This is a re-submission of a proposal to gain an understanding about the nature of the hyper-fucosylation of glycoproteins associated with primary human hepatocellular carcinoma (HCC). Compared to healthy individuals, the circulation of people with HCC contains an abundance of glycoproteins with fucosylation at their N-glycan cores. Little is known about why this modification is so elevated, if it relates to protein function and/or plays a role in disease. There is even uncertainty about whether or not it is the cancer cells that are producing the fucosylated glycoforms. This modified application will systematically determine which cells are producing three "sentinel" hyper-fucosylated glycoproteins, as well as the functional consequences of fucosylation, in comparative studies with fucosylated and unfucosylated glycoforms. The proteins hemopexin, kininogen and GP73, each determined to correlate in the fucosylated glycoform with HCC, are chosen to represent different categories. In doing this, the important hypothesis that fucosylation plays a role in directing the sorting of hepatocytes glycoproteins will also be tested. The results of this work are thus intended to answer the fundamental question as to why fucosylation seems to be a common feature in HCC and help in developing early detection and possibly therapeutic interventions.

Public Health Relevance

By proteins detected in the blood of people with a diagnosis of liver cancer contain the sugar, fucose. Understanding why will help in the development of new diagnostic methods, as well as provide clues for development of new therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136607-05
Application #
8458612
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Rinaudo, Jo Ann S
Project Start
2009-05-19
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$303,798
Indirect Cost
$107,165
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Thio, Chloe L; Smeaton, Laura; Saulynas, Melissa et al. (2013) Characterization of HIV-HBV coinfection in a multinational HIV-infected cohort. AIDS 27:191-201
Block, Timothy M; Gish, Robert; Guo, Haitao et al. (2013) Chronic hepatitis B: what should be the goal for new therapies? Antiviral Res 98:27-34
Evans, Alison A; London, W Thomas; Gish, Robert G et al. (2013) Chronic HBV infection outside treatment guidelines: is treatment needed? Antivir Ther 18:229-35
Safaie, Parham; Ham, Maggie; Kuang, Peter et al. (2013) Lectin-reactive anti-*-gal in patients with Crohn's disease: correlation with clinical phenotypes. Inflamm Bowel Dis 19:2796-800
Nie, Hui; Evans, Alison A; London, W Thomas et al. (2012) Quantitative dynamics of hepatitis B basal core promoter and precore mutants before and after HBeAg seroconversion. J Hepatol 56:795-802
Kawamoto, Sayuri; Moriwaki, Kenta; Nakagawa, Tsutomu et al. (2011) Overexpression of ?1,6-fucosyltransferase in hepatoma enhances expression of Golgi phosphoprotein 2 in a fucosylation-independent manner. Int J Oncol 39:203-8
Romano, Patrick R; Mackay, Andrew; Vong, Minh et al. (2011) Development of recombinant Aleuria aurantia lectins with altered binding specificities to fucosylated glycans. Biochem Biophys Res Commun 414:84-9
Comunale, Mary Ann; Wang, Mengjun; Rodemich-Betesh, Lucy et al. (2011) Novel changes in glycosylation of serum Apo-J in patients with hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev 20:1222-9