The role of O-glycosyltransferases and their clinical significance in neuroblastoma

• Main Authors: Wan-Ling Ho, 何宛玲
• Other Authors: 黃敏銓
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/87036613915110632818

博士 === 國立臺灣大學 === 臨床醫學研究所 === 103 === Aberrant expression of the simple mucin-type carbohydrate antigens such as Tn, sialyl-Tn, T, and sialyl-T antigens is associated with malignant transformation and cancer progression. N-acetylgalactosaminyltransferase 2 (GALNT2), one of the enzymes that mediate the initial step of mucin-type O-glycosylation, is responsible for forming Tn antigen. GALNT2 is expressed differentially in nervous tissues during mouse embryogenesis. T synthase galactosylates Tn to form the core 1 (Galβ1→3GalNAc, T antigen). β1,3-N-acetylglucosaminyltransferase-3 (B3GNT3), formerly called core 1 β3GlcNAcT, is responsible for adding GlcNAc to core 1 (T antigen) in a β1,3 linkage, forming extended core 1 oligosaccharides. However, the roles of these two glycosyltransferases in neuroblastoma (NB) remain unclear. Here we showed that increased B3GNT3 expression evaluated by immunohistochemistry in NB tumor tissues correlated well with the histological grade of differentiation as well as a favorable Shimada’s subset of pathology. Multivariate analyses revealed that positive B3GNT3 expression in tumor tissues predicted a favorable prognosis in NB patients independent of other prognostic markers. B3GNT3 overexpression suppresses T antigen formation and malignant phenotypes including migration and invasion of SK-N-SH cells, whereas B3GNT3 knockdown enhances these phenotypes of SK-N-SH cells. Moreover, B3GNT3 expression decreased phosphorylation of focal adhesion kinase (FAK), Src, paxillin, Akt, and ERK1/2. On the other hand, we showed that increased GALNT2 expression evaluated using immunohistochemistry in NB tumor tissues correlated well with the histological grade of differentiation as well as younger age at diagnosis, early clinical stage, primary tumor originated from the extra-adrenal site, favorable INPC histology, and MYCN non-amplification. Multivariate analysis showed that GALNT2 expression is an independent prognostic factor for better survival for NB patients. GALNT2 overexpression suppressed IGF-1-induced cell growth, migration, and invasion of NB cells, whereas GALNT2 knockdown enhanced these NB phenotypes. Mechanistic investigations demonstrated that GALNT2 overexpression modified O-glycans on IGF-1R, which suppressed IGF-1-triggered IGF-1R dimerization and subsequent downstream signaling events. Conversely, these properties were reversed by GALNT2 knockdown in NB cells. Our findings suggest that GALNT2 regulates malignant phenotypes of NB cells through the IGF-1R signaling pathway, suggesting a critical role for GALNT2 in the pathogenesis of NB. These results regarding B3GNT3 and GALNT2 may also provide an alternative approach for cancer therapy by means of modulating cancer-specific glycosylation.