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RHOA inactivation enhances Wnt signalling and promotes colorectal cancer.

Abstract
Activation of the small GTPase RHOA has strong oncogenic effects in many tumour types, although its role in colorectal cancer remains unclear. Here we show that RHOA inactivation contributes to colorectal cancer progression/metastasis, largely through the activation of Wnt/β-catenin signalling. RhoA inactivation in the murine intestine accelerates the tumorigenic process and in human colon cancer cells leads to the redistribution of β-catenin from the membrane to the nucleus and enhanced Wnt/β-catenin signalling, resulting in increased proliferation, invasion and de-differentiation. In mice, RHOA inactivation contributes to colon cancer metastasis and reduced RHOA levels were observed at metastatic sites compared with primary human colon tumours. Therefore, we have identified a new mechanism of activation of Wnt/β-catenin signalling and characterized the role of RHOA as a novel tumour suppressor in colorectal cancer. These results constitute a shift from the current paradigm and demonstrate that RHO GTPases can suppress tumour progression and metastasis.
AuthorsPaulo Rodrigues, Irati Macaya, Sarah Bazzocco, Rocco Mazzolini, Elena Andretta, Higinio Dopeso, Silvia Mateo-Lozano, Josipa Bilić, Fernando Cartón-García, Rocio Nieto, Lucia Suárez-López, Elsa Afonso, Stefania Landolfi, Javier Hernandez-Losa, Kazuto Kobayashi, Santiago Ramón y Cajal, Josep Tabernero, Niall C Tebbutt, John M Mariadason, Simo Schwartz Jr, Diego Arango
JournalNature communications (Nat Commun) Vol. 5 Pg. 5458 ( 2014) ISSN: 2041-1723 [Electronic] England
PMID25413277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Wnt Proteins
  • beta Catenin
  • RHOA protein, human
  • rhoA GTP-Binding Protein
Topics
  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms (enzymology, genetics, metabolism, pathology)
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Mice
  • Signal Transduction
  • Wnt Proteins (genetics, metabolism)
  • beta Catenin (genetics, metabolism)
  • rhoA GTP-Binding Protein (genetics, metabolism)

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