Role of ZEB1 in adenoma formation, inflammation and inflammation-driven carcinoma
[eng] Multiple studies have highlighted the role of ZEB1 as critical regulator of tumor progression through the regulation of different hallmarks of cancer beyond the induction of EMT. The general aim of this dissertation is to characterize new potential mechanisms that regulate oncogenic transforma...
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| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/145482 |
| Acesso em linha: | https://hdl.handle.net/2445/145482 http://hdl.handle.net/10803/667993 |
| Access Level: | acceso abierto |
| Palavra-chave: | Oncologia Regulació genètica Transcripció genètica Oncology Tumors Genetic regulation Genetic transcription |
| Resumo: | [eng] Multiple studies have highlighted the role of ZEB1 as critical regulator of tumor progression through the regulation of different hallmarks of cancer beyond the induction of EMT. The general aim of this dissertation is to characterize new potential mechanisms that regulate oncogenic transformation in colorectal carcinoma. The specific objectives of this dissertation are: 1. To identify new roles and targets of the transcription factor ZEB1 as a mediator of Wnt-induced intestinal adenoma formation. 2. To characterize ZEB1’s mechanism of action as a transcriptional regulator in inflammation and inflammation-induced carcinomas. To address these goals, a wide number of reagents and techniques have been used, namely, human samples of adenomas and CRC, CRC cell lines whose expression for different genes has been manipulated by overexpression or RNA interference, high throughput techniques (RNA and microbiota sequencing) and transgenic mouse models (ApcMin/+, Zeb1+/- and Mpg-/-). We found that ZEB1 expression in epithelial cells from intestinal adenomas increases adenoma formation and decreases life span in the ApcMin/+ mouse model, which is supported by decreased senescence and apoptosis in ApcMin/+/Zeb1+/+ mice when compared to ApcMin/+/Zeb1+/- counterparts. ZEB1 is both a target and a mediator of the Wnt signaling pathway. Here we provide two new mechanisms by which ZEB1 modulates the Wnt pathway through the regulation of AXIN2 and DACT2 expression. In addition, we found that ZEB1 promotes lipid accumulation in adenomas and colorectal cancer cell lines through the repression of the ATGL/PPARα/PGC-1α axis, which is critical for the degradation of lipid droplets. Besides, we show that ZEB1 is upregulated in the epithelial cells of ulcerative colitis patients and of mouse models of colitis, where its expression promotes intestinal inflammation and inflammatory tumorigenesis. ZEB1 exerts these functions, at least in part, through the increase of DNA damage and the inhibition of the MPG glycosylase, which is involved in DNA damage repair. Moreover, ZEB1 expression in CRC cells stimulates the production of ROS and IL1-β by macrophages which, in turn, reduce MPG expression in CRC cells. Altogether, from the results presented in this dissertation, it can be concluded that: 1. ZEB1 represses senescence and apoptosis during Wnt-induced intestinal adenoma formation. 2. ZEB1 potentiates Wnt signaling in intestinal adenomas through the activation of AXIN2 and the repression of DACT2. 3. ZEB1 induces accumulation of lipids in intestinal cells through Wnt-dependent repression of ATGL, PPARα and PGC-1α. 4. ZEB1 is upregulated in the epithelial cells of UC patients and of mouse models of colitis, where its expression promotes intestinal inflammation and inflammation-driven tumorigenesis. 5. ZEB1 promotes colitis and inflammation-driven CRC through the induction of DNA damage and the inhibition of the DNA repair glycosylase MPG. 6. ZEB1 expression in epithelial cells stimulates the production of ROS and IL1-β by macrophages that, in turn, reduce MPG expression in CRC cells. These results establish ZEB1 as an important regulator of intestinal adenoma formation, and describe ZEB1 as a mediator of inflammation and inflammation-driven carcinogenesis, setting ZEB1 as a potential therapeutic target in colorectal carcinoma. |
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