2024-03-29T02:14:36Zhttps://www.tdx.cat/oai/requestoai:www.tdx.cat:10803/3508052017-09-03T12:47:38Zcom_10803_1col_10803_96988
nam a 5i 4500
Càncer colorectal
Cáncer colorectal
Colorectal cancer
Dianes farmacològiques
Dianas terapéuticas
Drug targeting
Oncologia
Oncología
Oncology
Metilació
Metilación
Methylation
Identification of novel therapeutic targets and tumor suppressor genes in colon cancer using genome-wide high‐throughput approaches
[Barcelona] :
Universitat de Barcelona,
2016
Accés lliure
http://hdl.handle.net/10803/350805
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Bazzocco, Sarah,
autor
1 recurs en línia (152 pàgines)
Tesi realitzada a l'Institut de Recerca Vall d'Hebron
Tesi
Doctorat
Universitat de Barcelona. Facultat de Farmàcia
2016
Universitat de Barcelona. Facultat de Farmàcia
Tesis i dissertacions electròniques
Arango del Corro, Diego,
supervisor acadèmic
TDX
Colorectal cancer is a disease caused by genetic and epigenetic changes. Inactivation of tumor suppressor genes and activation of oncogenes are key landmarks in tumor progression. However, the list of tumor suppressor genes and oncogenes is far from complete, even in the case of the tumor types that are best characterized, such as colorectal cancer. Colorectal cancer is the second most frequent cause of cancer-related death in the Western world and is a serious health issue for the European Union. Patients having stage III or IV cancer undergo surgery followed by chemotherapy. However, the clinical management of these patients is far from optimal, and only about 30 % of the patients show an objective response to even the best chemotherapeutic agents available. In this study genome-wide high throughput assays were used to better characterize important aspects of the oncogenic progression such as deregulation of proliferation and aberrant expression caused by epigenetic mechanisms.
Because rapid tumor proliferation is associated with poor patient prognosis, here we characterized the transcriptional signature of rapidly proliferating colorectal cancer cells in an attempt to identify genes important to sustain tumor growth and that could be used as novel therapeutic targets. The proliferation rate of 52 colorectal cancer cell lines was determined and genome-wide expression profiling of a subset of these lines was assessed by microarray analysis. The expression of 1,290 genes was significantly correlated with the growth rates of colorectal cancer cells. These included genes involved in cell cycle, RNA processing/splicing and protein transport. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and protoporphyrinogen oxidase (PPDX) were shown to have higher expression in faster growing cancer cells. Importantly, pharmacological and genetic inhibition of GAPDH or PPDX reduced the growth of colon cancer cells in vitro and in vivo.
To better understand the mechanisms underlying the profound transcriptional reprogramming observed in cancer cells, we investigated the association between the levels of DNA methylation in the promoters of >14,000 genes and the levels of expression of these genes in a panel of 45 colorectal cancer cell lines. A group of cell lines with significantly higher methylation levels was observed, supporting the notion that there is a group of colorectal tumors with a CpG methylator phenotype (CIMP+). A significant negative regulation between methylation and expression levels was observed for 1,409 genes, suggesting that these genes are silenced during the tumorigenic process through this epigenetic mechanism. A significant number of these genes were zinc finger proteins, suggesting an important role of these DNA-binding proteins on the tumorigenic process. Strikingly, approximately one fourth of these genes are not associated with CpG islands, indicating that DNA methylation outside these CpG rich regions is an important mechanism regulating gene expression and significantly contribute to tumor progression. In addition, we postulate that at least some of those genes have tumor suppressor activity. As a proof-of-concept, we show that restoration of the expression of ZNF238, a gene showing a significant methylation/expression correlation, resulted in reduced growth of colon cancer cells in vitro and in vivo.
In conclusion, in this study we shed new light on the mechanisms underlying the uncontrolled proliferation of colon cancer cells and the expression reprograming imposed in these cells through CpG methylation. The results of this study may contribute to the identification of novel chemotherapeutic targets for patients with colorectal cancer, and the characterization of novel genes/pathways with tumor suppressor activity, that are epigenetically silenced.
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