title: Rnd3/RhoE Is down-regulated in hepatocellular carcinoma and controls cellular invasion.
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.
  
  
  CONCLUSIONS
  Rnd3 down-regulation provides an invasive advantage to tumor hepatocytes, suggesting that RND3 might represent a metastasis suppressor gene in HCC.
authors.affiliation: INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Grise
authors.forename: Sandra
authors.initials: S
authors.lastname: Sena
authors.forename: Aurélien
authors.initials: A
authors.lastname: Bidaud-Meynard
authors.forename: Jessica
authors.initials: J
authors.lastname: Baud
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Hiriart
authors.forename: Kassem
authors.initials: K
authors.lastname: Makki
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dugot-Senant
authors.forename: Cathy
authors.initials: C
authors.lastname: Staedel
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.forename: Jean
authors.initials: J
authors.lastname: Rosenbaum
authors.forename: Violaine
authors.initials: V
authors.lastname: Moreau
mesh_terms: D015820:Cadherins / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D012097:Repressor Proteins / Q000502:physiology; D000074165:Zinc Finger E-box Binding Homeobox 2; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins