The role of IKKalpha in sporadic and familial colorectal tumorigenesis
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- Tez No: 401587
- Danışmanlar: PROF. DR. M. SCHEMANN, DOÇ. DR. F. R. GRETEN
- Tez Türü: Doktora
- Konular: Biyoloji, Biology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2010
- Dil: İngilizce
- Üniversite: Technısche Unıversıtat Munchen
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: Belirtilmemiş.
Özet
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Özet (Çeviri)
In this thesis, the role of IKKα in colorectal tumorigenesis was investigated by the use of chemical and genetic mouse models of colorectal tumors. To do this, an inactive IKKα mutant mouse was used in conjunction with these tumor models and the development of colorectal tumors were monitored for morphological and physiological differences. As a result of these experiments, a distinct phenotype of tumor growth retardation and extended survivals of the animals were observed in all tumor models with IKKα inactivation. Molecular analysis of reduced tumor growth in IKKα mutants resulted in a clear IFNγ upregulation due to myeloid cell recruitment by epithelial secreted factors and autocrine myeloid cell activation by intrinsic factors like MCP-1 and IL-12. NF-κB activity was found to be crucial for activation of myeloid cells to release IFNγ, which further caused growth arrest in IKKα mutant enterocytes. In conclusion, phospho-activation of IKKα is characterized as an important regulator of immune responses in colorectal tumorigenesis. Therefore, the primary role of IKKα in colorectal tumorigenesis is to suppress IFNγ release. However, this role adversely promotes tumor growth in colorectal cancers. In this respect, these results strongly suggest that IKKα phospho-inactivation can be a potent therapeutic strategy for the therapy of colorectal tumors.
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