Chronic alcohol intake synergistically increases the incidence of hepatocellular carcinoma (HCC) in hepatitis C patients, however, the underlying mechanisms remain poorly understood. A critical event in HCC is the deregulated expansion of tumor initiating cells (TICs), which are stem-like cells that promote treatment resistant HCC. The p53 tumor suppressor acts as a barrier against stem cell proliferation, and inactivation of p53 or its stabilizing partner NUMB leads to expansion of TICs. However, little is known about the control of the NUMB-p53 interaction and the mechanistic basis for p53 inactivation in TICs from HCC induced by alcohol and HCV. Ectopic induction of TLR4 in hepatocytes in HCV NsSa transgenic (Tg) mice generates TICs and liver tumors when the mice are chronically given alcohol. We demonstrated that stemness and tumor-initiating properties of TICs are dependent on TLR4-NANOG pathway and diminished levels of p53. The NUMB-p53 complex disintegrates upon NANOG-mediated activation of aPKCzeta, a NUMB kinase, leading to MDM2 ubiquitin ligase-dependent proteolysis of p53. Using affinity purification and tandem mass spectrometry, we have identified TBC1D15 as a NUMB-associated oncoprotein that can also disengage p53 from its protective association with NUMB, causing p53 degradation and deregulated TIC propagation. The expression of TBC1D15 is induced by the TLR4-NAN0G pathway and elevated in HCC in alcoholic HCV patients. We hypothesize TLR4-NAN0G-medlated NUMB phosphorylation and TBC1D15 upregulation coordinately trigger p53 degradation to promote self-renewal of TICs in liver oncogenesis caused by HCV and alcohol. To test this hypothesis, we will investigate whether: 1) NANOG-mediated induction of upstream AurA kinase and inhibition of the aPKC inhibitor LGL are responsible for activation of aPKCzeta and p53 degradation in TICs; 2) the newly disclosed aPKCzeta-NUMB and TBC1D15 pathways are mutually required for p53 degradation; 3) these pathways are evident and required for self-renewal of TICs isolated from HCC of alcoholic HCV patients; and 4) hepatocyte-specific expression of a non-phosphorylatable mutant of NUMB or hepatocyte-specific ablation of TbcldlS suppresses tumorigenesis in alcohol-fed HCV NsSaTg mice.

Public Health Relevance

Increased liver cancer incidence by a combination of alcoholism and hepatitis C virus (HCV) is a major medical problem worldwide. Our proposed research will lead to a better understanding of the mechanism undedying this interaction and will help develop new treatments for liver cancer in alcoholic HCV patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA011999-20
Application #
9404948
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
20
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Khanova, Elena; Wu, Raymond; Wang, Wen et al. (2018) Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67:1737-1753
Zheng, Han; You, Yang; Hua, Meiyun et al. (2018) Chlorophyllin Modulates Gut Microbiota and Inhibits Intestinal Inflammation to Ameliorate Hepatic Fibrosis in Mice. Front Physiol 9:1671
Lew, Daniel; Wu, Bechien U; Pandol, Stephen J et al. (2018) Disease Course Differences in Acute Pancreatitis Based on Etiology Using the Pancreatitis Activity Scoring System. Pancreas 47:e40-e41
Ogawa, Tomohiro; Li, Yuchang; Lua, Ingrid et al. (2018) Isolation of a unique hepatic stellate cell population expressing integrin ?8 from embryonic mouse livers. Dev Dyn 247:867-881
Tripathi, Anupriya; Debelius, Justine; Brenner, David A et al. (2018) The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 15:397-411
Waldron, Richard T; Su, Hsin-Yuan; Piplani, Honit et al. (2018) Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model. Cell Mol Gastroenterol Hepatol 5:479-497
Waldron, Richard T; Lugea, Aurelia; Gulla, Aiste et al. (2018) Proteomic Identification of Novel Plasma Biomarkers and Pathobiologic Pathways in Alcoholic Acute Pancreatitis. Front Physiol 9:1215
Wu, Raymond; Murali, Ramachandran; Kabe, Yasuaki et al. (2018) Baicalein Targets GTPase-Mediated Autophagy to Eliminate Liver Tumor-Initiating Stem Cell-Like Cells Resistant to mTORC1 Inhibition. Hepatology 68:1726-1740
Buxbaum, James; Quezada, Michael; Chong, Bradford et al. (2018) The Pancreatitis Activity Scoring System predicts clinical outcomes in acute pancreatitis: findings from a prospective cohort study. Am J Gastroenterol 113:755-764
Zhao, Qinglan; Wei, Yi; Pandol, Stephen J et al. (2018) STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis. Gastroenterology 154:1822-1835.e2

Showing the most recent 10 out of 415 publications