed to the presence of a small subpopulation of tumor cells called GB stem-like cells (GSC). In the present work, the efficacy of a multimodal strategy combining microRNA (miRNA) modulation with new generation multitargeted tyrosine kinase inhibitors (imatinib and axitinib) was investigated aiming at tackling this subpopulation of GB cells. MiR-128 and miR-302a were selected as attractive therapeutic candidates on the basis of previous findings reporting that reestablishment of their decreased expression levels in GSC resulted in cell differentiation, which could represent a possible strategy to sensitize GSC to chemotherapy. Our results show that overexpression of miR-128 or miR-302a induced GSC differentiation, which enhanced senescence mediated by axitinib treatment, thus further impairing GSC proliferation. We also provided evidence for the capacity of GSC to efficiently internalize functionalized stable nucleic acid lipid particles, previously developed and successfully applied in our laboratory to target GB. Taken together, our findings will be important in the future design of a GB-targeted multimodal miRNA-based gene therapy, combining overexpression of miR-128 or miR-302a with axitinib treatment, endowed with the ability to overcome drug resistance.<\/jats:p>","DOI":"10.1093\/hmg\/ddab011","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T00:49:14Z","timestamp":1610239754000},"page":"160-171","source":"Crossref","is-referenced-by-count":13,"title":["Differentiation of glioblastoma stem cells promoted by miR-128 or miR-302a overexpression enhances senescence-associated cytotoxicity of axitinib"],"prefix":"10.1093","volume":"30","author":[{"given":"Ana M","family":"Cardoso","sequence":"first","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC\u2014Institute for Interdisciplinary Research, Coimbra, Portugal"}]},{"given":"Catarina M","family":"Morais","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC\u2014Institute for Interdisciplinary Research, Coimbra, Portugal"},{"name":"Department of Life Sciences, University of Coimbra, Cal\u00e7ada Martim de Freitas, 3000-456 Coimbra, Portugal Portugal"}]},{"given":"Frederico","family":"Pena","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC\u2014Institute for Interdisciplinary Research, Coimbra, Portugal"}]},{"given":"T\u00e2nia","family":"Marante","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC\u2014Institute for Interdisciplinary Research, Coimbra, Portugal"}]},{"given":"Pedro P","family":"Cunha","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC\u2014Institute for Interdisciplinary Research, Coimbra, Portugal"}]},{"given":"Am\u00e1lia S","family":"Jurado","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC\u2014Institute for Interdisciplinary Research, Coimbra, Portugal"},{"name":"Department of Life Sciences, University of Coimbra, Cal\u00e7ada Martim de Freitas, 3000-456 Coimbra, Portugal Portugal"}]},{"given":"Maria C","family":"Pedroso de Lima","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC\u2014Institute for Interdisciplinary Research, Coimbra, Portugal"}]}],"member":"286","published-online":{"date-parts":[[2021,1,12]]},"reference":[{"key":"2021050309031768000_ref1","doi-asserted-by":"crossref","first-page":"963","DOI":"10.3389\/fonc.2019.00963","article-title":"Glioblastoma multiforme: an overview of emerging therapeutic targets","volume":"9","author":"Taylor","year":"2019","journal-title":"Front. 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