beta 4-Integrin/PI3K Signaling Promotes Tumor Progression through the Galectin-3-N-Glycan Complex

摘要

Malignant transformation is associated with aberrant N-glycosylation, but the role of protein N-glycosylation in cancer progression remains poorly defined. beta 4-integrin is a major carrier of N-glycans and is associated with poor prognosis, tumorigenesis, and metastasis. Here, N-glycosylation of beta 4-integrin contributes to the activation of signaling pathways that promote beta 4-dependent tumor development and progression. Increased expression of beta 1,6GlcNAc-branched N-glycans was found to be colocalized with beta 4-integrin in human cutaneous squamous cell carcinoma tissues, and that the beta 1,6GlcNAc residue was abundant on beta 4-integrin in transformed keratinocytes. Interruption of beta 1,6GlcNAc-branching formation on beta 4-integrin with the introduction of bisecting GlcNAc by N-acetylglucosaminyltransferase III overexpression was correlated with suppression of cancer cell migration and tumorigenesis. N-Glycan deletion on beta 4-integrin impaired beta 4-dependent cancer cell migration, invasion, and growth in vitro and diminished tumorigenesis and proliferation in vivo. The reduced abilities of beta 4-integrin were accompanied with decreased phosphoinositol-3 kinase (PI3K)/Akt signals and were restored by the overexpression of the constitutively active p110 PI3K subunit. Binding of galectin-3 to beta 4-integrin via beta 1,6GlcNAc-branched N-glycans promoted beta 4-integrin-mediated cancer cell adhesion and migration. In contrast, a neutralizing antibody against galectin-3 attenuated beta 4-integrin N-glycanmediated PI3K activation and inhibited the ability of beta 4-integrin to promote cell motility. Furthermore, galectin-3 knockdown by shRNA suppressed beta 4-integrin N-glycan-mediated tumorigenesis. These findings provide a novel role for N-glycosylation of beta 4-integrin in tumor development and progression, and the regulatory mechanism for beta 4-integrin/PI3K signaling via the galectin-3-N-glycan complex. (C) 2018 AACR.