Circular RNA circPOSTN promotes neovascularization by regulating miR-219a-2-3p/STC1 axis and stimulating the secretion of VEGFA in glioblastoma

Abstract

Glioblastoma (GBM), the most malignant type of astrocytic tumor, is one of the deadliest cancers prevalent in adults. Along with tumor growth, patients with GBM generally suffer from extensive cerebral edema and apparent symptoms of intracranial hyper-pressure. Accumulating evidence has demonstrated that circRNA plays a critically important role in tumorigenesis and progression. However, the biological function and the underlying mechanism of circRNA in GBM remain elusive. In this study, by conducting gene expression detection based on 15 pairs of GBM clinical specimens and the normal adjunct tissues, we observed that circPOSTN showed abnormally higher expression in GBM. Both loss-of-function and gain-of-function biological experiments demonstrated that circPOSTN scheduled the proliferation, migration, and neovascularization abilities of GBM cells. Further, fluorescence in situ hybridization (FISH) assay, quantitative RT-PCR, and subcellular separation suggested that circPOSTN was predominately localized in the cytoplasm and may serve as a competing endogenous RNA (ceRNA). CircRNA-miRNA interaction prediction based on online analytical processing, AGO2-RIP assay, biotin labeled RNA pulldown assay, and dual-luciferase reporter assay revealed that circPOSTN sponged miR-219a-2-3p, limited its biological function, and ultimately upregulated their common downstream gene STC1. Finally, by carrying out in vitro and in vivo functional assays, we uncovered a new regulatory axis circPOSTN/miR-219a-2-3p/STC1 that promoted GBM neovascularization by increasing vascular endothelial growth factor A (VEGFA) secretion. Our study underscores the critical role of circPOSTN in GBM progression, providing a novel insight into GBM anti-tumor therapy.

miRNome Profiling Analysis Reveals Novel Hepatocellular Carcinoma Diagnostic, Prognostic and Treatment-Related Candidate Biomarkers: Post hoc Analysis of SORAMIC Trial

“…To our best knowledge, hsa-miR-219-2-3p and hsa-miR-218-5p down-regulation in plasma has not been previously reported in the case of HCC. hsa-miR-219-2-3p has been previously shown to be possibly involved in gastric cancerogenesis, the development of pituitary adenomas, and glioblastomas [33‒35]. In addition, functional miRNA studies report the role of hsa-miR-218-5p in the regulation of cell proliferation, metastasis, and invasion in vitro in HCC cell lines [36].…”

Identification and experimental verification of an anoikis and immune related signature in prognosis for lung adenocarcinoma

“…Meanwhile, DSG2 promoted the proliferation and migration of LUAD cell lines and increased the resistance to Osimertinib ( 54 ). In glioblastoma, the cyclic RNA circPOSTN can promote neovascularization by regulating the miR-219a-2-3p/STC1 axis and promoting the expression of VEGFA ( 55 ). Meanwhile, ABCA3 , FRS3 and other genes have also been reported in a variety of cancers ( 56 , 57 ).…”

Underlying mechanisms and clinical potential of circRNAs in glioblastoma

“…CircPOSTN was found to have significantly upregulated levels in GBM tissues and cell lines [ 92 ]. CircPOSTN overexpression was found to facilitate GBM cell proliferation, migration and neovascularization, whereas circPOSTN silencing showed the opposite effects [ 92 ], suggesting a promoting role of circPOSTN in GBM. Further experiments revealed that miR-219a-2-3p was the direct target of circPOSTN and that miR-219a-2-3p could target STC1.…”

“…Further experiments revealed that miR-219a-2-3p was the direct target of circPOSTN and that miR-219a-2-3p could target STC1. CircPOSTN suppressed miR-219a-2-3p activity and then increased the expression of STC1 [ 92 ], thus promoting tumorigenesis. Moreover, circPOSTN was revealed to facilitate GBM neovascularization by inducing VEGFA secretion.…”

“…Moreover, circPOSTN was revealed to facilitate GBM neovascularization by inducing VEGFA secretion. To sum up, circPOSTN plays a tumor-promoting role in GBM via the miR-219a-2-3p-STC1-VEGFA axis [ 92 ].…”