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Open Access Highly Accessed Research article

Differential expression of Caveolin-1 in hepatocellular carcinoma: correlation with differentiation state, motility and invasion

Murat Cokakli1, Esra Erdal1, Deniz Nart2, Funda Yilmaz2, Ozgul Sagol3, Murat Kilic4, Sedat Karademir5 and Nese Atabey1*

Author Affiliations

1 Dokuz Eylul University, Faculty of Medicine, Department of Medical Biology and Genetics, Inciralti- Izmir/Turkey

2 Ege University, Faculty of Medicine, Department of Pathology, Bornova- Izmir, Turkey

3 Dokuz Eylul University, Faculty of Medicine, Department of Pathology, Izmir, Turkey

4 Ege University, Faculty of Medicine, Department of Surgery, Bornova- Izmir, Turkey

5 Dokuz Eylul University, Faculty of Medicine, Department of Surgery, Izmir, Turkey

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BMC Cancer 2009, 9:65  doi:10.1186/1471-2407-9-65

Published: 24 February 2009

Abstract

Background

Caveolin-1 is the main component of caveolae membrane structures and has different roles during tumorigenesis in different cancer types with varying expression profiles, indicating that the role of caveolin-1 varies according to tumor type. In this study, we investigated the role and expression of caveolin-1 in hepatocellular carcinogenesis.

Methods

We analyzed the expression of Caveolin-1 in 96 hepatocellular carcinoma (HCC), 29 cirrhosis, 20 normal liver tissues and 9 HCC cell lines by immunostaining and western blotting, respectively. After caveolin-1 was stably transfected to HepG2 and Huh7 cells, the effects of Caveolin-1 on the cellular motility, matrix invasion and anchorage-independent growth were studied. Also, caveolae structure was disrupted in endogenously caveolin expressing cells, SNU 449 and SNU 475 by addition of methyl-β-cyclodextrin and analyzed cellular motility and invasion.

Results

In HCC cell lines, Caveolin-1 expression is correlated to differentiation and basal motility status of these cells. The percentage of Caveolin-1 positivity was found extremely low in normal liver tissue (5%) while it was increased in cirrhosis (45%) and in HCC (66%) (p = 0.002 and p = 0.001 respectively). Cav-1 expression in poorly differentiated HCC samples has been found significantly higher than well differentiated ones (p = 0.001). The caveolin-1 expression was found significantly higher in tumor cells than its peritumoral cirrhotic tissues in HCC samples (p < 0.001). Additionally, the patients with positive staining for Caveolin-1 had significantly higher portal vein invasion than those with negative staining (p = 0.02). Caveolin-1 overexpression increased motility and invasion of HepG2 and Huh7 cells. And disruption of caveolae results in a dramatic decline in both motility and invasion abilities in SNU-449 and SNU-475 cells. Furthermore, caveolin-1 overexpression resulted in down-regulation of E-cadherin while up-regulation of Vimentin. Also, it increased secreted MMP-2 and expression levels of MMP-9 and MT1-MMP. There was no significant difference in colony formation in soft agar between stable clones and parental ones.

Conclusion

In conclusion, stepwise increase in Cav-1 expression in neoplastic stage with respect to pre-neoplastic stage during hepatocellular carcinogenesis and its ability to stimulate HCC cell motility and invasiveness indicate that this protein plays a crucial role in tumor progression.