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P21-Activated Protein Kinase Is Overexpressed in Hepatocellular Carcinoma and Enhances Cancer Metastasis Involving c-Jun NH₂-Terminal Kinase Activation and Paxillin Phosphorylation

Departments of ¹ Pathology and ² Biochemistry, S.H. Ho Foundation Research Laboratories and Hong Kong Jockey Club Clinical Research Centre, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

Requests for reprints: Yick-Pang Ching, Department of Pathology, The University of Hong Kong, Room L7-04, Laboratory Block, Faculty of Medicine Building, Pokfulam, Hong Kong. Phone: 852-2819-9656; Fax: 852-2819-5375; E-mail: ypching{at}hkucc.hku.hk or Irene Oi-Lin Ng, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Room 127B, University Pathology Building, Pokfulam, Hong Kong. Phone: 852-2855-3967; Fax: 852-2872-5197; E-mail iolng{at}hku.hk.

Hepatocellular carcinoma (HCC) is one of the major malignancies in the world. The prognosis of HCC is poor, due to frequent intrahepatic metastasis and tumor recurrence. P21-activated protein kinase (Pak1), a main downstream effector of small Rho GTPases, Rac1 and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Here, we show that Pak1 gene was overexpressed in human HCCs. Overexpression of Pak1 in human HCCs was associated with more aggressive tumor behavior in terms of more metastatic phenotype and more advanced tumor stages. In addition, HCC cell line stably expressing Pak1 displayed increased cell motility rates and, conversely, knockdown of endogenous Pak1 expression by small interfering RNA reduced the migration rates of HCC cells. In an established metastatic HCC cell line, we found that Pak1 was overexpressed compared with its primary HCC cell line and this overexpression was associated with higher cell motility. Importantly, we found that c-Jun NH₂-terminal kinase (JNK) was activated in HCC cell lines overexpressing Pak1. Inhibition of the JNK activity by chemical inhibitor significantly reduced the migration rates of HCC cells via attenuation of paxillin phosphorylation at Ser¹⁷⁸. In conclusion, our results document that Pak1 is overexpressed in HCCs and plays an important role in the metastasis of HCC. The mechanism by which Pak1 induces cancer metastasis may involve activation of JNK and phosphorylation of paxillin. [Cancer Res 2007;67(8):3601–8]