Background and Objectives: Hepatocellular carcinoma (HCC) is one of most common human malignancies worldwide.Numerous studies have shown that a number of protocadherins functioned as tumor suppressors in human carcinogenesis.But little is known about the function of PCDH20 in HCC.Here we investigate the role of PCDH20 in hepatocarcinogenesis.Methods: The expression variant of PCDH20 in HCC cell lines as well as in HCC tissues and paired non-tumor tissues was verified by real-time quantitative RT-PCR and western blot.The DNA methylation status of PCDH20 promoter region was quantitative analyzed by Hha-I digestion and consequent real-time PCR.Finally,the function of PCDH20 on HCC tumor cells was studied by MTT assay,flow cytometry,wound-healing and transwell assays,soft agar assay,as well as tumorigenicity assays using nude mice.Results: We first identified that PCDH20 expression was silenced in 6 of 7 HCC cell lines and down-regulated in about 48% (51/107) primary HCC tissues.The lower expression of PCDH20 in tumor tissues was statistically significant,when compared to that in their paired non-tumor tissues (p<0.001),such lower expression in tumor tissues was much more common in younger patients group (aged <50 years) compared with the old group (≥ 50 years) (60% vs.33%,p=0.0303).Moreover,both in vitro and in vivo experiments demonstrated that ectopic expression of PCDH20 in silenced HCC cells significantly suppressed cell proliferation,migration and tumorigenicity.Moreover,we prove for the first time that PCDH20 could antagonize Wnt/β-catenin signaling pathway,via suppressing Akt and Erk activities and promoting GSK-3 β signaling activities.However,PCDH20 gene deletion and/or promoter hypermethylation attributed expression down-regulation were only observed in a small fraction of tumor specimens.Conclusions: Our data here strongly suggested that through antagonizing the Wnt/β-catenin signaling pathway,PCDH20 may act as a candidate tumor suppressor in HCC.