title: Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.
authors.forename: Lui
authors.initials: L
authors.lastname: Ng
authors.forename: Ronnie
authors.initials: R
authors.lastname: Tung-Ping Poon
authors.forename: Simon
authors.initials: S
authors.lastname: Yau
authors.forename: Ariel
authors.initials: A
authors.lastname: Chow
authors.forename: Colin
authors.initials: C
authors.lastname: Lam
authors.forename: Hung-Sing
authors.initials: HS
authors.lastname: Li
authors.forename: Thomas
authors.initials: T
authors.lastname: Chung-Cheung Yau
authors.forename: Wai-Lun
authors.initials: WL
authors.lastname: Law
authors.forename: Roberta
authors.initials: R
authors.lastname: Pang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D019012:Integrin beta1 / Q000502:physiology; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000473:pathology / Q000503:physiopathology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D034741:RNA, Small Interfering / Q000494:pharmacology; D015996:Survival Rate; D000096985:Calponins
chemical_list: D000970:Antineoplastic Agents; D019012:Integrin beta1; D008840:Microfilament Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D034741:RNA, Small Interfering; C486590:PARVA protein, human; D000096985:Calponins