Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion

Authors

  • Lui Ng,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Ronnie Tung-Ping Poon,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
    2. Centre for Cancer Research, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Simon Yau,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Ariel Chow,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
    2. Centre for Cancer Research, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Colin Lam,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Hung-Sing Li,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Thomas Chung-Cheung Yau,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
    2. Centre for Cancer Research, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Wai-Lun Law,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Roberta Pang

    Corresponding author
    1. Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
    2. Centre for Cancer Research, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
    • Address reprint requests to: Dr Roberta Pang, Ph.D., Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong. E-mail: robertap@hku.hk; fax: +852-28173903.

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  • Supported by the Central Allocation Group Research Grant “Molecular Pathology of Liver Cancer — A Multidisciplinary Study” from the Research Grant Council of Hong Kong (HKU-7-CRF09).

  • Potential conflict of interest: Nothing to report.

Abstract

Early reports suggested that actopaxin, a member of the focal adhesion proteins, regulates cell migration. Here we investigated whether actopaxin is involved in hepatocellular carcinoma (HCC) progression and metastasis. We examined actopaxin expression in human HCC samples using immunohistochemistry and western blotting. The functional and molecular effect of actopaxin was studied in vitro by overexpression in a nonmetastatic HCC cell line, as well as repression in a metastatic cell line. The in vivo effect of actopaxin repression was studied in nonobese diabetic and severe combined immunodeficient mice. We found that actopaxin was frequently overexpressed in human HCC patients and its overexpression positively correlated with tumor size, stage, and metastasis. Actopaxin expression also correlated with the metastatic potential of HCC cell lines. Actopaxin overexpression induced the invasion and migration ability of nonmetastatic HCC cells, whereas down-regulation of actopaxin reverted the invasive phenotypes and metastatic potential of metastatic HCC cells through regulating the protein expression of certain focal adhesion proteins including ILK, PINCH, paxillin, and cdc42, as well as regulating the epithelial-mesenchymal transition pathway. Furthermore, there was a close association between actopaxin and CD29. HCC cells with stronger CD29 expression showed a higher actopaxin level, whereas actopaxin repression attenuated CD29 activity. Finally, actopaxin down-regulation enhanced the chemosensitivity of HCC cells towards oxaliplatin treatment by way of a collective result of suppression of survivin protein, β-catenin, and mammalian target of rapamycin pathways and up-regulation of p53. Conclusion: This study provides concrete evidence of a significant role of actopaxin in HCC progression and metastasis, by way of regulation of cell invasiveness and motility, an epithelial-mesenchymal transition process, and chemosensitivity to cytotoxic drugs. (Hepatology 2013;58:667-679)

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