CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1α

Abstract

BackgroundGlioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion.MethodsIn order to perform the studies, we employed optimal cell culture methods and hypoxic conditions, lentivirus-mediated knockdown of protein expression, Western Blot analysis, migration assays and immunoprecipitation. We determined statistical significance by unpaired t-test.ResultsIn this report, we show that U87MG, LN229 and LN308 glioma cells express CXCR7 and that exposure to hypoxia upregulates CXCR7 protein expression in these cell lines. CXCR7-expressing U87MG, LN229 and LN308 glioma cells migrated towards stromal-derived factor (SDF)-1α/CXCL12 in hypoxic conditions in the Boyden chamber assays. While shRNA-mediated knockdown of CXCR7 expression did not affect the migration of any of the three cell lines in normoxic conditions, we observed a reduction in the migration of LN229 and LN308, but not U87MG, glioma cells towards SDF-1α in hypoxic conditions. In addition, knockdown of CXCR7 expression in LN229 and LN308 glioma cells decreased levels of SDF-1α-induced phosphorylation of ERK1/2 and Akt. Inhibiting CXCR4 in LN229 and LN308 glioma cells that were knocked down for CXCR7 did not further reduce migration towards SDF-1α in hypoxic conditions and did not affect the levels of phosphorylated ERK1/2 and Akt. Analysis of immunoprecipitated CXCR4 from LN229 and LN308 glioma cells revealed co-precipitated CXCR7.ConclusionsTaken together, our findings indicate that both CXCR4 and CXCR7 mediate glioma cell migration towards SDF-1α in hypoxic conditions and support the development of therapeutic agents targeting these receptors.

CD164 regulates the tumorigenesis of ovarian surface epithelial cells through the SDF-1α/CXCR4 axis

“…In addition to the induction of CD164 gene expression, HIF-1α enhances the expression and function of CXCR4, CXCR7 and SDF-1α on the surface of normal and malignant cells [43,45]. SDF-1α also enhances the expression of CD164 mRNA and alters the expression of the CD164 protein in prostate cancer cell lines [14].…”

Molecular Mechanisms of Glioma Cell Motility

“…These glioma cells activate migratory processes in an attempt to escape hypoxia and to reach oxygen-rich areas adjacent to blood vessels (18). Some of the pro-migratory and pro-invasive factors produced or activated in response to hypoxic conditions include: metalloproteases like MMP-9, A Disintegrin, and Metalloproteinase (ADAM)-17 (19,20); galectins (21); epithelial to mesenchymal transition (EMT) transcriptional regulators like SLUG and SNAIL and the zinc-finger E-Boxbinding homeobox proteins ZEB-1 and ZEB-2 (22,23); and CXCR4 and CXCR7, the latter mediating glioma cell migration toward stromal-derived factor (SDF)-1a/CXCL12 (24,25).…”

Hypoxia promotes C-X-C chemokine receptor type 4 expression through microRNA-150 in pancreatic cancer cells

“…These miRNAs affect tumor behavior by decreasing the expression of their respective target genes (2). However, certain miRNAs, such as miRNA-20b and miRNA-200b, have also been shown to be downregulated in response to hypoxia (4).…”

“…As a tumor increases in size, it quickly outgrows its blood supply, leaving regions of the tumor, in which the oxygen concentration is significantly lower than that in normal tissues. In order to support tumor growth and proliferation within hypoxic environments, the expression of a number of genes is altered, and changes in metabolism also occur (4). Recently, a novel class of endogenous small non-coding regulatory RNAs, termed microRNAs (miRNAs), has received increasing attention.…”