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Without treatment, the average patient survival time is about six months, which can be extended to fifteen months with multimodal therapies. The chemoresistance observed in GB is, in part, attributed to the presence of a subpopulation of glioblastoma-like stem cells (GSCs) that are characterized by heightened tumorigenic capacity and chemoresistance. GSCs are situated in hypoxic tumor niches, where they sustain and promote the stem-like phenotype and have also been correlated with high chemoresistance. GSCs have the particularity of generating high levels of extracellular adenosine (ADO), which causes the activation of the A3 adenosine receptor (A3AR) with a consequent increase in the expression and activity of genes related to chemoresistance. Therefore, targeting its components is a promising alternative for treating GB. This analysis determined genes that were up- and downregulated due to A3AR blockades under both normoxic and hypoxic conditions. In addition, possible candidates associated with chemoresistance that were positively regulated by hypoxia and negatively regulated by A3AR blockades in the same condition were analyzed. We detected three potential candidate genes that were regulated by the A3AR antagonist MRS1220 under hypoxic conditions: LIMD1, TRIB2, and TGFB1. Finally, the selected markers were correlated with hypoxia-inducible genes and with the expression of adenosine-producing ectonucleotidases. In conclusion, we detected that hypoxic conditions generate extensive differential gene expression in GSCs, increasing the expression of genes associated with chemoresistance. Furthermore, we observed that MRS1220 could regulate the expression of LIMD1, TRIB2, and TGFB1, which are involved in chemoresistance and correlate with a poor prognosis, hypoxia, and purinergic signaling.<\/jats:p>","DOI":"10.3390\/ph17050579","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T10:33:31Z","timestamp":1714559611000},"page":"579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Impact of A3AR Antagonism on the Differential Expression of Chemoresistance-Related Genes in Glioblastoma Stem-like Cells"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9562-2608","authenticated-orcid":false,"given":"Liuba","family":"Pe\u00f1ate","sequence":"first","affiliation":[{"name":"Laboratorio de Biolog\u00eda Tumoral, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Carrillo-Beltr\u00e1n","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Tumoral, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile"},{"name":"Laboratorio de Virolog\u00eda Molecular, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Spichiger","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular Aplicada, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0351-2541","authenticated-orcid":false,"given":"Alexei","family":"Cuevas-Zhbankova","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Tumoral, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngelo","family":"Torres-Ar\u00e9valo","sequence":"additional","affiliation":[{"name":"Escuela de Medicina Veterinaria, Facultad de Medicina Veterinaria Y Recursos Naturales, Sede Talca, Universidad Santo Tom\u00e1s, Talca 347-3620, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1353-6280","authenticated-orcid":false,"given":"Pamela","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Tumoral, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7224-9388","authenticated-orcid":false,"given":"Hans G.","family":"Richter","sequence":"additional","affiliation":[{"name":"Laboratorio de Cronobiolog\u00eda del Desarrollo, Instituto de Anatom\u00eda, Histolog\u00eda y Patolog\u00eda, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel","family":"Ayuso-Sacido","sequence":"additional","affiliation":[{"name":"Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain"},{"name":"Brain Tumour Laboratory, Fundaci\u00f3n Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rody","family":"San Mart\u00edn","sequence":"additional","affiliation":[{"name":"Laboratorio de Patolog\u00eda Molecular, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Quezada-Monr\u00e1s","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Tumoral, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, 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