An RNA interference phenotypic screen identifies a role for FGF signals in colon cancer progression

• Published in: PloS one 2011-08, Vol.6 (8), p.e23381-e23381
• Main Authors: Leushacke, Marc, Spörle, Ralf, Bernemann, Christof, Brouwer-Lehmitz, Antje, Fritzmann, Johannes, Theis, Mirko, Buchholz, Frank, Herrmann, Bernhard G, Morkel, Markus
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Biology; Cancer; Cascades; Cell adhesion; Cell adhesion & migration; Cell Adhesion - genetics; Cell growth; Cell Line, Tumor; Cell morphology; Cell Movement - genetics; Colon; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Cytology; Deregulation; Development and progression; Disease Progression; Epithelial cells; Epithelium - metabolism; Epithelium - pathology; Fibroblast growth factor; Fibroblast growth factor receptor 9; Fibroblast growth factors; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genes, Neoplasm - genetics; Genetic Testing; Guanosine triphosphatases; Humans; Inhibition; Interference; JNK protein; Kinases; MAP kinase; MAP Kinase Signaling System - genetics; Medicine; Mesoderm - metabolism; Mesoderm - pathology; Mice; Mitogens; Morphology; Mutation; Phenotype; Protein kinase; Protein kinases; rho GTP-Binding Proteins - metabolism; Ribonucleic acid; RNA; RNA Interference; RNA-mediated interference; Signal Transduction - genetics; Signaling; Small intestine; Survival Analysis; Tumor cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023381

In tumor cells, stepwise oncogenic deregulation of signaling cascades induces alterations of cellular morphology and promotes the acquisition of malignant traits. Here, we identified a set of 21 genes, including FGF9, as determinants of tumor cell morphology by an RNA interference phenotypic screen in SW480 colon cancer cells. Using a panel of small molecular inhibitors, we subsequently established phenotypic effects, downstream signaling cascades, and associated gene expression signatures of FGF receptor signals. We found that inhibition of FGF signals induces epithelial cell adhesion and loss of motility in colon cancer cells. These effects are mediated via the mitogen-activated protein kinase (MAPK) and Rho GTPase cascades. In agreement with these findings, inhibition of the MEK1/2 or JNK cascades, but not of the PI3K-AKT signaling axis also induced epithelial cell morphology. Finally, we found that expression of FGF9 was strong in a subset of advanced colon cancers, and overexpression negatively correlated with patients' survival. Our functional and expression analyses suggest that FGF receptor signals can contribute to colon cancer progression.