Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases including acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). There are 350-400 million people in the world chronically infected by this virus, resulting in an estimated 1 million deaths every year. In the U.S., the chronic HBV carrier population is about 1.2 million and in China, the carrier population is about 100 million. Recently, we discovered that HBV could induce autophagy to enhance its DNA replication. We also found that impairing autophagy could induce the initiation but impede the progression of hepatocarcinogenesis in a mouse model. These previous studies of ours demonstrated an important role of autophagy in HBV replication and carcinogenesis. Our proposed research is to continue these novel findings to further study the interplay between HBV and its host. Specifically, we will study the molecular mechanism of HBV-induced autophagy. Our recent studies indicated that the HBV X protein could bind to the class III phosphatidylinositol-3-kinase (PI3KC3) to enhance its enzymatic activity. For that reason, we will further determine how this interaction between HBx and PI3KC3 induces autophagy. We will also investigate how autophagy enhances HBV DNA replication. We will determine whether autophagic vacuoles serve as the platform for HBV DNA replication and whether autophagy affects cellular factors that regulate HBV DNA replication. Finally, we will determine the role of autophagy in HBV-induced hepatocarcinogenesis. We will examine why impairing autophagy facilitates the initiation of hepatocarcinogenesis and yet in the mean time inhibits its progression. Our attention will be focused on the phenotypic difference of liver tumors produced in the absence and presence of autophagy, the role of tumor suppressors in hepatocarcinogenesis, and the effect of autophagy on hepatic tumor-initiating stem cells. Our proposed research will generate important information for us to understand the interaction between HBV and its host cell and lead to a better understanding of HBV replication and carcinogenesis.

Public Health Relevance

Hepatitis B virus (HBV) is an important human pathogen. There are approximately 1.2 million people in the U.S. that are chronically infected by this virus. Many of these patients will develop severe liver diseases including liver cirrhosis and liver cancer and will require liver transplantation for survival. The goal of our proposed research is to understand the interaction between HBV and hepatocytes and how that interaction affects HBV replication and the progression of liver diseases. Our research will improve our knowledge about this important pathogen and lead to the improvements of treatments for HBV patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA177337-01
Application #
8544645
Study Section
Special Emphasis Panel (ZCA1-SRLB-1 (M1))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2013-09-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$200,052
Indirect Cost
$78,131
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Tsai, Kuen-Nan; Kuo, Cheng-Fu; Ou, Jing-Hsiung James (2018) Mechanisms of Hepatitis B Virus Persistence. Trends Microbiol 26:33-42
Kim, Ja Yeon; Wang, Linya; Lee, Jiyoung et al. (2017) Hepatitis C Virus Induces the Localization of Lipid Rafts to Autophagosomes for Its RNA Replication. J Virol 91:
Liu, Kai; Lee, Jiyoung; Kim, Ja Yeon et al. (2017) Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells. Mol Cell 68:281-292.e5
Tian, Yongjun; Kuo, Cheng-Fu; Akbari, Omid et al. (2016) Maternal-Derived Hepatitis B Virus e Antigen Alters Macrophage Function in Offspring to Drive Viral Persistence after Vertical Transmission. Immunity 44:1204-14
Luo, Guangxiang George; Ou, Jing-hsiung James (2015) Oncogenic viruses and cancer. Virol Sin 30:83-4
Tian, Yongjun; Ou, Jing-hsiung James (2015) Genetic and epigenetic alterations in hepatitis B virus-associated hepatocellular carcinoma. Virol Sin 30:85-91
Tian, Y; Kuo, C-F; Sir, D et al. (2015) Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis. Cell Death Differ 22:1025-34
Tian, Yongjun; Wang, Linya; Ou, Jing-Hsiung James (2015) Autophagy, a double-edged sword in hepatocarcinogenesis. Mol Cell Oncol 2:e1004968
Wang, Linya; Ou, Jing-hsiung James (2015) Hepatitis C virus and autophagy. Biol Chem 396:1215-22
Slagle, Betty L; Andrisani, Ourania M; Bouchard, Michael J et al. (2015) Technical standards for hepatitis B virus X protein (HBx) research. Hepatology 61:1416-24

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