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Transcriptional basis of KRAS oncogene-mediated cellular transformation in ovarian epithelial cells

Oncogene volume 23, pages 4536–4555 (2004)Cite this article

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.

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Acknowledgements

Our work was supported by Deutsche Krebshilfe (Grant 10-332-Schä-1 to RS), Deutsche Forschungsgemeinschaft (Grant Scha 396/1-1 to RS), Monika Kutzner Foundation (grant to RS), European Union (Grant QLG2-CT-2000-05190), and Studienstiftung des Deutschen Volkes (JZ). We thank Dr N Auersperg (Vancouver, Canada) for ROSE 199 cells.

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  1. Contributed equally to this paper

Authors and Affiliations

  1. Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité, Humboldt-University Berlin, Schumannstr. 20/21, Berlin, D-10117, Germany

    Oleg I Tchernitsa, Christine Sers, Johannes Zuber, Martin Grips, Anja Schramme, Per Lund, Anke Schwendel & Reinhold Schäfer

  2. MetaGen Pharmaceuticals GmbH, Oudenarder Str.16, Berlin, 13347, Germany

    Bernd Hinzmann & André Rosenthal

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  1. Oleg I Tchernitsa
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Tchernitsa, O., Sers, C., Zuber, J. et al. Transcriptional basis of KRAS oncogene-mediated cellular transformation in ovarian epithelial cells. Oncogene 23, 4536–4555 (2004). https://doi.org/10.1038/sj.onc.1207585

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