ERA

Download the full-sized PDF of The Tumor Suppressor RASSF1A Links Inflammation and CancerDownload the full-sized PDF

Analytics

Share

Permanent link (DOI): https://doi.org/10.7939/R39W0945J

Download

Export to: EndNote  |  Zotero  |  Mendeley

Communities

This file is in the following communities:

Graduate Studies and Research, Faculty of

Collections

This file is in the following collections:

Theses and Dissertations

The Tumor Suppressor RASSF1A Links Inflammation and Cancer Open Access

Descriptions

Other title
Subject/Keyword
inflammation
inflammatory bowel disease
YAP
imatinib
RASSF1A
colon cancer
colitis
cancer
tyrosine kinases
Type of item
Thesis
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)
Department
Medical Sciences-Paediatrics
Specialization

Date accepted
2015-01-22T13:35:03Z
Graduation date
2015-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R39W0945J
Rights
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

File Details

Date Uploaded
Date Modified
2015-06-15T07:04:32.708+00:00
Audit Status
Audits have not yet been run on this file.
Characterization
File format: pdf (PDF/A)
Mime type: application/pdf
File size: 10030574
Last modified: 2016:08:08 12:37:54-06:00
Filename: Gordon_Marilyn_H_201501_PhD.pdf
Original checksum: f1f5130b33f07d2042a7ab397db4c0ea
Activity of users you follow
User Activity Date