IER2-induced senescence drives melanoma invasion through osteopontin

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.

A Human Skin Model Recapitulates Systemic Sclerosis Dermal Fibrosis and Identifies COL22A1 as a TGFβ Early Response Gene that Mediates Fibroblast to Myofibroblast Transition

: Systemic sclerosis (SSc) is a complex multi-system autoimmune disease characterized by immune dysregulation, vasculopathy, and organ fibrosis. Skin fibrosis causes high morbidity and impaired quality of life in affected individuals. Animal models do not fully recapitulate the human disease. Thus, there is a critical need to identify ex vivo models for the dermal fibrosis characteristic of SSc. We identified genes regulated by the pro-fibrotic factor TGFβ in human skin maintained in organ culture. The molecular signature of human skin overlapped with that which was identified in SSc patient biopsies, suggesting that this model recapitulates the dermal fibrosis characteristic of the human disease. We further characterized the regulation and functional impact of a previously unreported gene in the setting of dermal fibrosis, COL22A1, and show that silencing COL22A1 significantly reduced TGFβ-induced ACTA2 expression. COL22A1 expression was significantly increased in dermal fibroblasts from patients with SSc. In summary, we identified the molecular fingerprint of TGFβ in human skin and demonstrated that COL22A1 is associated with the pathogenesis of fibrosis in SSc as an early response gene that may have important implications for fibroblast activation. Further, this model will provide a critical tool with direct relevance to human disease to facilitate the assessment of potential therapies for fibrosis.

Immediate Early Response Gene X-1 (IEX-1) Mediates Ischemic Preconditioning-Induced Cardioprotection in Rats

Reversible myocardial ischemia/reperfusion (I/R) or ischemic preconditioning (IPC) is associated with an immediate genomic response; IPC-induced immediate early genes are associated with reduced infarct size. Because the immediate early response gene X-1 (IEX-1) plays a central role in cell apoptosis, we examine whether IEX-1 exerts protective effects against I/R injury. We found that the IEX-1 mRNA level was increased in the IPC-imposed rat heart. However, it was downregulated in the I/R rat heart, which was prevented by in situ IPC. When IEX-1 was knocked down, the protective effects imposed by IPC were lessened. Local gene delivery of Ad-IEX-1 to the left ventricle greatly diminished cardiac infarct size and improved systolic functions of I/R hearts in rats. In contrast, knocking down IEX-1 expression exacerbates myocardial infarction. Overexpression of IEX-1 in neonatal rat cardiomyocytes significantly reduced hypoxia-reoxygenation-induced intracellular and mitochondrial ROS accumulation and cell apoptosis. Furthermore, IPC-induced phosphorylation and particle translocation of PKCε were impaired by knocking down IEX-1 in vivo, and overexpressing IEX-1 showed similar cardioprotection imposed by IPC. Our results demonstrate that IPC increases IEX-1 expression, which may promote phosphorylation and particle translocation of PKCε and thus reduce intracellular ROS accumulation. These beneficial effects reduce cardiomyocyte apoptosis and necrosis to alleviate cardiac infarction.