Advertisement

Rnd3/RhoE Is down-regulated in hepatocellular carcinoma and controls cellular invasion

Authors

  • Florence Grise,

    1. INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    2. Université Bordeaux, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    Search for more papers by this author
    • *

      These authors contributed equally.

  • Sandra Sena,

    1. INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    2. Université Bordeaux, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    Search for more papers by this author
    • *

      These authors contributed equally.

  • Aurélien Bidaud-Meynard,

    1. INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    2. Université Bordeaux, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    Search for more papers by this author
  • Jessica Baud,

    1. INSERM, U869, Laboratoire ARNA, Bordeaux, France
    Search for more papers by this author
  • Jean-Baptiste Hiriart,

    1. INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    2. Université Bordeaux, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    Search for more papers by this author
  • Kassem Makki,

    1. INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    2. Université Bordeaux, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    Current affiliation:
    1. CNRS UMR8199, Université Lille 2, Lille, France
    Search for more papers by this author
  • Nathalie Dugot-Senant,

    1. IFR66, Université Bordeaux, Bordeaux, France
    Search for more papers by this author
  • Cathy Staedel,

    1. INSERM, U869, Laboratoire ARNA, Bordeaux, France
    Search for more papers by this author
  • Paulette Bioulac-Sage,

    1. INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    2. Université Bordeaux, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    3. CHU de Bordeaux, Groupement des Spécialités Digestives, Bordeaux, France
    Search for more papers by this author
  • Jessica Zucman-Rossi,

    1. INSERM, U674, Paris, France; Université Paris Descartes, Paris, France
    Search for more papers by this author
  • Jean Rosenbaum,

    1. INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    2. Université Bordeaux, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    3. CHU de Bordeaux, Groupement des Spécialités Digestives, Bordeaux, France
    Search for more papers by this author
  • Violaine Moreau

    Corresponding author
    1. INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    2. Université Bordeaux, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
    • INSERM U1053, Université Bordeaux Segalen, 146 rue Léo Saignat, 33076 Bordeaux, France
    Search for more papers by this author
    • fax: 33 (0)5 56 51 40 77


  • Potential conflict of interest: Nothing to report.

  • This work was supported by grants from La Ligue Contre le Cancer (comité de la Dordogne), Association pour la Recherche sur le Cancer (grant 5077), Association Française pour l'Etude du Foie and Schering-Plough laboratory (to V.M.), La Ligue Nationale Contre le Cancer “Equipe labellisée” (to J.R.), INCa-ARC-ANRS (PAIR-CHC “No-FLiC”), and BioIntelligence (OSEO) (to J.Z-R.). S.S. was supported by a postdoctoral fellowship from the Fondation pour la Recherche Médicale.

Abstract

We performed a review of public microarray data that revealed a significant down-regulation of Rnd3 expression in hepatocellular carcinoma (HCC), as compared to nontumor liver. Rnd3/RhoE is an atypical RhoGTPase family member because it is always under its active GTP-bound conformation and not sensitive to classical regulators. Rnd3 down-regulation was validated by quantitative real-time polymerase chain reaction in 120 independent tumors. Moreover, Rnd3 down-expression was confirmed using immunohistochemistry on tumor sections and western blotting on human tumor and cell-line extracts. Rnd3 expression was significantly lower in invasive tumors with satellite nodules. Overexpression and silencing of Rnd3 in Hep3B cells led to decreased and increased three-dimensional cell motility, respectively. The short interfering RNA-mediated down-regulation of Rnd3 expression induced a loss of E-cadherin at cell-cell junctions that was linked to epithelial-mesenchymal transition through the up-regulation of the zinc finger E-box binding homeobox protein, ZEB2, and the down-regulation of miR-200b and miR-200c. Rnd3 knockdown mediated tumor hepatocyte invasion in a matrix-metalloproteinase–independent, and Rac1-dependent manner. Conclusion: Rnd3 down-regulation provides an invasive advantage to tumor hepatocytes, suggesting that RND3 might represent a metastasis suppressor gene in HCC. (HEPATOLOGY 2012;55:1766–1775)

Ancillary