Mala, U and Baral, TK and Somasundaram, K (2022) Integrative analysis of cell adhesion molecules in glioblastoma identified prostaglandin F2 receptor inhibitor (PTGFRN) as an essential gene. In: BMC Cancer, 22 (1).
|
PDF
BMC_can_22-1_2022.pdf - Published Version Download (2MB) | Preview |
|
|
PDF
12885_2022_9682_MOESM6_ESM.pdf - Published Version Download (313kB) | Preview |
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 =Â 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 =Â 181, 34.9), major proportion of them were found to be regulated by miRNAs (n =Â 95, 49.7) followed by DNA methylation (n =Â 32, 16.7), and gene copy number variation (n =Â 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.
Item Type: | Journal Article |
---|---|
Publication: | BMC Cancer |
Publisher: | BioMed Central Ltd |
Additional Information: | The copyright for this article belongs to the Authors. |
Keywords: | CAM; Glioblastoma; Growth; GSC; Migration; miR-137; PTGFRN |
Department/Centre: | Division of Biological Sciences > Microbiology & Cell Biology |
Date Deposited: | 28 Jun 2022 09:49 |
Last Modified: | 27 Jul 2022 11:09 |
URI: | https://eprints.iisc.ac.in/id/eprint/73956 |
Actions (login required)
View Item |