lewis-y-antigen and Mouth-Neoplasms

Lewis y is expressed in oral squamous cell carcinoma (OSCC) cells and tumors. Previously, we reported that Lewis y was not expressed in invasion areas, and attenuation of proliferation and invasion in OSCC cells was caused by over-expression of Lewis y. However, the roles of Lewis y in the attenuation of malignant properties have not been clarified. In this study, we investigated the roles of Lewis y in OSCC.. The levels of Lewis y on EGFR and the phosphorylation levels of EGFR in OSCC cells were analyzed by immunoprecipitation and western blot. EGFR cross-linking and binding kinetics of EGF were performed.. Upon EGF stimulation, phosphorylation and dimer formation of EGFR were more prominent in Lewis y- cells. EGF binding kinetics showed reduced binding sites in Lewis y+ cells.. Lewis y reduced EGF binding to EGFR, leading to suppression of malignant properties through suppression of EGF signaling.

Topics: Binding Sites; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Shape; Epidermal Growth Factor; ErbB Receptors; Humans; Kinetics; Lewis Blood Group Antigens; Mouth Neoplasms; Neoplasm Invasiveness; Phosphorylation; Protein Binding; Signal Transduction; Squamous Cell Carcinoma of Head and Neck

Aberrant glycosylation changes normal cellular functions and represents a specific hallmark of cancer. Lewisy (Ley) carbohydrate upregulation has been reported in a variety of cancers, including oral squamous cell carcinoma (OSCC). A high level of Ley expression is related to poor prognosis of patients with oral cancer. However, it is unclear how Ley mediates oral cancer progression. In this study, the role of Ley in OSCC was explored. Our data showed that Ley was upregulated in HSC-3 and OC-2 OSCC cell lines. Particularly, glycosylation of epidermal growth factor receptor (EGFR) with Ley was found in OC-2 cells, and this modification was absent upon inhibition of Ley synthesis. The absence of Ley glycosylation of EGFR weakened phosphorylation of AKT and ERK in response to epidermal growth factor (EGF). Additionally, EGF-triggered cell migration was reduced, but cell proliferation was not affected. Ley modification stabilized EGFR upon ligand activation. Conversely, absence of Ley glycosylation accelerated EGFR degradation. In summary, these results indicate that increased expression of Ley in OSCC cells is able to promote cell migration by modifying EGFR which in turn stabilizes EGFR expression and downstream signaling. Targeting Ley on EGFR could have a potential therapeutic effect on oral cancer.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cells, Cultured; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Glycosylation; Humans; Keratinocytes; Lewis Blood Group Antigens; Male; Mouth Neoplasms; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt

Expression and implication of carbohydrate antigens in squamous cell carcinomas (SCCs) in oral cavity was examined. In the cell lines, type 2H and Lewis y antigens were markedly expressed. In the tissues from SCC patients and benign disorders, type 2H was highly expressed in hyperplasia (96.4 %), displasia (92.9 %) and SCC (100 %). Lewis y was, in turn, expressed mainly in cancer tissues (91.3 %), suggesting that Lewis y is a cancer-associated antigen. Normal oral mucosa showed no expression of these blood group antigens. Surprisingly, Lewis y antigen disappeared in the invasion sites where Ki-67 was definitely stained. Over-expression of Lewis y with manipulation of a fucosyltransferase cDNA resulted in suppression of cell growth and invasion, and knockdown of Lewis y also brought about increased cell growth and invasion. In either situations, no changes in the expression of sialyl-Lewis x could be found. Lowered tumor growth and invasion into surrounding tissues were also shown in Lewis y-positive SCC grafts in nu/nu mice. All these results together with alternative staining between Lewis y and Ki-67 in cancer tissues and FUT1 transfectants suggested that loss of Lewis y is a crucial event for the late stage of SCCs.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase; Gene Expression Regulation, Neoplastic; Humans; Ki-67 Antigen; Lewis Blood Group Antigens; Mice; Mice, Inbred BALB C; Mouth Mucosa; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Transplantation; Oligosaccharides; Organ Specificity; Sialyl Lewis X Antigen