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IER2-induced senescence drives melanoma invasion through osteopontin.

Oncogene (2021-10-07)
Lenka Kyjacova, Rafael Saup, Kerstin Rönsch, Sabine Wallbaum, Stefanie Dukowic-Schulze, Amelia Foss, Sandra D Scherer, Melanie Rothley, Antje Neeb, Nicole Grau, Wilko Thiele, Sonja Thaler, Natascha Cremers, Carsten Sticht, Norbert Gretz, Boyan K Garvalov, Jochen Utikal, Jonathan P Sleeman
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-MDM2 Antibody, clone 3G9, clone 3G9, from mouse
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
Akt1/2 kinase inhibitor, ≥98% (HPLC)
Sigma-Aldrich
Monoclonal Anti-Vinculin antibody produced in mouse, clone hVIN-1, ascites fluid