J Cancer 2017; 8(9):1598-1608. doi:10.7150/jca.18744

Research Paper

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

Jing-Hua Zhang1, Li-Yan Jiao2*, Tie-Jun Li3, 4, York Yuanyuan Zhu3, 4, Jian-Wei Zhou5, Jian Tian3, 5, 6✉

1. Department of Surgery, Tangshan People's Hospital/Tangshan Cancer Hospital, Tangshan 063001, China;
2. School of Medicine, Nantong University, Nantong 226001, China;
3. Small RNA Technology and Application Institute, Nantong University, Nantong 226016, China;
4. Biomics Biotechnologies Co., Ltd., Nantong 226016, China;
5. Department of Oncology, Henan People's Hospital, Zhengzhou University, Zhengzhou, Henan 45003, China;
6. Cancer Institute, Tangshan People's Hospital/Tangshan Cancer Hospital, Tangshan 063001, China.
* Contributing to this manuscript equally.

Abstract

Glycogen synthase kinase-3β (GSK-3β) 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-3β in modulating the metastatic behaviors of human HCC cell lines in vitro. In this study, the expression level of GSK-3β was measured in 4 human HCC cell lines, and the small interfering RNA (siRNA) vectors against or plasmids encoding GSK-3β were used to evaluate the responses of target cells to the knockdown or overexpression of this kinase, respectively. Our results showed that GSK-3β 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-3β 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 (β-catenin), resulting in enhanced tumor cell dissemination. In contrast, gain-of-function studies revealed that ectopic expression of GSK-3β reduced invasive and migratory abilities of HCC cells accompanied by decreased HCC cell proliferation and induced apoptosis. More importantly, downregulation of GSK-3β led to an increase in the expression and accumulation of β-catenin in the nuclei, promoting gene transcription. In conclusion, GSK-3β might play a vital role in suppressing HCC dissociation by preventing the disassembly of cancer cell epithelial junctional complex via the GSK-3β/β-catenin pathway.

Keywords: Glycogen synthase kinase-3β, hepatocellular carcinoma, metastatic behaviors, GSK-3β/β-catenin signaling pathway, epithelial junctional complex.

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How to cite this article:
Zhang JH, Jiao LY, Li TJ, Zhu YY, Zhou JW, Tian J. GSK-3β suppresses HCC cell dissociation in vitro by upregulating epithelial junction proteins and inhibiting Wnt/β-catenin signaling pathway. J Cancer 2017; 8(9):1598-1608. doi:10.7150/jca.18744. Available from http://www.jcancer.org/v08p1598.htm