The incidence and mortality of hepatocellular carcinoma (HCC) is high, but the mechanisms underlying the growth and progression of HCC have not been elucidated. Recently, the ZIC family member 5 (ZIC5) is emerging as an oncogene in various types of tumors. However, its expression and biological role in HCC have not been reported. This study first demonstrated that ZIC5 was up-regulated in HCC specimens, and high ZIC5 expression indicated poor prognosis of HCC patients. In addition, over-expressed ZIC5 promoted the proliferation, migration and invasion of HCC cell lines Huh7 and HepG2 in vitro and in vivo, while ZIC5 knockdown achieved the opposite effects. Actually, ZIC5 increased the expression of genes participating in Wnt/beta-catenin pathway such as beta-catenin and CyclinD1. ZIC5 also promoted beta-catenin to enter the nucleus of HCC cells. Furthermore, silencing beta-catenin abated the promoting role of ZIC5 in HCC. Overall, this study reveals a novel mechanism of ZIC5/beta-catenin that mediates the invasion and metastasis of HCC and ZIC5 serves as a novel indicator for prognosis of HCC patients. (C) 2018 Published by Elsevier Inc.