Frizzled7 Promotes Epithelial-to-mesenchymal Transition and Stemness Via Activating Canonical Wnt/β-catenin Pathway in Gastric Cancer

Abstract

Aberrant activation of Wnt signaling is a crucial event in tumor development and metastasis. Wnt signaling is commonly divided into canonical and non-canonical signaling pathways based on whether β-catenin is activated (canonical). The two signaling pathways are initiated by Wnt ligand binding to the surface Frizzled (FZD) receptors, and regulate cancer stem cell self-renewal and epithelial-mesenchymal transition (EMT). Frizzled 7 (FZD7), a member of Frizzled family, promotes cell proliferation and invasiveness in many cancers, suggesting that FZD7 transmitting Wnt signaling is important for driving cancer growth. FZD7 expression has been reported to be up-regulated in human primary gastric cancer tissues. However, the molecular mechanism by which FZD7 promotes gastric cancer(GC) development and progression is not fully understood. Our present study showed that FZD7 was overexpressed in clinical GC samples, and thus was correlated with tumor invasion, lymphatic and organ metastasis, late TNM stages and poor patient survival. The endogenous expression of FZD7 was significantly increased in cancer stem cell-enriched spheres compared with adherent cells. Furthermore, RNA interference-mediated silencing of FZD7 inhibited proliferation, migration and invasion in gastric cancer cells. Moreover, ablation of FZD7 down-regulated EMT and the expression levels of cancer stem cell markers, and these inhibitions were associated with attenuated canonical Wnt/β-catenin signaling. The results suggest that Wnt canonical pathway may contribute to tumorigenesis and metastasis, indicating that FZD7 could be a potential therapeutic target for gastric cancer.