Loss of RhoA Exacerbates, Rather Than Dampens, Oncogenic K-Ras Induced Lung Adenoma Formation in Mice

• Published in: PloS one Vol. 10; no. 6; p. e0127923
• Main Authors: Zandvakili, Inuk, Davis, Ashley Kuenzi, Hu, Guodong, Zheng, Yi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2015; Public Library of Science (PLoS)
• Subjects: Adenoma; Adenoma - genetics; Adenoma - pathology; Animal models; Animals; Blotting, Western; Cancer; Cell cycle; Clonal deletion; Developmental biology; Families & family life; Fibroblasts; Flox; Gene deletion; Gene expression; Genes, ras - genetics; Genes, ras - physiology; Genetic transformation; Hematology; Immunohistochemistry; K-Ras protein; Kinases; Liquid oxygen; Lung cancer; Lung diseases; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Mutation; Proteins; ras Proteins - genetics; ras Proteins - metabolism; rhoA GTP-Binding Protein - deficiency; rhoA GTP-Binding Protein - genetics; RhoA protein; rhoC GTP-Binding Protein; Rodents; Signal transduction; Studies; Transformation; Tumorigenesis; Tumors; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0127923

Numerous cellular studies have indicated that RhoA signaling is required for oncogenic Ras-induced transformation, suggesting that RhoA is a useful target in Ras induced neoplasia. However, to date very limited data exist to genetically attribute RhoA function to Ras-mediated tumorigenesis in mammalian models. In order to assess whether RhoA is required for K-Ras-induced lung cancer initiation, we utilized the K-RasG12D Lox-Stop-Lox murine lung cancer model in combination with a conditional RhoAflox/flox and RhoC-/- knockout mouse models. Deletion of the floxed Rhoa gene and expression of K-RasG12D was achieved by either CCSP-Cre or adenoviral Cre, resulting in simultaneous expression of K-RasG12D and deletion of RhoA from the murine lung. We found that deletion of RhoA, RhoC or both did not adversely affect normal lung development. Moreover, we found that deletion of either RhoA or RhoC alone did not suppress K-RasG12D induced lung adenoma initiation. Rather, deletion of RhoA alone exacerbated lung adenoma formation, whereas dual deletion of RhoA and RhoC together significantly reduced K-RasG12D induced adenoma formation. Deletion of RhoA appears to induce a compensatory mechanism that exacerbates adenoma formation. The compensatory mechanism is at least partly mediated by RhoC. This study suggests that targeting of RhoA alone may allow for compensation and a paradoxical exacerbation of neoplasia, while simultaneous targeting of both RhoA and RhoC is likely to lead to more favorable outcomes.