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Analysis of the role of SOX1 and SOX3 genes in promotion of malignant phenotype of glioblastoma cells

dc.contributor.advisorDrakulić, Danijela
dc.contributor.otherStevanović, Milena
dc.contributor.otherBrajušković, Goran
dc.contributor.otherDrakulić, Danijela
dc.contributor.otherStevanović, Milena
dc.creatorMarjanović, Jelena
dc.date.accessioned2020-01-27T12:20:32Z
dc.date.available2020-01-27T12:20:32Z
dc.date.available2020-07-03T08:07:57Z
dc.date.issued2019-06-28
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=7077
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/11740
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:20712/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025220274
dc.description.abstractGlioblastom, glioma tumor gradusa IV, je najčešći maligni tumor mozga kod odraslih i jedan od najsmrtonosnijih tipova tumora. I pored agresivne terapije koja obuhvata hirurško uklanjanje tumora, radio- i hemio-terapiju, prosečno preživljavanje bolesnika sa ovim tipom tumora je oko 15 meseci. Glioblastom (GBM), pored tumorskih ćelija, sadrži i populaciju samo-obnavljajućih tumor-inicirajućih matičnih ćelija (matične ćelije glioblastoma) koje se smatraju odgovornim za nastanak, progresiju, metastaziranje i rezistenciju na terapiju. Geni SOXB1 podgrupe (SOX1, SOX2 i SOX3) kodiraju regulatorne proteine koji imaju značajne uloge u mnogim procesima u toku razvića, kao što su održavanje pluripotentnosti matičnih ćelija i održavanje populacije neuralnih progenitora u pluripotentnom i proliferišućem stanju. Ovi geni imaju i značajne funkcije u procesu karcinogeneze. Ekspresija gena ove podgrupe detektovana je u GBM. Funkcija gena SOX2 je dobro proučena kod ovog tipa tumora; pokazano je da ovaj gen promoviše maligni potencijal ćelija GBM i neophodan je za održavanje tumorogenog potencijala matičnih ćelija glioblastoma. Za razliku od gena SOX2, uloga gena SOX1 i SOX3 u ćelijama GBM još uvek nije dovoljno istražena. Stoga, u okviru ove doktorske disertacije analizirana je uloga ovih gena u ćelijama glioblastoma. Dobijeni rezultati pokazuju da ćelijske linije GBM eksprimiraju gen SOX1. Pored toga, u uslovima utišane ekspresije proteina SOX1 detektovano je smanjenje proliferativnog kapaciteta, vijabilnosti i migratornog potencijala U251 ćelija GBM, kao i povećanje broja ovih ćelija u senescenciji. Nakon dediferencijacije ćelijskih linija GBM detektovano je povećanje ekspresije gena SOX1 u poređenju sa ekspresijom uočenom u njihovim parentalnim ćelijama. Nivo ekspresije gena SOX1 povećan je u kulturama matičnih ćelija glioblastoma u poređenju sa ekspresijom ovog gena u imortalizovanim U87 i U251 ćelijama; pri diferencijaciji ovih kultura uočeno je smanjenje ekspresije gena SOX1. Utišavanje ekspresije gena SOX1 u GNS166 kulturi matičnih ćelija GBM dovodi do smanjenja proliferativnog kapaciteta i vijabilnosti ovih ćelija...sr
dc.description.abstractone of deadliest cancers. Despite aggressive treatment, including surgical resection, chemotherapy and radiation, the median survival of patients with glioblastoma is 15 months. A growing body of evidence indicates that GBM contains a population of selfrenewing tumor-initiating cells (glioblastoma stem cells - GSCs) that drive tumor initiation, propagation, metastasis and therapy resistance. SOXB1 genes (SOX1, SOX2 and SOX3) encode transcription regulators with important roles in embryonic development and carcinogenesis. Literature date revealed that SOXB1 genes are expressed in GMB tumor samples. The role of one member of this group, SOX2 gene, is well documented in GBM. It was shown that SOX2 gene promotes malignant potential of GBM cells and it is mandatory for maintenance of tumorogenicity of GSCs. Since the function of SOX1 and SOX3 genes in GBM still remains to be established, the aim of this thesis was to analyze the role of these genes in GBM. Obtained results demonstrated that all analyzed GBM cell lines express SOX1. Downregulation of this gene expression decreases proliferation, viability and migration, and induces senescence of U251 cells. Furthermore, dedifferentiation of GBM cells is accompanied by increase of SOX1 level compared to that in parental cells. Expression of this gene was significantly increased in patient-derived GSC cultures compared to that in U87 and U251 cells; downregulation of SOX1 gene expression was seen upon differentiation of GSCs. In addition, knock-down of this gene expression reduced proliferation and viability of GSCs. Results obtained in this thesis reveal SOX3 expression in GBM cell lines and tumor tissue; the expression of this gene was elevated in the most of analyzed GBM samples compared to expression levels detected in non-tumoral brain tissues. A high SOX3 expression was not associated with the overall survival of GBM patients. Ectopic overexpression of this gene increased proliferation, viability, migration and invasion of GBM cells...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectglioblastomsr
dc.subjectglioblastomaen
dc.subjectSOX1en
dc.subjectSOX3en
dc.subjectglioblastoma stem cellsen
dc.subjectmalignant phenotypeen
dc.subjectdifferentiation therapyen
dc.subjectretinoic aciden
dc.subjectSOX1sr
dc.subjectSOX3sr
dc.subjectmatične ćelije glioblastomasr
dc.subjectmaligni fenotipsr
dc.subjectdiferencijaciona terapijasr
dc.subjectretinoična kiselinasr
dc.titleAnaliza uloge gena SOX1 i SOX3 u promovisanju malignog fenotipa ćelija glioblastomasr
dc.title.alternativeAnalysis of the role of SOX1 and SOX3 genes in promotion of malignant phenotype of glioblastoma cellsen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/1747/IzvestajKomisije21589.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/1746/Disertacija.pdf


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