title: (Pro)renin receptor is crucial for glioma development via the Wnt/β-catenin signaling pathway.
abstract: OBJECTIVE The (pro)renin receptor (PRR) plays an essential role in the early development of the central nervous system by activating the Wnt/β-catenin signaling pathway. The authors investigated the potential role of the PRR in the pathogenesis of glioma. METHODS The authors performed immunohistochemical analysis to detect both the PRR and isocitrate dehydrogenase 1 with mutations involving arginine 132 ( IDH1R132H) in paraffin sections of 31 gliomas. Expression of the PRR and Wnt pathway components in cultured human glioma cell lines (U251MG, U87MG, and T98G) was measured using Western blotting. The effects of PRR short interfering RNA (siRNA) on glioma cell proliferation (WST-1 assay and direct cell counting) and apoptosis (flow cytometry and the caspase-3 assay) were also examined. RESULTS PRR expression was significantly higher in glioblastoma than in normal tissue or in lower grade glioma, regardless of IDH1R132Hmutation. PRR expression was also higher in human glioblastoma cell lines than in human astrocytes. PRR expression showed a significant positive correlation with the Ki-67 labeling index, while it had a significant negative correlation with the survival time of glioma patients. Treatment with PRR siRNA significantly reduced expression of Wnt2, activated β-catenin, and cyclin D1 by human glioblastoma cell lines, and it reduced the proliferative capacity of these cell lines and induced apoptosis. CONCLUSIONS This is the first evidence that the PRR has an important role in development of glioma by aberrant activation of the Wnt/β-catenin signaling pathway. This receptor may be both a prognostic marker and a therapeutic target for glioma.
authors.affiliation: Departments of 1 Neurological Surgery and.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kouchi
authors.affiliation: Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shibayama
authors.affiliation: Departments of 1 Neurological Surgery and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.affiliation: Departments of 1 Neurological Surgery and.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Departments of 1 Neurological Surgery and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tamiya
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000737:chemistry / Q000209:etiology*; D005260:Female; D005910:Glioma / Q000737:chemistry / Q000209:etiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000093342:Prorenin Receptor
chemical_list: D011956:Receptors, Cell Surface; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor
keywords: (pro)renin receptor; DAB = 3,3′-diaminobenzidine; FITC = fluorescein isothiocyanate; GBM = glioblastoma; GSC = glioma stem cell; IDH1 = isocitrate dehydrogenase 1; IHC = immunohistochemical; IgG = immunoglobulin G; PBS = phosphate-buffered saline; PI = propidium iodide; PRR = (pro)renin receptor; V-ATPase = vacuolar H+-adenosine triphosphatase; Wnt/β-catenin signaling pathway; glioma; oncology; siRNA = short interfering RNA