Abstract:
Chronic inflammation is a major characteristic of the development and progression of several tumors, in particular colorectal cancer. The connection between inflammation and tumorigenesis has been well supported from pharmacological, epidemiological, and genetic data. However, the molecular mechanism by which inflammation promotes cancer cell growth constitutes a broad area of ongoing investigation. Hence, multiple key genes and signaling pathways involved in oxidative stress and inflammation, such as the kallikrein-kinin system, may play a key role in tumorigenesis. In fact, bradykinin has been shown to modulate tumor progression. We have also shown that bradykinin activates the extracellular signaling regulated kinase (ERK) 1-2 pathway which may promotes cell survival or cell death in cancer cells. Retinoids are major regulators of epithelial cell proliferation, apoptosis, and differentiation and have therefore been used in the prevention and treatment of some cancers. Retinoids have also shown promise in preclinical colorectal cancer studies. Therefore, we were interested in investigating a potential crosstalk between the kallikrein-kinin system, and the retinoic acid signaling pathway using a well-characterized human in vitro colorectal cancer model. In the present study, we tested for the effects of bradykinin receptor 1 and 2 (B1R and B2R) agonists on the proliferation of human colorectal cancer cells, and on the expression and modulation of B1R, B2R, and retinoid receptors (RARα, RARγ, RXRα). We investigated as well the subcellular localization of RARγ, and B2R upon treatment with its high affinity ligand bradykinin, and some of the downstream effector signaling pathways. We showed by MTT assay that the growth of the colorectal cancer cell lines (HCT116, HCT116 p53---, HCT116 p21---) was not affected by B1R and B2R agonists. However, we observed by real-time PCR and western blot analysis a differential expression of B1R, B2R, and retinoid receptors transcripts and prot
Description:
Thesis. M.Sc. American University of Beirut. Department of Biochemistry and Molecular Genetics. Faculty of Medicine 2015. W 4 K455d 2015
Advisor: Dr. Ayad Jaffa, Professor and Chair, Biochemistry and Molecular Genetics ; Co-Advisor: Dr. Nadine Darwiche, Professor, Biochemistry and Molecular Genetics ; Committee members:Dr. Fuad Ziyadeh, Professor and Chair, Internal Medicine, Biochemistry and Molecular Genetics ; Dr. Hiba El Hajj, Assistant Professor, Departments of Internal Medicine and Experimental Pathology, Immunology, and Microbiology.
Includes bibliographical references (leaves 85-93)