title: Transcriptional basis of KRAS oncogene-mediated cellular transformation in ovarian epithelial cells.
abstract: To understand the relationship between oncogenic signaling and the reprogramming of gene expression, we performed transcriptional profiling in rat ovarian surface epithelial cells (ROSE), in which neoplastic transformation is driven by a mutated KRAS oncogene. We identified >200 genes whose expression was elevated or reduced following permanent KRAS expression. Deregulated KRAS-responsive genes encode transcriptional regulators, signaling effectors, proteases, extracellular matrix and adhesion proteins, transformation-suppressing proteins and negative growth regulators. Many of them have not been previously identified in cells expressing oncogenic RAS genes or in other well-studied models of oncogenic signaling. The number of critical genes related to the execution of anchorage-independent proliferation and epithelial-mesenchymal transition was narrowed down to 79 by selectively inhibiting the mitogen-activated protein kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K) pathways. Blocking MAPK/ERK-signaling caused reversion to the normal epithelial phenotype in conjunction with the reversal of deregulated target transcription to pretransformation levels. In addition, silencing of the overexpressed transcriptional regulator Fra-1 by RNA interference resulted in growth reduction, suggesting that this factor partially contributes to, but is not sufficient for the proliferative capacity of KRAS-transformed epithelial cells.
authors.affiliation: Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité, Humboldt-University Berlin, Schumannstr. 20/21, D-10117 Berlin, Germany.
authors.forename: Oleg I
authors.initials: OI
authors.lastname: Tchernitsa
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Bernd
authors.initials: B
authors.lastname: Hinzmann
authors.forename: Martin
authors.initials: M
authors.lastname: Grips
authors.forename: Anja
authors.initials: A
authors.lastname: Schramme
authors.forename: Per
authors.initials: P
authors.lastname: Lund
authors.forename: Anke
authors.initials: A
authors.lastname: Schwendel
authors.forename: André
authors.initials: A
authors.lastname: Rosenthal
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines / Q000494:pharmacology; D010053:Ovary / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099169:Fos-Related Antigen 1
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D019908:Proto-Oncogene Proteins c-raf; D000099169:Fos-Related Antigen 1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one