Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway

Wu,Yongle; Liu,Hui; Weng,Honglei; Zhang,Xin; Li,Peng; Fan,Chun-Lei; Li,Bing; Dong,Pei-Ling; Li,Lei; Dooley,Steven; Ding,Hui-Guo

doi:10.3892/ijo.2015.2827

Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway

Authors:
- Yongle Wu
- Hui Liu
- Honglei Weng
- Xin Zhang
- Peng Li
- Chun-Lei Fan
- Bing Li
- Pei-Ling Dong
- Lei Li
- Steven Dooley
- Hui-Guo Ding
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Affiliations: Department of Gastroenterology and Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Fengtai District, Beijing 100069, P.R. China, Molecular Hepatology, University of Heidelberg, University Medical Center Mannheim, D-68167 Mannheim, Germany
Published online on: January 9, 2015 https://doi.org/10.3892/ijo.2015.2827
Pages: 1275-1285

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Abstract

Glypican-3 (GPC3), a membrane-associated heparan sulfate proteoglycan, is frequently upregulated in hepatocellular carcinoma (HCC). However, how GPC3 contributes to the progress of HCC is largely unclear. The present study investigated the association between GPC3 expression and HCC clinicopathological characteristics, and particularly focused on the role and underlying mechanisms of GPC3 in HCC epithelial-mesenchymal transition (EMT). Remarkably elevated expression of GPC3 was demonstrated in HCC tumor tissues compared with paired non-tumor tissues in 45 patients with HCC by quantitative real-time PCR, immunohistochemistry, and western blotting, respectively. Furthermore, the tissue expression of GPC3 was increased during HCC progression from Barcelona Clinic Liver Cancer stage A or B to stage C. The enhanced levels of GPC3 in HCC tumor tissues were tightly correlated to the expression of the EMT-associated proteins and tumor vascular invasion. Patients with GPC3-high expression in tumor tissues displayed significantly shorter survival time than those with GPC3-low expression (P=0.001). Consistent with the findings in patients, HepG2 cells, which expressed high levels of GPC3, showed stronger capacity of migration and significant EMT-like changes when compared to those HCC cells with low levels of GPC3, e.g., Hep3B and Huh7 in scratch, Transwell assays and western blotting. Furthermore, administration with exogenous GPC3 in HCC cells activated extracellular signal-regulated kinase (ERK) and significantly enhanced cell migration and invasion. The behavior was significantly inhibited by the ERK inhibitor PD98059. Together, our studies show that GPC3 contributes to HCC progression and metastasis through impacting EMT of cancer cells, and the effects of GPC3 are associated with ERK activation.

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