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Article

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
  • View Affiliations / Copyright

    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
  • Pages: 1275-1285
    |
    Published online on: January 9, 2015
       https://doi.org/10.3892/ijo.2015.2827
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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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1 

He J, Gu D, Wu X, et al: Major causes of death among men and women in China. N Engl J Med. 353:1124–1134. 2005. View Article : Google Scholar : PubMed/NCBI

2 

Farazi PA and DePinho RA: Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 6:674–687. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Huber MA, Kraut N and Beug H: Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 17:548–558. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Kreuger J, Perez L, Giraldez AJ and Cohen SM: Opposing activities of Dally-like glypican at high and low levels of Wingless morphogen activity. Dev Cell. 7:503–512. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Filmus J, Capurro M and Rast J: Glypicans. Genome Biol. 9:2242008. View Article : Google Scholar : PubMed/NCBI

6 

Capurro MI, Xiang YY, Lobe C and Filmus J: Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res. 65:6245–6254. 2005. View Article : Google Scholar : PubMed/NCBI

7 

Stigliano I, Puricelli L, Filmus J, Sogayar MC, Bal de Kier Joffe E and Peters MG: Glypican-3 regulates migration, adhesion and actin cytoskeleton organization in mammary tumor cells through Wnt signaling modulation. Breast Cancer Res Treat. 114:251–262. 2009. View Article : Google Scholar

8 

Peters MG, Farias E, Colombo L, Filmus J, Puricelli L and Bal de Kier Joffe E: Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model. Breast Cancer Res Treat. 80:221–232. 2003. View Article : Google Scholar : PubMed/NCBI

9 

Aviel-Ronen S, Lau SK, Pintilie M, et al: Glypican-3 is overexpressed in lung squamous cell carcinoma, but not in adenocarcinoma. Mod Pathol. 21:817–825. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Capurro M, Wanless IR, Sherman M, et al: Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 125:89–97. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Filmus J and Capurro M: Glypican-3 and alphafetoprotein as diagnostic tests for hepatocellular carcinoma. Mol Diagn. 8:207–212. 2004. View Article : Google Scholar

12 

Liu H, Li P, Zhai Y, et al: Diagnostic value of glypican-3 in serum and liver for primary hepatocellular carcinoma. World J Gastroenterol. 16:4410–4415. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Li B, Liu H, Shang HW, Li P, Li N and Ding HG: Diagnostic value of glypican-3 in alpha fetoprotein negative hepatocellular carcinoma patients. Afr Health Sci. 13:703–709. 2013.PubMed/NCBI

14 

Llovet JM, Chen Y, Wurmbach E, et al: A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology. 131:1758–1767. 2006. View Article : Google Scholar : PubMed/NCBI

15 

Wang XY, Degos F, Dubois S, et al: Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas. Hum Pathol. 37:1435–1441. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Miao HL, Pan ZJ, Lei CJ, et al: Knockdown of GPC3 inhibits the proliferation of Huh7 hepatocellular carcinoma cells through down-regulation of YAP. J Cell Biochem. 114:625–631. 2013. View Article : Google Scholar

17 

Zittermann SI, Capurro MI, Shi W and Filmus J: Soluble glypican 3 inhibits the growth of hepatocellular carcinoma in vitro and in vivo. Int J Cancer. 126:1291–1301. 2010.

18 

Bruix J and Sherman M; Practice Guidelines Committee AAftSoLD. Management of hepatocellular carcinoma. Hepatology. 42:1208–1236. 2005. View Article : Google Scholar : PubMed/NCBI

19 

Wu YL, Wang NN, Gu L, Yang HM, Xia N and Zhang H: The suppressive effect of metabotropic glutamate receptor 5 (mGlu5) inhibition on hepatocarcinogenesis. Biochimie. 94:2366–2375. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Vauthey JN, Lauwers GY, Esnaola NF, et al: Simplified staging for hepatocellular carcinoma. J Clin Oncol. 20:1527–1536. 2002. View Article : Google Scholar : PubMed/NCBI

21 

Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Ding W, You H, Dang H, et al: Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion. Hepatology. 52:945–953. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Zhang W, Mendoza MC, Pei X, et al: Down-regulation of CMTM8 induces epithelial-to-mesenchymal transition-like changes via c-MET/extracellular signal-regulated kinase (ERK) signaling. J Biol Chem. 287:11850–11858. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Chen X, Lingala S, Khoobyari S, Nolta J, Zern MA and Wu J: Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol. 55:838–845. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Sun CK, Chua MS, He J and So SK: Suppression of glypican 3 inhibits growth of hepatocellular carcinoma cells through up-regulation of TGF-beta2. Neoplasia. 13:735–747. 2011.PubMed/NCBI

26 

Cheng W, Tseng CJ, Lin TT, et al: Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway. Carcinogenesis. 29:1319–1326. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Pan Z, Chen C, Long H, et al: Overexpression of GPC3 inhibits hepatocellular carcinoma cell proliferation and invasion through induction of apoptosis. Mol Med Rep. 7:969–974. 2013.PubMed/NCBI

28 

Sung YK, Hwang SY, Farooq M, Kim JC and Kim MK: Growth promotion of HepG2 hepatoma cells by antisense-mediated knockdown of glypican-3 is independent of insulin-like growth factor 2 signaling. Exp Mol Med. 35:257–262. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Lin CW, Mars WM, Paranjpe S, et al: Hepatocyte proliferation and hepatomegaly induced by phenobarbital and 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene is suppressed in hepatocyte-targeted glypican 3 transgenic mice. Hepatology. 54:620–630. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Acloque H, Adams MS, Fishwick K, Bronner-Fraser M and Nieto MA: Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 119:1438–1449. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI

32 

Zhu M, Yin F, Fan X, et al: Decreased TIP30 promotes Snail-mediated epithelial-mesenchymal transition and tumor-initiating properties in hepatocellular carcinoma. Oncogene. Mar 31–2014.(Epub ahead of print). View Article : Google Scholar

33 

Cho NH, Shim HS, Rha SY, et al: Increased expression of matrix metalloproteinase 9 correlates with poor prognostic variables in renal cell carcinoma. Eur Urol. 44:560–566. 2003. View Article : Google Scholar : PubMed/NCBI

34 

Li H, Wang H, Wang F, Gu Q and Xu X: Snail involves in the transforming growth factor beta1-mediated epithelial-mesenchymal transition of retinal pigment epithelial cells. PLoS One. 6:e233222011. View Article : Google Scholar

35 

Suh Y, Yoon CH, Kim RK, et al: Claudin-1 induces epithelial-mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells. Oncogene. 32:4873–4882. 2013. View Article : Google Scholar

36 

Huang XY, Ke AW, Shi GM, et al: alphaB-crystallin complexes with 14-3-3zeta to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma. Hepatology. 57:2235–2247. 2013. View Article : Google Scholar : PubMed/NCBI

37 

Yoshida S, Kornek M, Ikenaga N, et al: Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma. Hepatology. 58:1667–1680. 2013. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Wu Y, Liu H, Weng H, Zhang X, Li P, Fan C, Li B, Dong P, Li L, Dooley S, Dooley S, et al: Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway. Int J Oncol 46: 1275-1285, 2015.
APA
Wu, Y., Liu, H., Weng, H., Zhang, X., Li, P., Fan, C. ... Ding, H. (2015). Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway. International Journal of Oncology, 46, 1275-1285. https://doi.org/10.3892/ijo.2015.2827
MLA
Wu, Y., Liu, H., Weng, H., Zhang, X., Li, P., Fan, C., Li, B., Dong, P., Li, L., Dooley, S., Ding, H."Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway". International Journal of Oncology 46.3 (2015): 1275-1285.
Chicago
Wu, Y., Liu, H., Weng, H., Zhang, X., Li, P., Fan, C., Li, B., Dong, P., Li, L., Dooley, S., Ding, H."Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway". International Journal of Oncology 46, no. 3 (2015): 1275-1285. https://doi.org/10.3892/ijo.2015.2827
Copy and paste a formatted citation
x
Spandidos Publications style
Wu Y, Liu H, Weng H, Zhang X, Li P, Fan C, Li B, Dong P, Li L, Dooley S, Dooley S, et al: Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway. Int J Oncol 46: 1275-1285, 2015.
APA
Wu, Y., Liu, H., Weng, H., Zhang, X., Li, P., Fan, C. ... Ding, H. (2015). Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway. International Journal of Oncology, 46, 1275-1285. https://doi.org/10.3892/ijo.2015.2827
MLA
Wu, Y., Liu, H., Weng, H., Zhang, X., Li, P., Fan, C., Li, B., Dong, P., Li, L., Dooley, S., Ding, H."Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway". International Journal of Oncology 46.3 (2015): 1275-1285.
Chicago
Wu, Y., Liu, H., Weng, H., Zhang, X., Li, P., Fan, C., Li, B., Dong, P., Li, L., Dooley, S., Ding, H."Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway". International Journal of Oncology 46, no. 3 (2015): 1275-1285. https://doi.org/10.3892/ijo.2015.2827
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