PCDH20 functions as a tumour-suppressor gene through antagonizing the Wnt/beta-catenin signalling pathway in hepatocellular carcinoma

摘要

Several members of protocadherins have been found involved in human carcinogenesis, but little is known about PCDH20 in HCC. Here in this study, using quantitative real-time RT-PCR assay, we demonstrated the downregulation of PCDH20 expression in 6 of 7 HCC cell lines tested. Similarly, PCDH20 expression in primary HCC tissues was also significantly downregulated in comparison with that in either disease-free normal liver tissues or the adjacent nontumour liver tissues (P < 0.001, respectively). Among HCC tumour tissues studied, about 48% (51/107) of them showed reduced PCDH20 mRNA level. Further statistic analysis revealed that the reduced PCDH20 mRNA level in tumour tissues was much more common in younger patients group (aged < 50 years) than that in older group (>= 50 years) (60% vs 33%, P = 0.0303). Loss of heterozygosity (LOH) and promoter hypermethylation analysis revealed that deletion and/or aberrant epigenetic modulation of PCDH20 gene account for its downregulation, at least in a fraction of tumour specimens. Moreover, ectopic expression of PCDH20 in HCC cells significantly suppressed cell proliferation, clonogenicity, migration and tumour formation. Notably, we proved for the first time that, via activating GSK-3b, PCDH20 could inhibit Wnt/beta-catenin signalling pathway. Furthermore, our data suggest that PCDH20 may conduct its Wnt/beta-catenin signalling antagonizing function through suppressing Akt and Erk activities and promoting GSK-3b signalling activities. However, the detailed mechanism remained undiscovered. In conclusion, our data here strongly suggested that PCDH20 may act as a candidate tumour suppressor in HCC.