Abstract
Aberrant expression of the simple mucin-type carbohydrate antigens such as Tn antigen 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; however, the role of GALNT2 in neuroblastoma (NB) remains unclear. Here 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.
Highlights
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and the most common solid tumor of infancy, accounting for about 8–10% of childhood cancers
We found that in addition to histological grade of differentiation, positive GALNT2 expression significantly correlated with younger age at diagnosis (≤ 1.5 year; P = 0.013, χ2 test), early clinical stage, primary tumor originated from the extraadrenal site (P = 0.019, χ2 test), favorable International Neuroblastoma Pathology Classification (INPC) histology (P = 0.001, χ2 test) and MYCN non-amplification (P = 0.025, χ2 test) (Table 1)
Three NB cell lines (SH-SY5Y, SK-N-AS, and SKN-DZ) were used for various experiments in this study, so we examined the general glycophenotypes of SH-SY5Y and SK-N-DZ cells by flow cytometry with the following lectins: VVA-FITC, which is specific for Tn antigen, PNAFITC, which preferentially binds to T antigen, Maackia amurensis lectin (MAL)-FITC, which is specific for N-acetylneuraminic acid (α-2,3) galactose structure, and Sambucus nigra lectin (SNA)-FITC, which is mainly specific for N-acetylneuraminic acid (α-2,6) galactose structure
Summary
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and the most common solid tumor of infancy, accounting for about 8–10% of childhood cancers. NB is an embryonal cancer of the peripheral sympathetic nervous system [1, 2]. This tumor exhibits extreme heterogeneity, from spontaneous differentiation or regression into ganglioneuroblastoma (GNB) or ganglioneuroma (GN) with a favorable prognosis to highly undifferentiated tumors with a rapid progression and very poor outcomes [3]. The overall prognosis of NB patients has improved remarkably with recent therapeutic advances, long-term survival of highrisk NB remains poor even with intensive multimodal therapy [1, 2, 4].
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