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    Investigating the Role of Obesity and Obstructive Sleep Apnea in Hepatocellular Carcinoma Progression

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    Author
    Sweeney, Nathan
    Issue Date
    2018
    Keywords
    Liver Cancer
    Obesity
    Sleep Apnea
    Advisor
    Martinez, Jesse
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Primary liver cancer is the seventh most common cancer worldwide and the second highest cause of cancer mortality. The incidence of hepatocellular carcinoma (HCC) has increased 80% in the past two decades and now comprises 85% of all primary liver cancer. Obesity increases the risk of developing HCC two-fold in women and five-fold in men. Co-morbidities common to obesity including non-alcoholic steatohepatitis (NASH), hepatic inflammation, and lipid accumulation increase the risk of developing HCC. Obstructive sleep apnea (OSA), a state of chronic intermittent hypoxia which is common in obese individuals, also increases the incidence of NASH. With a U.S. population that is approximately 33% obese, having OSA at 30-50%, we estimate the co-incidence of obesity and OSA is 10-16.5% of the entire U.S. population. Diet-induced obesity or intermittent hypoxia induces hepatic lipid accumulation and diet-induced obesity was recently shown to promote HCC tumor development. Whether obesity, chronic intermittent hypoxia, and their combination hasten hepatic lipid accumulation and HCC tumor progression remains unclear. In our studies, we monitored tumor development utilizing micro-computed tomography imaging and discovered that tumors developed fastest in mice that consumed a high fat diet. Upon further investigation, these mice also tended to have higher serum levels of AST and ALT and gained more weight than their counterparts. However, the addition of hypoxia lead to a decrease in weight gained, as well as a reduction in hepatic lipid accumulation and tumor formation. Extraction of mRNA from mouse livers revealed an up-regulation HIF-1α in mice fed a high fat diet without treatment with hypoxia that correlated strongly with tumorigenesis. Remarkably, hypoxia was found in mice treated with hypoxia as well as the mice that were fed a high fat diet only. These findings suggest that hepatic lipid accumulation produces endogenous hepatic hypoxia which associates with increased hepatic HIF-1α expression that correlates with tumorigenesis. Collectively, these data reveal a mechanism that potentially explains progression from early liver disease to HCC.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Cancer Biology
    Degree Grantor
    University of Arizona
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