Rho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion

Authors

  • Carmen Chak-Lui Wong,

    1. Department of Pathology, Liver Cancer and Hepatitis Research Laboratory and SH Ho Foundation Research Laboratory, The University of Hong Kong, Hong Kong
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  • Chun-Ming Wong,

    1. Department of Pathology, Liver Cancer and Hepatitis Research Laboratory and SH Ho Foundation Research Laboratory, The University of Hong Kong, Hong Kong
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  • Edmund Kwok-Kwan Tung,

    1. Department of Pathology, Liver Cancer and Hepatitis Research Laboratory and SH Ho Foundation Research Laboratory, The University of Hong Kong, Hong Kong
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  • Kwan Man,

    1. Department of Surgery, The University of Hong Kong, Hong Kong
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  • Irene Oi-Lin Ng

    Corresponding author
    1. Department of Pathology, Liver Cancer and Hepatitis Research Laboratory and SH Ho Foundation Research Laboratory, The University of Hong Kong, Hong Kong
    • Department of Pathology, University Pathology Building, Room 127B, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
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    • fax: (852)-2872-5197.

    • I. O. L. N. is Loke Yew Professor in Pathology.


  • Potential conflict of interest: Nothing to report.

Abstract

Deregulation of Rho family small guanosine triphosphatases has been implicated in human carcinogenesis. Rho-kinases are downstream effectors of Rho guanosine triphosphatases in the regulation of cytoskeletal reorganization and cell motility. However, their functions in human cancers remain elusive. In this study, we aimed to investigate the role of Rho-kinases in hepatocellular carcinoma (HCC) tumor progression and invasion. We first examined the expression of the two Rho-kinases (ROCK1 and ROCK2) in human HCC, and found that ROCK2 was frequently overexpressed in primary HCCs (22/41 [53.66%]). Clinico-pathological analysis revealed that overexpression of ROCK2 was significantly associated with the presence of tumor microsatellite formation (P = 0.005), suggesting that deregulation of ROCK2 may contribute to the intrahepatic metastasis of HCC. Consistently, we demonstrated that stable overexpression of ROCK2 significantly enhanced cell motility and invasiveness in HCC cells. Conversely, stable knockdown of ROCK2 by short hairpin RNA approach remarkably reduced HCC cell migration and invasion. Moreover, orthotopic liver xenograft models provided further support that stable knockdown of ROCK2 suppressed HCC invasion in vivo. Stable knockdown of ROCK2 in HCC cells significantly inhibited Golgi reorientation, myosin phosphatase phosphorylation, and formations of stress fibers, filopodia, and lamellipodia; these molecular and cellular events are crucial for cell motility and cancer invasion. Conclusion: Our results indicate that ROCK2 was overexpressed in human HCCs, and this overexpression was associated with a more aggressive biological behavior. Our findings also demonstrate that ROCK2 played a significant role in regulating cytoskeletal events and contributed to the invasion of HCC. (HEPATOLOGY 2009.)

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