Chronic sun exposure can lead to severe skin disorders such as carcinogenesis. The cell death process triggered by ultraviolet B (UVB) irradiation is crucial because it protects the surrounding tissue from the emergence and the accumulation of cells that bear the risk of becoming transformed. Here, we show that repression of NF‐κB and Egr‐1 expression drastically inhibits UVB‐mediated cell death. Furthermore, we demonstrate that Egr‐1 is induced upon UVB irradiation through NF‐κB activation and the binding of p65/RelA within the Egr‐1 promoter. We show that Egr‐1 contributes to the regulation of the Gadd45a and Gadd45b genes, which are involved in the control of cell cycle, DNA repair and apoptosis, by direct binding to their promoter. Our study demonstrates for the first time a signaling cascade involving sequential activation of NF‐κB, Egr‐1 and Gadd45 to induce UVB‐mediated cell death. Failure in the induction of each protagonist of this pathway alters the UVB‐mediated cell death process. Therefore, impairment of the cascade could be at the onset of skin carcinogenesis mediated by genotoxic stress.

Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.

Stem cell-like properties of glioma initiating cells (GiCs) fuel glioblastoma (GBM) development by providing the different cell types that comprise the tumor. It is therefore likely that the molecular circuitries that regulate their decision to self-renew or commit to a more differentiated state may offer targets for future innovative therapies. In previous micro-RNA profiling studies to search for regulators of stem cell plasticity, we identified miR-18a* as a potential candidate and its expression correlated with the stemness state. Here, using human GiCs we found that miR-18a* expression promotes clonal proliferation in vitro and tumorigenicity in vivo. Mechanistically, ERK-dependent induction of miR-18a* directly represses expression of DLL3, an autocrine inhibitor of NOTCH, thus enhancing the level of activated NOTCH-1. Activated NOTCH-1 in turn is required for sustained ERK activation. This feed-forward loop, driven by miR-18a*, is required to turn on the SHH-GLI-NANOG network, essential for GiC self-renewal. Hence, by tightly regulating expression of DLL3, miR-18a* constitutes an important signaling mediator for fine tuning the level of GiC self-renewal.