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Thesis
Dysregulation of the Wnt signaling pathway in the development of colorectal cancer in HIV-infected patients
Master of Science (M.S.), Drexel University
Aug 2018
DOI:
https://doi.org/10.17918/D8WH45
Abstract
With the advent of antiretroviral therapy (ART), patients with human immunodeficiency virus-1 (HIV-1) have experienced an improvement in morbidity and life expectancy. As this patient population ages, there has been evidence of an elevated risk and earlier onset of colonic neoplasia. The average age of developing colon cancer in HIV-1-infected patients is 48 compared to 60 in the general population. Moreover, the stage of colorectal cancer diagnosed in HIV-1-infected patients is more advanced compared to uninfected individuals. During primary HIV-1 infection, an observed loss of CD4+ T cells is seen in the gastrointestinal (GI) tract along with subsequent systemic immune hyperactivation. Additionally, increased expression of proinflammatory cytokines in the GI tract during HIV-1 infection results in chronic mucosal inflammation. While HIV-induced immunodeficiency and immune activation certainly play a role, there are other possible avenues through which HIV-1 promotes the pathogenicity of oncogenesis. Many of the proteins produced upon viral genomic integration have been demonstrated to interact with components of various cellular pathways. In an effort to elucidate how viral and cellular interaction might aid in colorectal oncogenesis, this study investigates the HIV-1-encoded protein Negative Regulatory Factor (Nef) and its interaction within the Wnt signaling pathway. This pathway is critical within the gastrointestinal stem cell niche for its role in repopulating the intestinal tract lining. Upon dysregulation of the Wnt signaling pathway, [beta]-catenin begins to accumulate in the cytosol and translocates into the nucleus where is binds with transcription factors TCF/LEF leading to an increase in transcription/translation of several key target genes known to upregulate cellular proliferation. The Nef protein has been shown to directly bind to [beta]-catenin in HEK293T cells. What has not been demonstrated is which gene products of the Wnt signaling pathway are dysregulated in the presence of Nef. Understanding the molecular mechanisms behind how HIV may modulate the Wnt signaling pathway will be crucial to better understand the link between HIV and cancer. Therefore, these studies will proceed to examine how HIV-1-encoded Nef modulates the Wnt signaling pathway by interacting with the [beta]-catenin complex in colorectal carcinoma cells leading to accelerated colon tumor outgrowth.
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Details
- Title
- Dysregulation of the Wnt signaling pathway in the development of colorectal cancer in HIV-infected patients
- Creators
- Jennifer Marcy - DU
- Contributors
- Todd Strochlic (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 68 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 8128; 991014632534804721