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

Abstract

β1,4-N-acetylgalactosaminyltransferase III (B4GALNT3) promotes the formation of GalNAcβ1,4GlcNAc (LacdiNAc or LDN). Drosophila β1,4-N-acetylgalactosaminyltransferase A (B4GALNTA) contributes to the synthesis of LDN, which helps regulate neuronal development. In this study, we investigated the expression and role of B4GALNT3 in human neuroblastoma (NB). We used IHC analysis to examine 87 NB tumors, and we identified 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. Increased expression of B4GALNT3 in NB tumors correlated with a favorable histologic profile (P < 0.001, χ² test) and early clinical staging (P = 0.041, χ² test) and was a favorable prognostic factor for survival as evaluated by univariate and multivariate analyses. Reexpression of B4GALNT3 in SK-N-SH and SH-SY5Y cells suppressed cell proliferation, colony formation, migration, and invasion. Moreover, B4GALNT3 increased the LacdiNAc modification of β₁ integrin, leading to decreased phosphorylation of focal adhesion kinase (FAK), Src, paxillin, Akt, and ERK1/2. B4GALNT3-mediated suppression of 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 suppresses the malignant phenotype via decreasing β₁ integrin signaling.