B4GALNT3 expression predicts a favorable prognosis and suppresses cell migration and invasion via β1-integrin signaling in neuroblastoma

Wen-Ming Hsu^1,8,10, Mei-Ieng Che^2,8,10, Yung-Feng Liao³, Hsiu-Hao Chang⁴, Chia-Hua Chen^2,8, Yu-Ming Huang², Yung-Ming Jeng ⁵, John Huang¹, Michael J. Quon⁶, Hsinyu Lee^7,8

Hsiu-Chin Huang⁹, Min-Chuan Huang^2,8,*

Departments of ¹Surgery, ⁴Pediatrics, and 5Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; 2Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan; 3Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan; 6Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD, USA; 7Department of Life Science, National Taiwan University; ⁸Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan; ⁹Animal Technology Institute Taiwan, Miaoli, Taiwan

¹⁰equal contribution

*correspondence to Dr. Min-Chuan Huang. mchuang@ntu.edu.tw

American Journal of Pathology, in press.

ABSTRACT

β1,4-N-acetylgalactosaminyltransferase III (B4GALNT3) promotes formation of GalNAcβ1,4GlcNAc (LacdiNAc or LDN). Drosophila β1,4-N-acetylgalactos- aminyltransferase A (B4GALNTA) contributes to synthesis of LDN that helps regulate neuronal development. In this study, we investigated the expression and role of B4GALNT 3 in human neuroblastoma (NB). We examined 87 NB tumors by immunohistochemistry to determine correlations between B4GALNT3 expression and clinicopathologic factors including patient survival. Effects of recombinant B4GALNT3 on cell behavior and signaling were studied in SK-N-SH and SH-SY5Y NB cells. We found that increased expression of B4GALNT 3 in NB tumors correlated with a favorable histology (P < 0.001, χ2 test) and early clinical stage (P = 0.041, χ2 test). B4GALNT3 expression was an independent favorable prognostic factor for survival by both univariate and multivariate analyses. Reexpression of B4GALNT 3 in SK-N-SH and SH-SY5Y cells suppressed cell proliferation, colony formation, migration, and invasion. Moreover, B4GALNT3 increased LacdiNAc in β1 integrin leading to decreased phosphorylation of focal adhesion kinase (FAK), Src, paxillin, Akt and ERK1/2. Effects of B4GALNT3 to suppress cell migration and invasion were substantially reversed by concomitant expression of constitutively active Akt or MEK. We conclude that B4GALNT3 predicts a favorable prognosis for NB and that B4GALNT3 suppresses the malignant phenotype via decreasing β1 integrin signaling.

Min-Chuan Huang (黃敏銓), PhD (Dr. rer nat)

Associate Professor

Graduate Institute of Anatomy and Cell Biology

National Taiwan University College of Medicine

6F, No.1, Jen Ai Rd., Sec. 1,Taipei,100,Taiwan

Tel:+886-2-23123456 ext. 88177

Fax:+886-2-23915292

http://homepage.ntu.edu.tw/~mchuang

聯絡人:劉麗芳

發育生物學與再生醫學研究中心

Research Center of Developmental Biology and Regenerative Medicine

Tel：02-23123456轉71632

E-mail：polocz9082@yahoo.com.tw

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