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The Tumor Suppressor RASSF1A Links Inflammation and Cancer Open Access


Other title
inflammatory bowel disease
colon cancer
tyrosine kinases
Type of item
Degree grantor
University of Alberta
Author or creator
Gordon, Marilyn H
Supervisor and department
Baksh, Shairaz (Medical Sciences- Pediatrics)
Foley, Edan (Medical Microbiology and Immunology)
Examining committee member and department
Dieleman, Levinus (Medicine)
Wine, Eytan (Medical Sciences- Pediatrics)
MacNaughton, Wallace (Physiology and Pharmacology)
Shaw, Andrew (Oncology)
Medical Sciences-Paediatrics

Date accepted
Graduation date
Doctor of Philosophy
Degree level
The tumor suppressor protein Ras association domain family 1A (RASSF1A) has roles in multiple signaling pathways including modulating apoptosis, the cell cycle, DNA damage, and microtubule organization. RASSF1A has been shown to be one of the most frequently epigenetically silenced genes in a variety of cancer types and thought to be one of the earliest changes in cancer development. Loss of RASSF1A has also been documented in approximately 26% of ulcerative colitis, a subset of inflammatory bowel disease (IBD) patients and 12-80% of colorectal cancer (CRC) patients. As IBD patients are known to be at an increased risk of developing colorectal cancer due to their chronic inflammatory disease, this study was to determine the molecular mechanisms whereby RASSF1A may influence the pathogenesis of inflammatory bowel disease and inflammation-associated colorectal cancer. We used acute and chronic mouse models of colitis-like inflammation and inflammation driven carcinogenesis brought on by addition of dextran sodium sulfate (DSS) in the drinking water. Our results revealed a novel role for RASSF1A in restricting acute inflammation through inhibition of nuclear factor kappa B (NFB) activation. Loss of RASSF1A resulted in exacerbated colitis symptoms and decreased survival in mice. Loss of RASSF1A also resulted in a novel tyrosine phosphorylation of Yes associated protein (YAP) on tyrosine 357 (pY357-YAP) to drive an aberrant transcriptional up-regulation of p73/YAP target pro-apoptotic genes, resulting in increased epithelial cell death, inefficient epithelial repair, and poor survival of Rassf1a-/- knockout mice following inflammation induced injury. Furthermore, under a chronic model of DSS-induced colitis-associated colon cancer, we observed that loss of RASSF1A accelerated tumor development/severity and poor survival of AOM/DSS treated Rassf1a-/- mice. Loss of RASSF1A also led to dysregulation of YAP (a proto-oncogene) and YAP driven transcriptional regulation potentially contributing to the increased inflammation-driven carcinogenesis seen in AOM/DSS treated Rassf1a-/- mice. We propose a possible use of pY357-YAP as a biomarker of severe colitis with likely progression to colitis-associated colon cancer. In addition, the use of tyrosine kinase inhibitors (such as imatinib/gleevec) to restrict pY357-YAP and the abnormal up-regulation of pro-apoptotic genes in the absence of RASSF1A may also be beneficial in treating inflammatory diseases, especially in early onset of disease. Our observations will aid in a better understanding of the key molecular link between inflammation and cancer, the importance of the RASSF1A signaling pathway in restricting inflammation and the identification of potentially novel biomarkers of early onset disease. The identification of novel biomarkers of early onset disease will allow the rational design of useful therapeutics to reduce inflammation and interfere with inflammation driven-malignancies such as inflammation bowel disease pre-disposition to CRC.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Gordon M, and Baksh S. RASSF1A: Not a prototypical Ras effector. Small GTPases 2011;2(3):148-157Gordon M, Mohamed El-Kalla, Baksh S. RASSF1 Polymorphisms in Cancer. Molecular Biology International 2012Gordon M, El-Kalla M, Zhao Y, Fiteih Y, Law J, Volodko N, et al. The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury. PLoS One 2013 10/16;8(10):e75483-e75483

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