Transcriptional responses of tumor cell lines to interferon-alpha.
PhD Thesis, University of Basel,
Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10349
Interferon is an antiviral and antiproliferative cytokine therapeutically applied to treat hepatitis infection and cancer expansion. The beneficial effects of interferon-alpha are dependent on efficient signaling by activation of defined JAK-STAT pathway and the induction of interferon stimulation genes. These genes are translated to proteins with antiviral, antiproliferative, anti-tumor and apoptotic properties. Induction of gene expression is consolidated by binding of interferon activated transcription factors to interferon-specific elements in the promoter of such genes. This interaction is dependent on the accessibility of the chromosomal region given by an open chromatin structure. Some interferon-induced proteins are negatively regulating the signal transduction to avoid overreactions such as triggering senescence and to restore responsiveness to a next round of cytokine stimulation. The response to interferon was characterized using whole-genome gene-expression microarrays. Interferon induced proteins were characterized for their antiproliferative effects by measuring growth in cell culture. These proteins were tagged fluorescently to localize them to cell compartments. Suppressor of cytokine signaling proteins were overexpressed in cancer cell lines and their effect on gene expression was described by genome-wide micro-array analyzes. The epigenetic state in tumor samples was determined, the effect of interferon-alpha on DNA mehtylation was described for one gene and the epigenetic changes documented in embryonic cells defective in a gene involved in DNA damage repair. Our results document antiproliferative action for the interferon-stimulated genes IFI44 and IFITM3. Induction of gene expression can be blocked by overexpression of SOCS1 proteins in cancer cell lines. The epigenetic DNA methylation status is altered in tumor cells and methylation of unique CpG sites can dynamically change during cytokine treatment and may involve a DNA demethylation factor. The interferon-alpha response of cancer cell lines depends on the expression, the inducibility and the epigenetic state of interferon-stimulated genes. The genes studied here are effective in blocking proliferation or signal transduction in interferon-alpha sensitive cell lines. Screening of clinical samples for the expression of these genes or their proteins or determination of the DNA methylation status therein is promising in customization of drug therapy for personalized healthcare.
|Committee Members:||Schär, Primo-Leo|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Molecular Genetics (Schär)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Bd.|
|Last Modified:||30 Jun 2016 10:52|
|Deposited On:||03 May 2013 11:46|
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