Expression profile of multidrug resistance genes and proteins in cancerous and stem cells

Lu, Chen (2008) Expression profile of multidrug resistance genes and proteins in cancerous and stem cells. Doctoral thesis, University of Central Lancashire.

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Despite improved knowledge and advanced treatments of high-grade gliomas, the overall survival rate of glioma patients remains low due to the recurrences and locations of the tumour. Evidence shows that the existence of a subpopulation of cells - cancer stem cells (CSCs) may be the major obstacle in treating gliomas. CD133 and nestin have been suggested as the markers of CSCs and natural stem cells.
The primary focus of this study was to identify CD133+/nestin+ stem-like cells and discover their association with multidrug resistance (MDR) related genes, i.e. multiple drug resistance I (mdrl) gene and anti-apoptotic gene (bcl-2) in human glioma compared to normal brain tissues and cell lines. Glioma and normal astrocyte cell lines have been employed for CD133 isolating purposes to characterise the association with MDR related genotype and phenotype. The chemosensitivity of the
isolated CD 133 population was investigated using chemosensitivity assay.
Meanwhile, a serum deprivation method was established in this study to enrich and select CD 133+ CSCs in a glioma (GOS-3) cell line.
As a secondary focus of this project, the possibility of immortalisation enzyme hTERT being a discriminative masker between normal and cancer brain stem cells and the transcriptional correlation between cd133 and bmi-lIc-myc oncogenes were
For the first time, findings of the current study demonstrated that
1) there was an evident increase of CD133 gene expression in glioma compared to normal brain tissues where the latter expressed low levels of CD133, P-gp and Bcl-2 than glioma tissues, with an exception of nestin expression,
2) serum deprivation enriched CD133 expression and demonstrated a direct coexpression between CD133 and drug resistance in GOS-3 cells,
3) hTERT may not be a discriminative marker for normal and cancer brain stem cells,
4) although there was a strong transcriptional association between bmil and cmyc, there was an inverse transcriptional association between these genes and cd133 in serum deprived glioma cells, suggesting that bmil may not be essential for the maintenance of glioma stem cells, and
5) CD133+ glioma and normal brain cells showed a significantly high resistance towards chemotherapeutic drugs compared to the autologous CD133- cells.
In conclusion, an improved understanding of molecules contributing to the maintenance of CSCs may lead to a combined treatment, targeting both CSCs and their protective MDR phenotypes leading eventually to attractive strategies for the
treatment of gliomas.

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