Glycoproteins in colon cancer : possible role of tumor associated antigen 90K
Ulmer, Tricia ann
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One of the most consistent biochemical changes associated with colon cancer progression is the altered expression of cell-associated carbohydrates. For example, the elevated expression of β1-6 branched N-linked oligosaccharides correlates with the presence of metastatic disease in colon cancer patients. Thus, it has become desirable to identify glycoproteins that are modified by these cancer-associated carbohydrates. Previous work in our laboratory identified the tumor-associated antigen 90 kDa (TAA90K) as a carrier of these cancer-associated carbohydrates. Since TAA90K has been previously implicated in cancer progression and metastasis, we examined its expression and function in human colon tumors. Immunohistochemical analysis revealed elevated expression of TAA90K in all tumor samples analyzed compared to normal colon. To examine the function of TAA90K in colon cancer, we performed protein binding and cellular assays with TAA90K purified from HT-29 human colon cancer cells infected with recombinant vaccinia virus expressing TAA90K. Purified TAA90K bound to ECM proteins including fibronectin, collagen IV, laminins-1, -5 and -10 and galectin-3. Unlike TAA90K isolated from other cell types, TAA90K isolated from HT-29 cells failed to mediate adhesion of colon cancer and normal cell lines, due in part to cell-specific glycosylation differences. Although TAA90K did not directly mediate cellular adhesion, it did modulate galectin-3-dependent adhesion of HT-29 cells. In addition, TAA90K bound to and was a substrate for MMP-7, a matrix metalloproteinase previously implicated in colon cancer progression. MMP-7-cleavage of TAA90K had little effect on its binding to pro- and active MMP-7, laminin-1 and galectin-3, but reduced significantly its binding to fibronectin and laminin-10. In addition, treatment of cells with MMP-7-cleaved TAA90K resulted in lower levels of proMMP-7 in the conditioned medium than cells treated with intact TAA90K. This may be mediated by the reduced binding of MMP-7-cleaved TAA90K to IL-6 and IL-1β, cytokines previously implicated in enhanced proMMP-7 expression in prostate cancer cells. Thus, a possible mechanism by which TAA90K may contribute to colon cancer progression is by modulating tumor cell adhesion to extracellular proteins and extracellular matrix remodeling through interactions with MMP-7 and galectin-3.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorLoh, Lambert; Laferte, Suzanne
CommitteeRoesler, William J.; Forsyth, George W.; Carlsen, Svein; Warrington, Rob C.
Copyright DateApril 2007