Human tumorigenesis resembles embryogenesis by aberrant activation of several developmental pathways including Wnt/beta-catenin signaling. Norrin is an atypical ligand for Frizzled receptor that is preferentially expressed in the endothelium to promote retinal vascularization during development. However, its expression pattern and potential roles in human cancers remain unclear. Here we report that Norrin expression is elevated in the parenchymal cells, but not endothelial cells, in gastric cancer (GC). Moreover, Norrin is required for growth and invasion of GC cells and its expression status is associated with unfavorable outcomes. However, analysis of the TGCA database demonstrates that Norrin expression status is not correlated with key target genes of Wnt/beta-catenin signaling. Among several signaling pathways hyperactivated in cancer, Norrin-depleted GC cells also display down-regulated AKT signaling except the canonical Wnt/beta-catenin signaling. Consistently, small molecule-induced cytosolic activation of AKT partially rescues the proliferative and invasive capability of Norrin-depleted cells. Together, these findings suggest a novel role of Norrin in gastric tumorigenesis that could be exploited for adjuvant therapy against the deadly malignancy. (C) 2019 Elsevier Inc. All rights reserved.