Hepatocellular carcinoma (HCC) accounts for 85% of primary malignant tumors of the liver and is the third most-common cause of cancer-related death in the world. Although its etiology is diverse, the development of HCC follows a common pathogenic profile with repetitive hepatic injury leading to cirrhosis, formation of hyperplastic nodules and accumulation of genetic aberrations. Using a forward genetic approach, we have identified an N-ethyl-N-nitrosourea (ENU)-induced germline mutant phenotype, called Sphinx that develops spontaneous multicentric liver tumors. Tumor formation is apparent by 5 weeks of age and histological analyses revealed that the tissue is well differentiated and no etastases were observed. In addition to hepatocellular tumor development, homozygous Sphinx mice exhibit abnormal lymphocyte development and lack peripheral CD8+ T and NK cells. The phenotypes behave as recessive traits and C57BL/6JSphinx/Sphinx mice die by 12 weeks of age. Coarse mapping placed the mutation in a small interval on chromosome 6, in which no obvious candidate genes were found. The goal of this proposal is to identify the gene carrying the mutation responsible for the described phenotypes. In addition, we intend to characterize the Sphinx phenotype in more detail and to study the interaction between the immune system and tumor cell development. We believe our studies will reveal a novel gene involved in HCC development and provide a new, useful, model system in which to study the interaction between the immune system and hepatocellular tumor formation.

Public Health Relevance

The studies are aimed to identify a yet unknown tumor suppressor gene involved in hepatocellular adenoma/carcinoma development. In addition, using a unique mouse model identified in our laboratory, we aim to study the involvement of the immune system in the pathophysiology of hepatocellular tumor development. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA133649-01
Application #
7449784
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2008-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$195,750
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Endale, Mehari; Aksoylar, H Ibrahim; Hoebe, Kasper (2015) Central role of gimap5 in maintaining peripheral tolerance and T cell homeostasis in the gut. Mediators Inflamm 2015:436017
Aksoylar, H Ibrahim; Lampe, Kristin; Barnes, Michael J et al. (2012) Loss of immunological tolerance in Gimap5-deficient mice is associated with loss of Foxo in CD4+ T cells. J Immunol 188:146-54
Barnes, Michael J; Aksoylar, Halil; Krebs, Philippe et al. (2010) Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. J Immunol 184:3743-54