WWC3 downregulation correlates with poor prognosis and inhibition of Hippo signaling in human gastric cancer

The aim of this study was to investigate the clinicopathological significance and biological roles of WWC3 in human gastric cancer (GC). Clinical significance of WWC3 in human GCs was examined by using immunohistochemistry (IHC). WWC3 was downregulated in 48 of 111 human GCs, and its downregulation was associated with advanced stage, positive nodal status, and higher relapse rate. Importantly, WWC3 downregulation correlated with poor survival. It was also found that WWC3 protein expression was downregulated in GC cell lines compared with normal cell line GES-1. On one hand, WWC3 overexpression inhibited the cell growth rate and invading ability in HGC-27 cell line. On the other hand, depleting WWC3 by small interfering RNA (siRNA) promoted proliferation rate and invading ability in the SGC-7901 cell line. In addition, cell cycle analysis showed that WWC3 overexpression inhibited while its depletion accelerated cell cycle progression at the G1/S transition. Western blot (WB) analysis demonstrated that WWC3 repressed cyclin D1 and cyclin E while upregulated p27 expression. Luciferase reporter assay showed that WWC3 activated Hippo signaling pathway by suppressing TEAD transcription activity, with downregulation of total and nuclear YAP and its target CTGF. WWC3 siRNA depletion exhibited the opposite effects. In conclusion, this study indicates that WWC3 serves as a tumor suppressor in GC by activating Hippo signaling.