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Carcinogenesis Advance Access published online on December 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgi002
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Oxford University Press
Received September 7, 2004
Revised December 6, 2004
Accepted December 7, 2004

CARCINOGENESIS

The significance of Rac signaling pathway in HCC cell motility: implication for new therapeutic target

Terence K. Lee 1, Kwan Man 1*, Joanna W. Ho 1, Xiang Hong Wang 2, Ronnie T. Poon 1, Kin Wai Sun 1, Kevin T. Ng 1, Irene O. Ng 3, Ray Xu 4, and Sheung Tat Fan 1

1 Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
2 Centre for the Study of Liver Disease and Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong, China
3 Centre for the Study of Liver Disease and Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China
4 Institute of Molecular Biology, The University of Hong Kong, Pokfulam, Hong Kong, China

* To whom correspondence should be addressed.
Kwan Man, E-mail: kwanman{at}hkucc.hku.hk


  Abstract

Recurrence and metastasis are commonly associated with poor prognosis of hepatocellular carcinoma (HCC). Therefore, a better understanding of molecular mechanisms involved in HCC metastasis may lead to more effective treatment for HCC patients. Rac plays important roles in cytoskeletal reorganization leading to cell motility in renal and breast carcinomas. However, the role of Rac is controversial in tumors and has not been studied in HCC. This study aims to investigate the importance of Rac signaling pathway in HCC cell motility, and the anti-metastatic potential of FTY720. Recently, a pair of HCC cell lines from a primary (H2P) and its matched metastatic (H2M) was established. These two cell lines provide a useful tool for the study of HCC metastasis. From the result, Rac signaling pathway was activated in the metastatic HCC cell line (H2M) compared with the primary HCC cell line (H2P). FTY720 specifically suppressed H2M cell motility by down-regulation of the Rac-GTP level through inhibition of phosphoinositide 3-kinase activity. To conclude, this study first demonstrated the essential role of Rac signaling pathway activation in HCC metastasis and suppression of cell motility by FTY720 through blocking Rac pathway.

Keywords: FTY720; HCC; JNK; motility.
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