Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The genetic changes underlying the development and progression of HCC are incompletely understood. The long-term objective of my laboratory is to understand the molecular pathogenesis of HCC and translate new research findings into methods for prevention, early diagnosis, prognostic prediction, and treatment of HCC. In preliminary studies, we have identified a novel gene, hSulfl, which is downregulated in a significant proportion of human HCCs and HCC cell lines, hSulfl is a plasma membrane associated sulfatase. We observed that HCC cell lines lacking hSulfl expression are more resistant to induction of apoptosis. Conversely, forced expression of hSulfl significantly decreased cell growth and increased the sensitivity of HCC cell lines to pro-apoptotic agents; hSulfl therefore may either inactivate a cell survival pathway or activate a cell death pathway. Cell survival signaling by a number of growth factors, particularly fibroblast growth factor (FGF), is dependent on the sulfation state of cell surface heparan sulfate glycosaminoglycans (HSGAGs). Based on these data, we hypothesize that inactivation of hSulfl leads to an increased sulfation state of cell surface HSGAGs, thus promoting cell growth and survival. Our goal is to elucidate the role of hSulfl in the development of HCCs.
In Specific Aim 1 we will test the hypothesis that hSulfl directly desulfates cell surface HSGAGs, leading to decreased activation of cellular growth signaling pathways.
In Specific Aim 2 we will test the hypothesis that inactivation of hSulfl expression contributes to the malignant phenotype through increased cellular survival signaling by growth factors and/or decreased sensitivity of hepatocytes to apoptosis. Finally, in Specific Aim 3 we will determine if hSulfl expression is inactivated in HCCs through allelic loss and/or hypermethylation. Successful completion of these studies will provide insight into the molecular pathogenesis of HCC, and may lead to the development of novel chemotherapeutic strategies against HCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100882-04
Application #
7191698
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (01))
Program Officer
Jhappan, Chamelli
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2007-03-02
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$258,035
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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