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The role of mitochondrial DNA in tumorigenesis
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Dickinson, Adam (2013) The role of mitochondrial DNA in tumorigenesis. PhD thesis, University of Warwick.
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WRAP_THESIS_Dickinson_2013.pdf - Submitted Version Download (8Mb) | Preview |
Official URL: http://webcat.warwick.ac.uk/record=b2691697~S1
Abstract
Mitochondria are cytoplasmic organelles that are found in almost all mammalian
cells. Mitochondria contain their own genome, mitochondrial DNA (mtDNA) that
encodes 13 subunits of the electron transfer chain, which is the primary
generator of cellular energy. Precise regulation of mtDNA copy number is
essential for normal cell function and also the differentiation of stem cells into
specialized cell types. Abnormal regulation of mtDNA copy number is
associated with cellular dysfunction, mitochondrial disease and more recently
cancer. Glioblastoma multiforme (GBM) is a highly malignant subgroup of brain
tumors that exhibit similar characteristics to human neural stem cells (hNSCs)
including multipotency and the expression of the stem cell factors. It is unknown
how GBM cells regulate their mtDNA copy number during differentiation and
whether this differs to hNSCs. Furthermore, it is unknown what role mtDNA
plays in the gene expression profiles and the tumorigenicity of GBM.
To address these issues, GBM cells and hNSCs were differentiated for 28 days
and their mtDNA copy number and gene expression were analyzed. In addition,
GBM cells were progressively depleted of their mtDNA using the depletion
agent, 2'-3'-dideoxycytidine, and their in vivo tumorigenicity assessed.
hNSCs and GBM cell lines regulated their copy number in a differential manner
during differentiation. hNSCs progressively expanded their mtDNA copy number
and adopted a differentiated phenotype whilst GBM cells failed to mimic these
processes and their differentiation was incomplete. In addition, progressive
depletion of mtDNA copy number in GBM cells resulted in reduced proliferation
rates and the down regulation of stem cell factors. In vivo, mtDNA depleted
GBM cells formed tumors at a reduced rate and frequency relative to nondepleted
cells.
These outcomes demonstrate that mtDNA copy number is abnormally regulated
in GBM cells and hinders their ability to complete differentiation. The failure of
mtDNA-depleted GBM cells to consistently generate tumors strongly suggests
that maintenance of mtDNA copy number is essential for GBM cells to be
tumorigenic.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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Library of Congress Subject Headings (LCSH): | Mitochondrial DNA, Carcinogenesis | ||||
Official Date: | October 2013 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | St. John, Justin C. | ||||
Extent: | 292 leaves : illustrations, charts. | ||||
Language: | eng |
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