Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide, causing an estimated 600,000 deaths/yr. Alcohol abuse and hepatitis C virus (HCV) infection cause inflammation and chronic liver diseases, including cirrhosis, and synergistically increase risk for HCC. Cirrhosis is a well-defined precancerous lesion, yet its molecular underpinnings at the level of the epigenome have not been examined. Alcohol consumption is rising in many countries and results in ~1.8 million deaths/yr. Approximately 170 million people worldwide are infected with HCV, 4 million in the United States, making it the most common blood-borne disease in the U.S. The etiologic agents responsible for the majority of HCCs (>85%) are perhaps better understood than for any other cancer, and all are due to environmental agents or human behaviors (e.g. alcohol, HCV), yet there is much that we do not understand about how these agents exert their carcinogenic effects over >30 years with significant clinical variability. There is no definitive evidence for alcohol or HCV directly mediating genetic damage. There is mounting evidence, however, for early and progressive epigenetic changes during liver disease and for a role of diet and inflammation in disrupting the epigenome. Based on studies from our group and others, genes regulating development appear to be one of the preferential targets of epigenetic defects in cancers, including HCC. A comprehensive analysis of the epigenetic regulation of developmental pathways has never been performed in normal or diseased liver, limiting our knowledge of the full extent and timing of epigenetic changes in the etiology of human liver disease and how these changes may be used as prognostic markers to improve treatment. We hypothesize that epigenetic changes in developmental pathways caused by chronic alcohol exposure and/or HCV infection play a key role in the pathogenesis of liver disease, HCV-induced cellular damage, and HCC development. We propose four aims to address this hypothesis.
In aim 1 we will epigenetically profile human liver tissues from patients with cirrhosis or HCC caused by alcohol and/or HCV by coupling a large liver tissue bank with a custom tiling array focused on developmental regulatory genes.
In aim 2 we will epigenetically profile untreated and alcohol treated/HCV infected primary hepatocytes using a cell culture system.
In aim 3 we will confirm our array data with sensitive and quantitative assays and examine the mechanisms by which ethanol/HCV modulate epigenetic control of model developmental genes and how aberrant expression of developmental genes regulates cell growth. Finally, in aim 4 we will examine how epigenetic marks/expression of developmental genes relates to clinical and pathological changes during liver disease progression. Results from these studies are expected to greatly enhance our understanding of the epigenetic etiology of HCC, provide new targets for therapy and diagnosis/prognosis, and yield novel information on how a ubiquitous recreational drug and a widespread infectious agent impact the epigenome.

Public Health Relevance

Hepatocellular carcinoma (HCC) is the 5th leading cause of cancer related deaths and its incidence is rising in the United States. Unlike many other tumor types, the predisposing factors for the majority of HCCs are known and all are due to external environmental agents and/or human behaviors such as chronic alcohol abuse and hepatitis C infection. While it is known that these agents alter our epigenome, a regulatory system directing gene activity and genome stability, and preferentially target certain gene pathways, the full extent of the epigenetic changes and when they occur in precancerous liver lesions (cirrhosis) remains unknown. It is therefore critical to undertake a comprehensive analysis of the epigenome in these targeted pathways in normal and diseased liver to understand how epigenetic changes lead to HCC and how they may be developed into novel treatments and diagnostic tools to improve patient survival and quality of life. Such studies are the focus of this proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
7R01AA019976-04
Application #
8733345
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Murray, Gary
Project Start
2011-09-20
Project End
2016-06-30
Budget Start
2013-07-03
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$560,612
Indirect Cost
$142,071
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Piao, Yongjun; Lee, Seong Keon; Lee, Eun-Joon et al. (2017) CAME: identification of chromatin accessibility from nucleosome occupancy and methylome sequencing. Bioinformatics 33:1139-1146
Hlady, Ryan A; Zhou, Dan; Puszyk, William et al. (2017) Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer. Epigenetics 12:215-225
Zhou, Dan; Hlady, Ryan A; Schafer, Marissa J et al. (2017) High fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver. Epigenetics 12:55-69
Tiedemann, Rochelle L; Hlady, Ryan A; Hanavan, Paul D et al. (2016) Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. Oncotarget 7:1927-46
Zhao, Xiangxuan; Puszyk, William M; Lu, Zaiming et al. (2015) Small molecule inhibitor YM155-mediated activation of death receptor 5 is crucial for chemotherapy-induced apoptosis in pancreatic carcinoma. Mol Cancer Ther 14:80-9
Kim, Sung-Hwan; Ezenwoye, Onyeka; Cho, Hwan-Gue et al. (2015) iTagPlot: an accurate computation and interactive drawing tool for tag density plot. Bioinformatics 31:2384-7
Tiedemann, Rochelle L; Putiri, Emily L; Lee, Jeong-Heon et al. (2014) Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome. Cell Rep 9:1554-66
Sheng, Weian; Ogunwobi, Olorunseun O; Chen, Tao et al. (2014) Capture, release and culture of circulating tumor cells from pancreatic cancer patients using an enhanced mixing chip. Lab Chip 14:89-98
Hlady, Ryan A; Tiedemann, Rochelle L; Puszyk, William et al. (2014) Epigenetic signatures of alcohol abuse and hepatitis infection during human hepatocarcinogenesis. Oncotarget 5:9425-43
Ogunwobi, Olorunseun O; Puszyk, William; Dong, Hui-Jia et al. (2013) Epigenetic upregulation of HGF and c-Met drives metastasis in hepatocellular carcinoma. PLoS One 8:e63765

Showing the most recent 10 out of 17 publications