Infection with hepatitis B virus (HBV) (and/or hepatitis C virus) is the major etiology of hepatocellular cancer (HCC). In the United States, chronic hepatitis B and C account for about 30%- 40% of HCC and, worldwide, more than 350 million people are chronically infected with either HBV or HCV. Alteration in the oligosaccharides associated with glycoproteins and glycolipids is one of the many molecular changes that accompany malignant transformations. However, accurate and reliable detection and quantification of oligosaccharides has been technically very difficult or time consuming. It is well established that in HCC there is an elevation in the amount of fucosylated oligosaccharides associated with a-fetal protein (AFP). The increase of a l-6-fucosylated glycans is due, in part, to an abnormal secretion system and other proteins have been shown to be aberrantly glycosylated. However, no systematic analysis has been carried out to identify all the proteins that have an increase in fucosylation. Our hypothesis is that by combining our high throughput oligosaccharide sequencing methodology with our laboratory's proteome expertise, we will be able to use lectin extraction methods to purify and identify fucosylated glycoproteins from HCC sera. Hence, proof of principle experiments will be carried out in the R21 phase using cultured liver cells to demonstrate the utility of the technology; while in the R33 phase the technology will be evaluated in a pilot study using sera obtained from woodchuck, a well established animal model of HBV induced HCC. It is anticipated that this methodology will allow the identification of an array of molecules that show increased fucosylation in HCC. These proteins may be then further evaluated as members of a fucose index to act as a surrogate marker for HCC progression. Obviously the technology would be applicable to any cancer system where oligosaccharide changes are associated with development to neoplasia.
| Comunale, Mary Ann; Wang, Mengjun; Hafner, Julie et al. (2009) Identification and development of fucosylated glycoproteins as biomarkers of primary hepatocellular carcinoma. J Proteome Res 8:595-602 |
