Specific Aims Hepatocellular carcinoma (HOC) is common following hepatitis C virus (HCV) infection and in diabetics or alcoholics with inflammation-related liver pathology. Alcoholism and obesity increases the gut-derived endotoxin whose co-receptor is TLR4. We have previously shown that HCV infection increases expression of TLR4. Commonality of TLR4 suggests synergism between HCV and alcoholism/obesity. Our studies in a mouse model of HCC suggest that the combination of inflammation-induced hepatocyte regeneration plus impairment of DNA damage repair caused by the viral core protein leads to chromosomal instability and hepatic oncogenesis. According to the model diagrammed below, activation of the IKKp/c-Jun/Stat3 plus inflammation cytokines (TNF-a, IL-6) by viral infection and alcoholism/obesity leads to hepatocyte DNA damage plus upregulation of mitogens and hepatocyte proliferation. Together, these changes lead to increased incidence of HCC. HYPOTHESES 1. HCV-induced Toll-like receptor 4 (TLR4) enhances TNF-a, leading to synergism between HCV and alcoholism/diabetes for oncogenic potential. 2. HCV inhibits DNA damage defense barrier, including DNA damage-induced signal transduction (ATM sand ATR) and complex formation of nonhomologous end-joining (NHEJ). 3. HCV infection-associated inflammation facilitates carcinogenesis through IKKp/c-jun/STAT3 activation.
SPECIFIC AIMS 1. Determine the effect of TLR4 gene disruption on HCC in an alcohol/diabetes mouse model and core/NS5A transgenic mice. 2. Determine the mechanism of inhibition of DNA damage-repair by viral proteins, and the possible association of the core with the NHEJ complex by proteomics analysis with Dr. Deshaies (California Institute of Technology). 3. Determine the role of c-jun/IKKp/STAT3 in HCV-associated HCC in a conditional knockout animal model.
|Machida, Keigo (2017) Existence of cancer stem cells in hepatocellular carcinoma: myth or reality? Hepatol Int 11:143-147|
|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|
|Chen, Chia-Lin; Tsukamoto, Hidekazu; Liu, Jian-Chang et al. (2013) Reciprocal regulation by TLR4 and TGF-? in tumor-initiating stem-like cells. J Clin Invest 123:2832-49|
|Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58|
|Tian, Yongjun; Kuo, Cheng-fu; Chen, Wen-ling et al. (2012) Enhancement of hepatitis B virus replication by androgen and its receptor in mice. J Virol 86:1904-10|
|Wang, Qian; Na, Bing; Ou, Jing-hsiung James et al. (2012) Hepatitis B virus alters the antioxidant system in transgenic mice and sensitizes hepatocytes to Fas signaling. PLoS One 7:e36818|
|Tian, Yongjun; Chen, Wen-ling; Kuo, Cheng-fu et al. (2012) Viral-load-dependent effects of liver injury and regeneration on hepatitis B virus replication in mice. J Virol 86:9599-605|
|Feldman, Douglas Edmund; Chen, Chialin; Punj, Vasu et al. (2012) Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells. Proc Natl Acad Sci U S A 109:829-34|
|Tang, Chi-Hui; Wei, Wei; Liu, Limin (2012) Regulation of DNA repair by S-nitrosylation. Biochim Biophys Acta 1820:730-5|
|Sir, Donna; Kuo, Cheng-fu; Tian, Yongjun et al. (2012) Replication of hepatitis C virus RNA on autophagosomal membranes. J Biol Chem 287:18036-43|
Showing the most recent 10 out of 25 publications