MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma

Abstract

Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O2)-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression, and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR-124 levels contribute to pro-survival adaptive pathways in this disease. Since miR-124 expression is repressed in various cancers (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival, during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared to regions replete in O2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo, and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1, MAPK14/p38α and SERP1, factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR-124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 re-introduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression.

REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells

“…27 Our findings describe the novel REST-miR-203 pathway, which regulates invasion in HR-GSC tumors, with REST suppressing miR-203 gene expression and miR-203 functioning as a tumor suppressor. The recent observation that miR-203 expression was significantly lower in a large number of high-grade GBM tumor tissues than in low-grade glioma tissues or normal brain tissues 28,29 supports miR-203's role …”

MicroRNA-378 enhances radiation response in ectopic and orthotopic implantation models of glioblastoma

“…It was conducted on a custom-built MPLSM using a confocal laser-scanning microscope body (BX-51, Optical Analysis) and a femtosecond laser source (High Performance Mai Tai, Spectra-Physics) [21, 22, 38]. Imaging studies were performed at 20 magnification, 0.95 NA water immersion objective (Olympus XLUMPlanFl, 1-UB965, Optical Analysis).…”

Role of Tat-interacting protein of 110 kDa and microRNAs in the regulation of hematopoiesis

“…Thus, miR-124 has been viewed as a potential master regulator of differentiation in the central nervous system [29]. Studies have shown repressed miR-124 expression in various cancer cells including glioblastoma, gastric cancer, ovarian cancer, and bladder cancer [30][31][32][33]. It is conceivable that miR-124 functions to inhibit cellular proliferation, invasion, and inducing apoptosis.…”