title: RhoGDIα-dependent balance between RhoA and RhoC is a key regulator of cancer cell tumorigenesis.
abstract: RhoGTPases are key signaling molecules regulating main cellular functions such as migration, proliferation, survival, and gene expression through interactions with various effectors. Within the RhoA-related subclass, RhoA and RhoC contribute to several steps of tumor growth, and the regulation of their expression affects cancer progression. Our aim is to investigate their respective contributions to the acquisition of an invasive phenotype by using models of reduced or forced expression. The silencing of RhoC, but not of RhoA, increased the expression of genes encoding tumor suppressors, such as nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), and decreased migration and the anchorage-independent growth in vitro. In vivo, RhoC small interfering RNA (siRhoC) impaired tumor growth. Of interest, the simultaneous knockdown of RhoC and NAG-1 repressed most of the siRhoC-related effects, demonstrating the central role of NAG-1. In addition of being induced by RhoC silencing, NAG-1 was also largely up-regulated in cells overexpressing RhoA. The silencing of RhoGDP dissociation inhibitor α (RhoGDIα) and the overexpression of a RhoA mutant unable to bind RhoGDIα suggested that the effect of RhoC silencing is indirect and results from the up-regulation of the RhoA level through competition for RhoGDIα. This study demonstrates the dynamic balance inside the RhoGTPase network and illustrates its biological relevance in cancer progression.
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, B-4000 Sart-Tilman, Belgium.
authors.forename: T T
authors.initials: TT
authors.lastname: Giang Ho
authors.forename: Audrey
authors.initials: A
authors.lastname: Stultiens
authors.forename: Johanne
authors.initials: J
authors.lastname: Dubail
authors.forename: Charles M
authors.initials: CM
authors.lastname: Lapière
authors.forename: Betty V
authors.initials: BV
authors.lastname: Nusgens
authors.forename: Alain C
authors.initials: AC
authors.lastname: Colige
authors.forename: Christophe F
authors.initials: CF
authors.lastname: Deroanne
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015676:Osteonectin / Q000378:metabolism; D034622:RNA Interference; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D054460:rho-Associated Kinases / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
chemical_list: C569639:Arhgdia protein, mouse; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D020730:Guanine Nucleotide Dissociation Inhibitors; D015676:Osteonectin; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; C066737:RHOA protein, human; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein