Transcriptional basis of KRAS oncogene-mediated cellular transformation in ovarian epithelial cells.
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.
Tchernitsa
Oleg I
OI
Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité, Humboldt-University Berlin, Schumannstr. 20/21, D-10117 Berlin, Germany.
Sers
Christine
C
Zuber
Johannes
J
Hinzmann
Bernd
B
Grips
Martin
M
Schramme
Anja
A
Lund
Per
P
Schwendel
Anke
A
Rosenthal
André
A
Schäfer
Reinhold
R
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
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