GALNT2 suppresses malignant phenotypes through IGF-1 receptor and predicts favorable prognosis in neuroblastoma

// Wan-Ling Ho 1,4,6,7,* , Chih-Hsing Chou 5,* , Yung-Ming Jeng 2 , Meng-Yao Lu 1 , Yung-Li Yang 1 , Shiann-Tarng Jou 1 , Dong-Tsamn Lin 1 , Hsiu-Hao Chang 1 , Kai-Hsin Lin 1 , Wen-Ming Hsu 3,8 and Min-Chuan Huang 5,8 1 Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 2 Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 3 Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 4 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan 5 Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan 6 Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 7 School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan 8 Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan * These authors contributed equally to this work Correspondence: Hsiu-Hao Chang, email: // Wen-Ming Hsu, email: // Min-Chuan Huang, email: // Keywords : glycosyltransferase; insulin-like growth factor-1 receptor; N-Acetylgalactosaminyltransferase 2; neuroblastoma Received : July 31, 2014 Accepted : October 23, 2014 Published : October 24, 2014 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.