Document Type
Dissertation
Date of Award
2008
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Many different tumors have been documented to have elevated levels of the enzyme ST6Gal I, a Golgi glycosyltransferase that adds α2-6 sialic acids to glycoproteins. Concurrently, upregulated ST6Gal I is associated with metastasis and poor patient prognosis. We initially showed that HD3 colonocytes made to express oncogenic-ras, a common mutation in colon carcinoma, have increased expression of ST6Gal I and elevated α2-6 sialylated integrins. Having established that ras regulates ST6Gal I expression in colon epithelial cells, we found that colonocytes carrying hyper α2-6 sialylated β1 integrins exhibit increased adhesion to and migration toward collagen I. Further, we found that β1 integrins in human colon adenocarcinoma samples consistently carry higher levels of α2-6 sialic acids. These results led us to hypothesize that hypersialylated β1 integrins may have a role in augmenting tumor progression by affecting cell adhesion and motility. To determine whether the effects of oncogenic ras on cell behavior were mediated via upregulated ST6Gal I and consequent hypersialylation of β1 integrins, we individually manipulated ras and ST6Gal I levels in HD3 colonocytes. These cells were engineered to express oncogenic ras with high and low ST6Gal I levels. Initially we confirmed that shRNA mediated dowregulation of ST6Gal I in HD3 cells having oncogenic-ras intact leads to decreased α2-6 sialylation of β1 integrins. We found that cells with diminished integrin sialylation show decreased in vitro invasiveness and impaired binding to and migration toward collagen I, as compared iii with oncogenic-ras expressing HD3 cells that have high ST6Gal I. We also found that ST6Gal I can protect against apoptosis. Specifically, while downregulating ST6Gal I in HD3 cells restored the sensitivity to apoptotic stimuli, forced ST6Gal I expression in SW48 cells actually protected cells from entering the apoptotic cascade. This finding, to our knowledge, represents a novel function attributable to ST6Gal I. Taken together, results presented in this dissertation establish that altered sialylation of surface glycoprotein receptors in general, and β1 integrins in particular, plays a direct role in regulating tumor cell behavior.
Recommended Citation
Shaikh, Faheem M., "Role Of Variant Sialylation In Regulating Tumor Cell Behavior" (2008). All ETDs from UAB. 3799.
https://digitalcommons.library.uab.edu/etd-collection/3799
