Primary liver cancer is the fifth most common cancer worldwide and the third 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. We have developed a mouse model of chronic intermittent hypoxia to study the combined effects of diet-induced obesity and chronic intermittent hypoxia on HCC progression. We will apply a newly developed magnetic resonance imaging technique to non-invasively and repeatedly monitor tumor development and hepatic triglyceride content in parallel over the course of the experiments. We hypothesize that obesity, chronic intermittent hypoxia, and their combination will hasten hepatic lipid accumulation and HCC tumor progression. Both obesity and intermittent hypoxia increase HIF- 1?, which promotes hepatic lipid accumulation and is associated with the development and prognosis of HCC. Using mice with liver specific deletion of HIF- 1?, we will test the hypothesis that HIF- 1? activation is essential for promotion of HCC tumorigenesis induced by diet-induced obesity and/or chronic intermittent hypoxia. This study is a significant preclinical step in characterizing mechanisms that may explain obesity associated HCC and will identify targets for disease prevention. With the exception of significant weight loss there are no established therapies for reversal of NASH. Further, there are no prevention agents for HCC. Importantly, HIF- 1? inhibitors are in preclinical testing for the treatment of establishe cancers. Success here will provide the necessary scientific evidence to justify moving forward with preclinical testing of drugs that target HIF- 1? to prevent HCC.

Public Health Relevance

Primary liver cancer is the fifth most common cancer worldwide and the third highest cause of cancer mortality. Obesity, prevalent in 33% of U.S. adults, increases the risk of developing Hepatocellular carcinoma two-fold in women and five-fold in men. This study is a significant preclinical step in characterizing mechanisms that may explain obesity associated hepatocellular carcinoma and will identify targets for disease prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA184920-01
Application #
8686225
Study Section
Special Emphasis Panel (ZCA1-RTRB-L (J1))
Program Officer
Johnson, Ronald L
Project Start
2014-06-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$230,659
Indirect Cost
$78,409
Name
University of Arizona
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721