GSK-3ß suppresses HCC cell dissociation in vitro by upregulating epithelial junction proteins and inhibiting Wnt/ß-catenin signaling pathway.

ABSTRACT

Glycogen synthase kinase-3ß (GSK-3ß) is required in the expression of epithelial junction proteins. It was found downregulated in hepatocellular carcinoma (HCC) tissues. The purpose of this study was to investigate the role of GSK-3ß in modulating the metastatic behaviors of human HCC cell lines in vitro. In this study, the expression level of GSK-3ß was measured in 4 human HCC cell lines, and the small interfering RNA (siRNA) vectors against or plasmids encoding GSK-3ß were used to evaluate the responses of target cells to the knockdown or overexpression of this kinase, respectively. Our results showed that GSK-3ß expression was significantly lower in human HCC cell lines with high metastatic potential than that in HCC cell lines without metastatic characteristics or in a normal human liver cell line. The knockdown of GSK-3ß by siRNA led to a decreased expression of the epithelial junction molecules (ZO-1, E-cadherin) and an increase in the expression of a mesenchymal cell marker (α-SMA) and a gene transcription factor (ß-catenin), resulting in enhanced tumor cell dissemination. In contrast, gain-of-function studies revealed that ectopic expression of GSK-3ß reduced invasive and migratory abilities of HCC cells accompanied by decreased HCC cell proliferation and induced apoptosis. More importantly, downregulation of GSK-3ß led to an increase in the expression and accumulation of ß-catenin in the nuclei, promoting gene transcription. In conclusion, GSK-3ß might play a vital role in suppressing HCC dissociation by preventing the disassembly of cancer cell epithelial junctional complex via the GSK-3ß/ß-catenin pathway.