PloS one, 2012-04, Vol.7 (4), p.e34343-e34343
2012
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Details
- Autor(en) / Beteiligte
- Titel
- Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells
- Ist Teil von
- PloS one, 2012-04, Vol.7 (4), p.e34343-e34343
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- Elektronische Zeitschriftenbibliothek (Open access)
- Beschreibungen/Notizen
- Changes in expression and localization of proteins that regulate cell and tissue polarity are frequently observed in carcinoma. However, the mechanisms by which changes in cell polarity proteins regulate carcinoma progression are not well understood. Here, we report that loss of polarity protein expression in epithelial cells primes them for cooperation with oncogenes or changes in tissue microenvironment to promote invasive behavior. Activation of ErbB2 in cells lacking the polarity regulators Scribble, Dlg1 or AF-6, induced invasive properties. This cooperation required the ability of ErbB2 to regulate the Par6/aPKC polarity complex. Inhibition of the ErbB2-Par6 pathway was sufficient to block ErbB2-induced invasion suggesting that two polarity hits may be needed for ErbB2 to promote invasion. Interestingly, in the absence of ErbB2 activation, either a combined loss of two polarity proteins, or exposure of cells lacking one polarity protein to cytokines IL-6 or TNFα induced invasive behavior in epithelial cells. We observed the invasive behavior only when cells were plated on a stiff matrix (Matrigel/Collagen-1) and not when plated on a soft matrix (Matrigel alone). Cells lacking two polarity proteins upregulated expression of EGFR and activated Akt. Inhibition of Akt activity blocked the invasive behavior identifying a mechanism by which loss of polarity promotes invasion of epithelial cells. Thus, we demonstrate that loss of polarity proteins confers phenotypic plasticity to epithelial cells such that they display normal behavior under normal culture conditions but display aggressive behavior in response to activation of oncogenes or exposure to cytokines.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0034343Titel-ID: cdi_plos_journals_1324570012
- Format
- –
- Schlagworte
- Activation, Adaptor Proteins, Signal Transducing - genetics, Adaptor Proteins, Signal Transducing - metabolism, AKT protein, Animals, B cells, Behavior, Bioassays, Biology, Bone marrow, Breast cancer, Cell adhesion & migration, Cell culture, Cell division, Cell Line, Cell Movement - genetics, Cell Polarity - genetics, Cellular Microenvironment, Collagen, Cooperation, Cooperativity, Cytokines, Cytokines - metabolism, Dendritic cells, Epidermal growth factor receptors, Epithelial cells, Epithelial Cells - cytology, Epithelial Cells - metabolism, Epithelial Cells - physiology, ErbB Receptors - genetics, ErbB Receptors - metabolism, ErbB-2 protein, Exposure, Female, Gene Expression, Gene Expression Regulation, Genetic aspects, Growth factors, Humans, Inflammation Mediators - metabolism, Inhibition, Interleukin 6, Invasiveness, Kinases, Kinesin - genetics, Kinesin - metabolism, Laboratories, Localization, Male, Medical research, Medicine, Membrane Proteins - genetics, Membrane Proteins - metabolism, Metastasis, Mice, Mice, 129 Strain, Myosins - genetics, Myosins - metabolism, Oncogenes, Oncology, Phenotypic plasticity, Polarity, Proteins, Proto-Oncogene Proteins c-akt - genetics, Proto-Oncogene Proteins c-akt - metabolism, Receptor, ErbB-2 - genetics, Receptor, ErbB-2 - metabolism, Regulators, Rodents, Stem cells, Synergism, Tumor necrosis factor-α, Tumorigenesis