Numerous studies suggest that inactivation or deletion of one or more tumor suppressor genes may represent early and/or necessary steps in the neoplastic transformation of liver. Furthermore, comparative chromosomal mapping studies suggest that the development of liver tumors in humans and rodents may share a common molecular mechanism that involves inactivation of analogous tumor suppressor genes. Based upon these observations, we have suggested that chromosome transfer studies utilizing human chromosomes and rat liver tumor cell lines may facilitate the facile localization, identification, and cloning of human genes responsible for tumor suppression in liver. To this end, we have established and characterized a model for the functional identification of human tumor suppressor genes in rat liver tumor cell lines. Human chromosome 11, which has been implicated in the pathogenesis of human liver tumors, was introduced into highly aggressive rat liver epithelial tumor cell lines using a microcell-mediated chromosome transfer technique. We have demonstrated that human chromosome 11 suppresses the tumorigenic potential of some rat liver tumor cell lines, providing direct evidence for the presence of a liver tumor suppressor gene on this human chromosome. Further, we have established a microsatellite- based map of the liver tumor suppressor region, localizing the gene(s) to a 950-kb segment of human 11p11.2-p12 and forming the basis for positional cloning of candidate tumor suppressor genes. The studies contained in this proposal seek to identify, isolate, and characterize the human 11p11.2-p12 liver tumor suppressor gene. The goals of this proposal are to (i) establish a PAC contig spanning the liver tumor suppressor region of human 11p11.2-p12, (ii) utilize the isolated PAC clones in the construction of a complete physical map of this chromosomal region, (iii) isolate candidate liver tumor suppressor genes based upon complementarity to PAC clones corresponding to this region, (iv) characterize candidate liver tumor suppressor genes by DNA sequence analysis, and (v) determine the ability of candidate genes to express tumor suppressor activity in transfected rate liver tumor cell lines.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078434-03
Application #
6173823
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Okano, Paul
Project Start
1998-07-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
3
Fiscal Year
2000
Total Cost
$186,103
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Jahn, Jennifer E; Best, D Hunter; Coleman, William B (2010) Exogenous expression of synaptotagmin XIII suppresses the neoplastic phenotype of a rat liver tumor cell line through molecular pathways related to mesenchymal to epithelial transition. Exp Mol Pathol 89:209-16
Jahn, Jennifer E; Coleman, William B (2008) Re-expression of tumorigenicity after attenuation of human synaptotagmin 13 in a suppressed microcell hybrid cell line. Int J Oncol 32:441-9
Rivenbark, Ashley G; Livasy, Chad A; Boyd, Courtney E et al. (2007) Methylation-dependent silencing of CST6 in primary human breast tumors and metastatic lesions. Exp Mol Pathol 83:188-97
Best, D Hunter; Coleman, William B (2007) Treatment with 2-AAF blocks the small hepatocyte-like progenitor cell response in retrorsine-exposed rats. J Hepatol 46:1055-63
Best, D Hunter; Butz, Genelle M; Moller, Karen et al. (2004) Molecular analysis of an immature ovarian teratoma with gliomatosis peritonei and recurrence suggests genetic independence of multiple tumors. Int J Oncol 25:17-25
Rider, Michelle A; Butz, Genelle M; Ricketts, Sharon L et al. (2002) Suppression of tumorigenicity of rat liver tumor cells by human chromosome 13: evidence against the involvement of pRb and BRCA2. Int J Oncol 20:235-45
Gordon, Gavin J; Butz, Genelle M; Grisham, Joe W et al. (2002) Isolation, short-term culture, and transplantation of small hepatocyte-like progenitor cells from retrorsine-exposed rats. Transplantation 73:1236-43
Ricketts, Sharon L; Garcia, Nicole F; Betz, Bryan L et al. (2002) Identification of candidate liver tumor suppressor genes from human 11p11.2-p12. Genes Chromosomes Cancer 33:47-59
Gordon, G J; Coleman, W B; Hixson, D C et al. (2000) Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response. Am J Pathol 156:607-19
Gordon, G J; Coleman, W B; Grisham, J W (2000) Bax-mediated apoptosis in the livers of rats after partial hepatectomy in the retrorsine model of hepatocellular injury. Hepatology 32:312-20

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