Silencing hypoxia-inducible factor-1α inhibits cell migration and invasion under hypoxic environment in malignant gliomas

Abstract

Malignant gliomas are characterized by active invasiveness, necrosis, and vascular proliferation. These pathological features have been speculated to be caused by tissue hypoxia. Hypoxia-inducible factor-1 (HIF-1), which is controlled by rapid stabilization of the HIF-1• subunit, is a pivotal transcriptional factor in the cellular response to hypoxia. Although many studies have described the relationship between tumor angiogenesis and hypoxic environment, the roles of HIF-1 in cell invasion have been barely elucidated in malignant gliomas. We investigated the role of HIF-1• in the motile and invasive activities of human glioma cells under hypoxia. Four malignant glioma cell lines, U87MG, U251MG, U373MG, and LN18, were cultured under 21 and 1% oxygen concentration. Expression of HIF-1• under hypoxia was observed to be much higher than that under normoxia in all cell lines. Introducing HIF-1•-targeted small interfering RNA (HIF-1• siRNA) into the glioma cell lines resulted in downregulation of HIF-1• expression, and significantly suppressed glioma cell migration in vitro. Furthermore, invasiveness was significantly reduced in the cells transfected with HIF-1• siRNA compared with those transfected with the control siRNA. Co-culture of glioma spheroids and rat brain slices showed that HIF-1• siRNAtransfected glioma cells failed to invade the surrounding normal brain tissue in an organotypic brain slice model. These effects of HIF-1• siRNA were more conspicuous under hypoxia than under normoxia. In addition, under hypoxic conditions, the level of matrix metalloproteinase (MMP)-2 mRNA was upregulated, and that of tissue inhibitor of metalloproteinase (TIMP)-2 was downregulated in all glioma cell lines. Treatment with HIF-1• siRNA resulted in downregulation of MMP-2 mRNA and upregulation of TIMP-2 mRNA. Furthermore, the enzyme activities of MMP-2 and MMP-9, both of which were activated by hypoxia, decreased with the introduction of HIF-1• siRNA. These findings suggest that overexpression of HIF-1• induced by hypoxic stress is an essential event in the activation of glioma cell motility through alteration of invasion-related molecules. Targeting the HIF-1• molecule may be a novel therapeutic strategy for malignant gliomas.

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

“…Recent studies have shown that HIF-1α is widely found in all histiocytes, as well as in peripheral leukocytes (3,15,16). Moreover, increased HIF-1α expression occurs in a variety of solid tumor cells and stromal cells, which may be related to their migration and adhesion (17,18). In the current study, HIF-1α mRNA and protein expression in acute leukemia hBMSCs were significantly increased compared to control, suggesting that HIF-1α may have been involved in the formation of the leukemia bone marrow hypoxic microenvironment.…”

Oligomer procyanidins (F2) isolated from grape seeds inhibits tumor angiogenesis and cell invasion by targeting HIF-1α in vitro

“…F2 could inhibit the hypoxia-simulated tumor angiogenesis and cell invasion in vitro in a HIF-1α-dependent manner, and MMP-2 may be the key protein participating in the inhibitory effect of F2 on cell invasion because it could be involved in the breakdown of the extracellular matrix (31). However, there are other proteins participating in the hypoxia-induced tumor invasion, such as CXC chemokine receptor 4 (CXCR4) and interleukin-8 (IL-8) (38,39).…”

Recent advances in annular pathobiology provide insights into rim-lesion mediated intervertebral disc degeneration and potential new approaches to annular repair strategies

“…Unlike other mammalian cells, HIF-1a expression in NP cells is stabilised under normoxic conditions [119]. However, HIF-1a is also expressed in a number of tumours [20,21,29] where it promotes the transcription of glycolytic enzymes which switch cells from aerobic to anaerobic glycolysis. HIF-1a expression in the ovine and human IVD correlates with IVD pathology [39,115,119].…”