The Tumor Suppressor RASSF1A Links Inflammation and Cancer

• Author / Creator

  Gordon, Marilyn H

• 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.

• Subjects / Keywords

  • RASSF1A
  • Cancer
  • Inflammation
  • Tyrosine kinases
  • Inflammatory bowel disease
  • YAP
  • Imatinib
  • Colitis
  • Colon cancer

• Graduation date

  Spring 2015

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R39W0945J

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. 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.