Oncogene, 2021-11, Vol.40 (47), p.6494-6512
2021
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- Autor(en) / Beteiligte
- Titel
- IER2-induced senescence drives melanoma invasion through osteopontin
- Ist Teil von
- Oncogene, 2021-11, Vol.40 (47), p.6494-6512
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Expression of the immediate-early response gene IER2 has been associated with the progression of several types of cancer, but its functional role is poorly understood. We found that increased IER2 expression in human melanoma is associated with shorter overall survival, and subsequently investigated the mechanisms through which IER2 exerts this effect. In experimental melanoma models, sustained expression of IER2 induced senescence in a subset of melanoma cells in a p53/MAPK/AKT-dependent manner. The senescent cells produced a characteristic secretome that included high levels of the extracellular phosphoglycoprotein osteopontin. Nuclear localization of the IER2 protein was critical for both the induction of senescence and osteopontin secretion. Osteopontin secreted by IER2-expressing senescent cells strongly stimulated the migration and invasion of non-senescent melanoma cells. Consistently, we observed coordinate expression of IER2, p53/p21, and osteopontin in primary human melanomas and metastases, highlighting the pathophysiological relevance of IER2-mediated senescence in melanoma progression. Together, our study reveals that sustained IER2 expression drives melanoma invasion and progression through stimulating osteopontin secretion via the stochastic induction of senescence.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/s41388-021-02027-6Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8616759
- Format
- –
- Schlagworte
- 13/1, 13/106, 13/109, 13/21, 13/31, 13/44, 13/51, 13/89, 13/95, 38/39, 38/61, 38/77, 38/90, 42/41, 631/45/127, 631/67/1813/1634, 631/80/509, 631/80/84, 631/80/86, AKT protein, Animals, Apoptosis, Biomarkers, Tumor - genetics, Biomarkers, Tumor - metabolism, Cell Biology, Cell cycle, Cell migration, Cell Proliferation, Cellular Senescence, Development and progression, Gene Expression Regulation, Neoplastic, Genetic aspects, Glycoproteins, Health aspects, Human Genetics, Humans, Immediate-Early Proteins - genetics, Immediate-Early Proteins - metabolism, Internal Medicine, Localization, MAP kinase, Medicine, Medicine & Public Health, Melanoma, Melanoma - genetics, Melanoma - metabolism, Melanoma - pathology, Metastases, Metastasis, Mice, Neoplasm Invasiveness, Oncology, Osteopontin, Osteopontin - genetics, Osteopontin - metabolism, p53 Protein, Phosphoglycoprotein, Prognosis, Secretion, Secretome, Senescence, Stochasticity, Trans-Activators - genetics, Trans-Activators - metabolism, Tumor Cells, Cultured