Knock down of HIF-1α in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres

Abstract

BackgroundGlioblastoma (GBM) is the most common and malignant primary intracranial human neoplasm. GBMs are characterized by the presence of extensive areas of necrosis and hypoxia. Hypoxia and its master regulator, hypoxia inducible factor 1 (HIF-1) play a key role in glioma invasion.ResultsTo further elucidate the functional role of HIF-1α in glioma cell migration in vitro and in invasion in vivo, we used a shRNA approach to knock down HIF-1α expression complemented with genome-wide expression profiling, performed in both normoxic and hypoxic conditions. Our data show that knock down of HIF-1α in glioma cells significantly impairs their migration in vitro as well as their ability to invade into the brain parenchyma in vivo. Next, we assessed the role that HIF-1α plays in maintaining the characteristics of cancer stem cells (CSCs). By using the tumor sphere forming assay, we demonstrate that HIF-1α plays a role in the survival and self-renewal potential of CSCs. Finally, expression profiling experiments in glioma cells provided detailed insight into a broad range of specific biological pathways and processes downstream of HIF-1α. We discuss the role of these processes in the migratory and invasive properties, as well as the stem cell biology of glioblastomasConclusionsOur data show that knock down of HIF-1α in human and murine glioma cells impairs their migration in vitro and their invasion in vivo. In addition, our data suggest that HIF-1α plays a role in the survival and self-renewal potential of CSCs and identify genes that might further elucidate the role of HIF-1α in tumor migration, invasion and stem cell biology.

HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway

“…27,30 The data from our and other group also showed that HIF-1a enhances the self-renewal activity of CD133-positive glioblastoma cells and inhibits the induction of GSC differentiation. 8,31,32 These data suggest that the mechanism involved in hypoxia-mediated maintenance of GSC maybe cell type specific. Besides, different hypoxic condition may also cause different response.…”

High Expression of HIF-1α, BNIP3 and PI3KC3: Hypoxia-Induced Autophagy Predicts Cholangiocarcinoma Survival and Metastasis

“…Likewise, hypoxiamimetic agent CoCl 2 has previously been demonstrated that it has potential in modulating the invasive ability of primary and metastatic breast cancer cells (Fu et al, 2009). Knockdown HIF-1α by siRNA inhibiting cell migration and invasion under hypoxic environment was determined in malignant gliomas (Mendez et al, 2010). BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton (Agostinis et al, 2013).…”

Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model

“…After incubation, the inserts were fixed and stained and the number of migrating cells was counted as described. 22 Each assay was performed in duplicate and repeated twice. The data from at least three independent experiments were pooled for statistical analysis.…”