Project Details
Description
PROJECT SUMMARY
In mammals, majority of nitrogen waste is produced by gut microbiome in the form of ammonia. Ammonia is a
neurotoxin and is cleared by two major pathways: 1) conversion via the urea cycle enzymes (UCEs) into
nontoxic urea for excretion; and 2) assimilation into glutamate (Glu) by glutamate dehydrogenase (GDH) then
into glutamine (Gln) by glutamate ammonium ligase (GLUL), also termed glutamine synthetase (GS). In recent
years, UCEs and Glu/Gln synthesis have been found to be involved in tumor growth/development in various
tissues. Partially elevated UCE activities are implicated in tumor promotion via mechanisms such as enhanced
pyrimidine and polyamine production. Likewise, Glu/Gln biosynthesis is generally thought to be tumor-
promoting in various cancers. Curiously, while the liver is the main organ that handles ammonia waste, the
roles of the two ammonia handling pathways in liver cancer remain systematically unexplored. In
hepatocellular carcinoma (HCC), the major histological subtype of liver cancer, UCE expression is often down-
regulated and correlates with worse prognosis, and GS expression is frequently elevated yet correlates with
better outcomes. Using mouse models of HCC driven by oncogenic -catenin, we recently reported that -
catenin led to decreased expression of UCEs and increased expression of GS. Increased ammonia levels
were observed in the plasma and tumor interstitial fluids, which were exacerbated by the ablation of hepatic
GS. These data indicate that oncogenic -catenin leads to the disruption of nitrogen homeostasis, and that
defective ammonia-clearance promotes HCC growth. The main goals of this application are to study the roles
of the UCEs in HCC, and to test the hypothesis that lowering ammonia burden can be a therapeutic strategy
for HCC treatment/prevention. We propose three Specific Aims. Aim1: Test the hypothesis that suppression of
UCE expression contributes to the growth of HCC driven by -catenin. This will be done by 1) overexpressing
or knocking down UCEs in various HCC mouse models; 2) studying the mechanism how down-regulation of
UCEs may promote HCC. Aim 2: Study how oncogenic -catenin regulates UCE transcription. We will test how
-catenin interacts with other transcription factors such as C/EBP and HNF4a, and test how they interact with
the UCE promoter/enhancer regions to regulate expression. Aim 3: testing that lowering ammonia burden can
be a therapeutic/preventive strategy for HCC. This will be done by feeding mice with low protein diet and test
the effect on growth signaling and HCC progression in vivo. Successful accomplishment of the project will
determine the role of UCEs in HCC, identify hyperammonemia as a risk factor, and help establish dietary
intervention as a strategy for treating/preventing HCC.
Status | Finished |
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Effective start/end date | 7/1/24 → 6/30/25 |
Funding
- National Cancer Institute: $450,997.00
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