Protocadherin 9 (PCDH9) was found frequently lost in hepatocellular carcinoma (HCC). Here we investigated the role of PCDH9 in the development of HCC. We confirmed that PCDH9 was down-regulated in HCC tissues and cell lines compared with the adjacent non-tumor tissues. PCDH9 downregulation was significantly associated with malignant portal vein invasion of HCC patients. Gain- and loss-of-function studies revealed that downregulation of PCDH9 facilitated tumor cell migration and epithelial mesenchymal transition (EMT). We identified PCDH9 as a novel regulator of EMT by increasing the activity of GSK-3 beta and inhibiting Snail1, indicating its potential therapeutic value for reducing metastasis of HCC. (C) 2014 The Authors. Published by Elsevier Inc.