Abstract
α-L-fucosidase 1 (FUCA1) is a lysosomal enzyme that catalyzes the hydrolytic cleavage of the terminal fucose residue in breast cancer cells. FUCA1 mRNA levels were detected by real-time PCR, and there was a greater than 139-fold increase in FUCA1 mRNA expression in breast tumor samples compared with normal breast tissue samples (*P = 0.005, n = 236). Higher FUCA1 mRNA expression was preferentially detected in early-stage tumors (stage 0 to 2) compared with advanced-stage tumors (stage 3 to 4) (stage 0-1 versus stage 3, *P = 0.015; stage 0-1 versus stage 4, *P = 0.024). FUCA1 protein levels were higher in advanced-stage tumors concomitant with decreased fucosylated Lewis-x antigen expression, as evidenced using the immunohistochemical staining H-score method (*P < 0.001). Statistical analysis revealed that lower FUCA1 levels significantly predicted an inferior overall survival rate among triple-negative breast cancer (TNBC) patients compared with non-TNBC patients (*P = 0.009). Two stable FUCA1 siRNA knock-down MDA-MB-231 cell lines were established, and the results suggest that transient FUCA inhibition creates a selective pressure that triggers the metastasis of primary tumor cells, as detected by wound healing and invasion assays (*P < 0.01). The results suggest that FUCA1 may be a potential prognostic molecular target for clinical use, especially in TNBC patients.
Highlights
Glycosylation drives the specific arrangement of the linkages between oligosaccharides and glycoproteins or glycolipids in mammalian cells
The levels of phosphorylated FAK (p-FAK-Tyr-576) and phosphorylated Src (p-Src-Tyr-418) were lower in fucosidase 1 (FUCA1) stable knock-down cells (Figure 5D). These results suggest that FUCA facilitates invasive breast cancer cell migration and matrix adhesion via the FAK/Src signaling pathway and that this pathway may represent a potential target for preventing the metastasis of triplenegative breast cancer (TNBC) breast cancer cells www.impactjournals.com/oncotarget induced by the down-regulation of FUCA1
FUCA1 catalyzes the hydrolytic cleavage of terminal alpha-Lfucose residues in glycoproteins and glycolipids that are associated with the transformation to a malignant phenotype [1]
Summary
Glycosylation drives the specific arrangement of the linkages between oligosaccharides and glycoproteins or glycolipids in mammalian cells. Fucosylated Lewis-x antigen expression is a unique prognostic factor for recurrence-free survival and overall survival in younger patients with triplenegative breast cancer (TNBC) [6, 8]. Specific targeting of these proteins with a radiolabeled humanized monoclonal antibody significantly inhibited tumor growth in an MCF7 breast cancer xenograft model in BALB/c nude mice [9]. These results suggest that fucosylated glycoconjugates on the breast cancer cell surface can be used as therapeutic molecules [2, 10, 11]
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