Identifying Protein Kinase Tbk1 As A Novel Inhibitor of Intestinal Tumorigenesis

<p>Colorectal cancer (CRC) is the third most common cancer diagnosed in women and men， causing almost 600,000 annual deaths worldwide. There is a clear need to understand how CRC forms and progresses in order to improve the strategies of CRC prevention and therapy. A major factor that drives the development of CRC is genetic mutations that lead to activation of oncogenes and inactivation of tumor suppressor genes in intestinal epithelial cells (IECs). In addition, the initiation and progression of CRC involve environmental and immunological factors. In particular, chronic inflammatory conditions are known as an important risk factor for CRC. Intestinal inflammation can be caused by deregulated signaling events in IECs or immune cells; and chronic inflammation is often associated with reduced production of immunosuppressive cytokines such as interleukin (IL)-10 and aberrant production of inflammatory cytokines. However, the signaling factors involved in the regulation of intestinal inflammation and tumorigenesis are still poorly defined. Given the complexity of the molecular and cellular components contributing to these pathogenic processes, animal models represent an important tool for CRC studies.</p> <p>This dissertation focuses on the study of a serine/threonine kinase, TANK Binding Kinase 1 (TBK1). Although TBK1 is best known as a mediator of type I interferon induction in antiviral innate immunity, recent evidence suggests the involvement of TBK1 in several other biological processes including cancer development. Based on <em>in vitro</em> studies using cancer cell lines, TBK1 has been implicated as an oncogenic kinase that mediates survival of KRAS-dependent lung and other cancers. However, the oncogenic role of TBK1 is controversial, since this finding has been challenged by a more recent study. Moreover, the <em>in vivo</em> role of TBK1 in CRC development, particularly during the early phase of adenoma formation, has not been studied. This dissertation project took an <em>in vivo</em> approach that involves the generation and characterization of an innovative mouse model in which <em>Tbk1</em> is conditionally ablated in IECs. The data from my dissertation reveals an unexpected finding that TBK1 has a tumor-suppressive function in the intestine. IEC-specific <em>Tbk1</em> ablation promotes adenoma formation in mice carrying a mutation in the <em>Apc</em> gene, a tumor-suppressor gene commonly mutated in the early stages of colon cancer development. Interestingly, <em>Tbk1</em> expression is important for the crosstalk of IECs with intraepithelial lymphocytes that maintain the expression of immunosuppressive cytokine IL-10. These studies present the first <em>in vivo </em>model demonstrating the function of TBK1 during the process of intestinal adenoma development and suggest a mechanism of TBK1 action. These data also present a novel approach in determining the <em>in vivo</em> function of TBK1 early in the tumorigenic process as compared to previous findings based on the xenograft model of late-staged cancers. In addition, because the use of TBK1 inhibitor has been suggested for possible treatment in cancers of other tissue types, my findings argue for the precaution in the selection of treatment modalities targeting TBK1 in these patients; it is possible that long-term use of TBK1 inhibitors may pose an increased risk for adenoma growth in the intestine.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2015

Author dc:creator

• Mathews, Amber L

Contributors dc:contributor

• Shao-Cong Sun, Ph.D.
• Gary Gallick, Ph.D.
• Qingyun Liu, Ph.D.

• TBK1
• TANK binding kinase 1
• colon cancer
• adenomatous polyposis coli
• APC min/+ mouse model
• intestinal adenoma growth
• IL-10
• colorectal cancer
• intestinal epithelial cell
• intraepithelial lymphocyte
• Cancer Biology
• Digestive System Diseases
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/605

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1686