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Clinical significance and cross talk of Wnt canonical pathway in cancer

  • Author / Creator
    Armanious, Hanan A R
  • ABSTRACT Wnt signalling is of great biological importance as it has been implicated in development and cancer. The Wnt canonical pathway (WCP) is the best characterized signalling pathway. Based on my preliminary studies in my first and second years I found that the WCP is not linear and that it is interacting with many other signalling proteins. Thus, I hypothesized that WCP is cross talking with oncogenic networks in lymphoid and solid tumors. Through my work in this thesis I examined different models of cross talk between WCP and other signalling pathways implicated in cancer pathogenesis. The first objective of this thesis examined the biological and clinical significance of the WCP member pGSK-3β, which also acts as a key member in the PI3K/Akt pathway. pGSK-3β was shown to be expressed in two cancer models; breast cancer and mantle cell lymphoma (MCL). In MCL, pGSK-3β expression was shown to correlate to WCP activation, however, in breast cancer it correlated to PI3K/Akt activation. Importantly, pGSK-3β expression correlated with a worse clinical outcome in breast cancer and MCL patients. The second objective of this thesis examined the regulation of β-catenin (WCP member) by signal transducer and activator of transcription 3 (STAT3) in breast cancer. STAT3 was shown to regulate β-catenin at the transcriptional level, as STAT3 binds to the promoter of β-catenin. Moreover, STAT3 was shown to correlate with nuclear β-catenin expression in patient samples. The third objective of this thesis was to study the regulatory role of β-catenin on a disintegrin and metalloproteinase 10 (ADAM10) in mantle cell lymphoma. However, ADAM10 was shown to regulate the TNFα/NFκB signalling pathway. The fourth objective of this thesis examined the cross talk between the WCP and NPM-ALK the major oncogenic protein in ALK+ALCL. In ALK+ALCL, cross talk between WCP and NPM-ALK through casein kinase 2α was identified. Overall, the identification of the cross talk between WCP and various signalling pathways in different cancer models furthers our current understanding of the importance of the WCP and about the complexity of signalling networks in cancer. These findings provide a framework for the development of novel anti-cancer targeting strategies.

  • Subjects / Keywords
  • Graduation date
    2011-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R39X2Q
  • 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.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Medical Sciences - Laboratory Medicine and Pathology
  • Supervisor / co-supervisor and their department(s)
    • Lai, Raymond (Laboratory Medicine and Pathology)
  • Examining committee members and their departments
    • Bonni, Shirin (Department of Biochemistry and Molecular Biology - University of Calgary)
    • Goping, Ing Swie (Department of Biochemistry)
    • Hugh, Judith (Laboratory Medicine and Pathology)
    • Deschenes, Jean (Laboratory Medicine and Pathology)
    • Keelan, Monica (Laboratory Medicine and Pathology)