RELN signaling modulates glioblastoma growth and substrate‐dependent migration

Abstract

Glioblastoma (GBM) represents the most common and most malignant type of primary brain tumor and significantly contributes to cancer morbidity and mortality. Invasion into the healthy brain parenchyma is a major feature of glioblastoma aggressiveness. Reelin (RELN) is a large secreted extracellular matrix glycoprotein that regulates neuronal migration and positioning in the developing brain and sustains functionality in the adult brain. We here show that both RELN and its main downstream effector DAB1 are silenced in glioblastoma as compared to non-neoplastic tissue and mRNA expression is inversely correlated with malignancy grade. Furthermore, RELN expression is positively correlated with patient survival in two large, independent clinically annotated datasets. RELN silencing occurs via promoter hypermethylation as shown by both database mining and bisulfite sequencing of the RELN promoter. Consequently, treatment with 5'-Azacytidine and trichostatin A induced RELN expression in vitro. On the functional level, we found RELN to regulate glioblastoma cell migration both in a DAB1 (tyrosine phosphorylation)-dependent and -independent fashion, depending on the substrate provided. Moreover, stimulation of RELN signaling strongly reduced proliferation in glioblastoma cells. This phenotype depends on DAB1 stimulation by RELN, as a mutant that lacks all RELN induced tyrosine phosphorylation sites (DAB1-5F) failed to induce a growth arrest. Proteomic analyzes revealed that these effects are mediated by a reduction in E2F targets and dephosphorylation of ERK1/2. Taken together, our data establish a relevance of RELN signaling in glioblastoma pathology and thereby might unearth novel, yet unrecognized treatment options.

Disabled‐1 is down‐regulated in clinical breast cancer and regulates cell apoptosis through NF‐κB/Bcl‐2/caspase‐9

“…No change was observed in the expression of active caspase-8 ( Figure 2H-J). Bcl2 family was reported to be crucial in regulating the intrinsic apoptosis pathway, 13 and we found decreased Dab1 has been reported to be strongly down-regulated in glioblastoma 17 and neuroblastoma. 18 In breast cancer, McAvoy has firstly reported the down-regulation of Dab1, and overexpression of Dab1 resulted in decreased cell survival.…”

“…Dab1 has been reported to be strongly down‐regulated in glioblastoma and neuroblastoma . In breast cancer, McAvoy has firstly reported the down‐regulation of Dab1, and overexpression of Dab1 resulted in decreased cell survival .…”

Multiple paragangliomas: a case report

“…Stop-gain variants were determined in NRXN3 and RELN encoding for proteins that are involved in cell adhesion and cell-cell interactions in neural cells, respectively. Both genes were shown to be associated with glioblastoma pathogenesis [ 21 – 23 ] and variants in these genes were also detected in a number of tumors [ 24 – 26 ]. We also found two variants in the TP53 gene in the right CPGL.…”

Identification of Key Genes and Signaling Pathways Associated with the Progression of Glioblastoma multiform

“…Similarly, GO enrichment analysis for down regulated genes was performed. Enriched genes such as MAG (myelin associated glycoprotein) [176], ASIC2 [177], MBP (myelin basic protein) [178], CNP (2’,3’-cyclic nucleotide 3’ phosphodiesterase) [179], CPEB3 [180], SLC8A2 [181], PRKCZ (protein kinase C zeta) [182], RELN (reelin) [183], CYP46A1 [184], SNAP91 [185], CNTN2 [186], NPY (neuropeptide Y) [187], RGS4 [188], IL1RAPL1 [189], ERBB3 [190], SH3GL2 [191], SH3GL3 [192], ARRB1 [193], DNM3 [194], SPOCK1 [195], CCK (cholecystokinin) [196] and INA (internexin neuronal intermediate filament protein alpha) [197] were identified with progression of GBM. Decrease expression of enriched genes such as such as SCN8A [198], BRSK1 [199], ANKS1B [200], CALB2 [201], GRM3 [202], BCAS1 [203] and CLCA4 [204] were responsible for advancement of different cancer types, but low expression of these genes were identified first time in GBM and may be involved in progression of GBM.…”