Analiza uloge gena SOX1 i SOX3 u promovisanju malignog fenotipa ćelija glioblastoma
Analysis of the role of SOX1 and SOX3 genes in promotion of malignant phenotype of glioblastoma cells
Author
Marjanović, JelenaMentor
Drakulić, DanijelaCommittee members
Stevanović, MilenaBrajušković, Goran
Drakulić, Danijela
Stevanović, Milena
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Show full item recordAbstract
Glioblastom, 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...
one 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...