β-1,4-Galactosyltransferase III enhances invasive phenotypes via β1-integrin and predicts poor prognosis in neuroblastoma.

Abstract

PURPOSE:

Neuroblastoma (NB) is a neural crest-derived tumor that commonly occurs in childhood. β-1,4-Galactosyltransferase III (B4GALT3) is highly expressed in human fetal brain and is responsible for the generation of poly-N-acetyllactosamine, which plays a critical role in tumor progression. We therefore investigated the expression and role of B4GALT3 in NB.

EXPERIMENTAL DESIGN:

We examined B4GALT3 expression in tumor specimens from 101 NB patients by immunohistochemistry and analyzed the correlation between B4GALT3 expression and clinicopathologic factors or survival. The functional role of B4GALT3 expression was investigated by overexpression or knockdown of B4GALT3 in NB cells for in vitro and in vivo studies.

RESULTS:

We found that B4GALT3 expression correlated with advanced clinical stages (P = 0.040), unfavorable Shimada histology (P < 0.001), and lower survival rate (P < 0.001). Multivariate analysis showed that B4GALT3 expression is an independent prognostic factor for poor survival of NB patients. B4GALT3 overexpression increased migration, invasion, and tumor growth of NB cells, whereas B4GALT3 knockdown suppressed the malignant phenotypes of NB cells. Mechanistic investigation showed that B4GALT3-enhanced migration and invasion were significantly suppressed by β1-integrin blocking antibody. Furthermore, B4GALT3 overexpression increased lactosamine glycans on β1-integrin, increased expression of mature β1-integrin via delayed degradation, and enhanced phosphorylation of focal adhesion kinase. Conversely, these properties were decreased by knockdown of B4GALT3 in NB cells.

CONCLUSIONS:

Our findings suggest that B4GALT3 predicts an unfavorable prognosis for NB and may regulate invasive phenotypes through modulating glycosylation, degradation, and signaling of β1-integrin in NB cells.

• Authors: Hsiu-Hao Chang, Chia-Hua Chen, Chih-Hsing Chou, Yung-Feng Liao, Miao-Juei Huang, Ya-Hsin Chen, Wei-Jen Wang, John Huang, Ji-Shiang Hung, Wan-Ling Ho, Yung-Ming Jeng, Mei-Ieng Che, Hsinyu Lee, Meng-Yao Lu, Yung-Li Yang, Shiann-Tarng Jou, Dong-Tsamn Lin, Kai-Hsin Lin, Wen-Ming Hsu, Min-Chuan Huang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 7 Pg. 1705-16 (Apr 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23444218 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Integrin beta1
• Galactosyltransferases

Topics

• Cell Line, Tumor
• Cell Movement (genetics)
• Child, Preschool
• Female
• Galactosyltransferases (genetics, metabolism)
• Gene Expression
• Glycosylation
• Humans
• Infant
• Infant, Newborn
• Integrin beta1 (metabolism)
• Male
• Neoplasm Invasiveness
• Neoplasm Staging
• Neuroblastoma (genetics, metabolism, mortality, pathology)
• Phenotype
• Prognosis
• Proteolysis
• Signal Transduction