Smurf1 promotes gastric cancer progression by regulating Axin2-dependent Wnt signaling pathway

SMAD-specific E3 ubiquitin protein ligase 1 (Smurf1) is involved in various biological processes through targeting specific proteins for ubiquitin-dependent degradation. Emerging evidence has shown that Smurf1 functions as an oncogene in many types of human tumours, including gastric cancer (GC). We aimed to investigate the role of Smurf1 in regulating GC progression and reveal its underlying mechanism. Smurf1 expression was analyzed using two publicly available datasets. Additionally, it was assayed in 29 pairs of GC tissues and para-cancerous tissues using quantitative reverse transcriptase PCR (qRT-PCR). The biological roles of Smurf1 in GC cells were assessed in vitro and in a mouse xenograft model. The results showed that Smurf1 levels were significantly up-regulated in GC tissues compared with normal tissues, and high Smurf1 expression was significantly correlated with worse disease-free survival (DFS). Forced expression of Smurf1 accelerated AGS cell growth, proliferation, and invasion in vitro and in vivo. Mechanistically, Smurf1 directly interacted with axis inhibition protein 2 (Axin2) and diminished the stability of the Axin2 protein by promoting its ubiquitination and subsequent degradation. As a result, Smurf1 promoted the activation of Wnt/β-catenin signaling. Importantly, IWR-1, a specific inhibitor of the Wnt pathway, effectively inhibited Smurf1-induced GC cell proliferation and invasion. These data suggest that upregulated Smurf1 facilitates GC progression through degrading Axin2 and activating Wnt/β-catenin signaling.