N-Acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyzes the formation of a beta 1,6-N-acetylglucosamine (GlcNAc) side chain to a core mannosyl residue in N-linked glycoproteins. Besides its direct function of producing aberrant glycoproteins, it promotes cancer progression by its involvement in the stimulation of oncoproteins. Herein, we report that GnT-V guided the transcriptional activation of membrane-type matrix metalloproteinase-1 (MT1-MMP) in cancer cells. The activated MT1-MMP expression had dual effects on cancer progression. It not only promoted proteolytic activity for cancer cells per se, but also led to the activation of MMP-2. Consequently, the activation of the two MMPs triggered by GnT-V intensified the invasive potential. A quantitative analysis using clinical tissues revealed a relatively strong correlation between GnT-V overexpression and MT1-MMP upregulation. In this study, we report for the first time that GnT-V directs cancer progression by modulating MMPs in cancer. (C) 2013 Elsevier Inc. All rights reserved.