Open AccessGPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth
Author(s) -
N. Sumru Bayın,
Joshua D. Frenster,
Jason M. Kane,
Jordan Rubenstein,
Aram S. Modrek,
Rabaa Baitalmal,
Igor Dolgalev,
Katie Rudzenski,
Lia Scarabottolo,
D. Crespi,
Loredana Redaelli,
Matija Snuderl,
John G. Golfinos,
Werner Doyle,
Donato Pacione,
Erik C. Parker,
Anand P.S.,
Adriana Heguy,
Douglas J. MacNeil,
Nadim Shohdy,
David Zagzag,
Dimitris G. Placantonakis
Publication year - 2016
Publication title -
oncogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.497
H-Index - 42
ISSN - 2157-9024
DOI - 10.1038/oncsis.2016.63
Subject(s) - gene knockdown , cancer research , downregulation and upregulation , small hairpin rna , biology , tumor progression , angiogenesis , microbiology and biotechnology , cell culture , gene , genetics
Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1α (Hif1α)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro . Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.