Integrative analysis of cell adhesion molecules in glioblastoma identified prostaglandin F2 receptor inhibitor (PTGFRN) as an essential gene

Abstract

Background Glioblastoma (GBM) is the most common primary malignant brain tumor in adults exhibiting infiltration into surrounding tissues, recurrence, and resistance to therapy. GBM infiltration is accomplished by many deregulated factors such as cell adhesion molecules (CAMs), which are membrane proteins that participate in cell-cell and cell-ECM interactions to regulate survival, proliferation, migration, and stemness. Methods A comprehensive bioinformatics analysis of CAMs (n = 518) in multiple available datasets revealed genetic and epigenetic alterations among CAMs in GBM. Univariate Cox regression analysis using TCGA dataset identified 127 CAMs to be significantly correlated with survival. The poor prognostic indicator PTGFRN was chosen to study its role in glioma. Silencing of PTGFRN in glioma cell lines was achieved by the stable expression of short hairpin RNA (shRNA) against the PTGFRN gene. PTGFRN was silenced and performed cell growth, migration, invasion, cell cycle, and apoptosis assays. Neurosphere and limiting dilution assays were also performed after silencing of PTGFRN in GSCs. Results Among the differentially regulated CAMs (n = 181, 34.9%), major proportion of them were found to be regulated by miRNAs (n = 95, 49.7%) followed by DNA methylation (n = 32, 16.7%), and gene copy number variation (n = 12, 6.2%). We found that PTGFRN to be upregulated in GBM tumor samples and cell lines with a significant poor prognostic correlation with patient survival. Silencing PTGFRN diminished cell growth, colony formation, anchorage-independent growth, migration, and invasion and led to cell cycle arrest and induction of apoptosis. At the mechanistic level, silencing of PTGFRN reduced pro-proliferative and promigratory signaling pathways such as ERK, AKT, and mTOR. PTGFRN upregulation was found to be due to the loss of its promoter methylation and downregulation of miR-137 in GBM. PTGFRN was also found to be higher in glioma stem-like cells (GSCs) than the matched differentiated glioma cells (DGCs) and is required for GSC growth and survival. Silencing of PTGFRN in GSCs reduced transcript levels of reprogramming factors (Olig2, Pou3f2, Sall2, and Sox2). Conclusion In this study, we provide a comprehensive overview of the differential regulation of CAMs and the probable causes for their deregulation in GBM. We also establish an oncogenic role of PTGFRN and its regulation by miR-137 in GBM, thus signifying it as a potential therapeutic target.

Identification of Subtypes in Triple-negative Breast Cancer Based on Shared Genes Between Immunity and Cancer Stemness

“…This study identified 3 DEGs shared by immunity and CSC, namely PTGFR, AVPR1B, and VIP, which were significantly associated with the survival of TNBC patients. Prostaglandin F2 receptor inhibitor (PTGFRN) is a transmembrane protein on cell surface in the immunoglobulin superfamily that has been shown to be upregulated in various cancers, including gliomas, colorectal cancer, and melanoma 19–22 . Currently, PTGFRN is considered a target for antibody-drug conjugate development in cancer cells 23 .…”

“…Prostaglandin F2 receptor inhibitor (PTGFRN) is a transmembrane protein on cell surface in the immunoglobulin superfamily that has been shown to be upregulated in various cancers, including gliomas, colorectal cancer, and melanoma. [19][20][21][22] Currently, PTGFRN is considered a target for antibody-drug conjugate development in cancer cells. 23 AVPR1B is a member of the AVP receptor family and a protein-coding gene with an unclear function.…”

EPDR1 is a noncanonical effector of insulin-mediated angiogenesis regulated by an endothelial-specific TGF-β receptor complex

“…Indeed, while research has shown that hyperinsulinemia mediates pathologic angiogenesis through the proliferative actions of the ERK MAPK pathway ( 42 , 43 ), chronically elevated levels of insulin may also trigger the expression of EPDR1 and potentially many others through the endoglin/ALK1/Smad1/5 signaling axis. For instance, chondroitin sulfate synthase 2 ( 44 , 45 ) and prostaglandin F2 receptor-associated protein ( 46 , 47 , 48 ) are two of the top hits ranked higher than EPDR1, whereas others, including osteopontin ( 49 , 50 ) and platelet-derived growth factor receptor beta ( 51 , 52 ), represent promising candidates ranked slightly lower based on several parameters including fold changes over negative control and unique peptide counts identified ( Fig. S3 B ).…”

Acquisition of Immune Privilege in GBM Tumors: Role of Prostaglandins and Bile Salts

“…PTGFRN is found in various cancers, including aggressive GBM [ 45 , 46 ]. PTGFRN is elevated in GBM tumors with a hypoxic phenotype, with its expression modulated by hypoxia-responsive microRNA, miR-137 [ 47 , 48 ].…”