(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 ( IDH1) 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 IDH1 mutation. 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.

The (pro)renin receptor: a novel biomarker and potential therapeutic target for various cancers

“…Based on this evidence, further studies convincingly revealed that (P) RR promotes pancreatic [11], brain [13] and colorectal [10] cancers through the Wnt/β-catenin pathway. Interestingly, research also suggests that (P) RR not only serves as a membrane adaptor protein but also exists in the cytoplasm and positively affects the protein expression level of Wnt2 in glioma cells [13] as well as that of Wnt3 and total LRP6 in CRC cells [10]. In summary, (P) RR is a potential novel onco-protein in Wnt/β-catenin pathway-related oncogenesis (Fig.…”

“…Kouchi et al [13] reported that aberrant (P) RR overexpression was observed in WHO grade II-IV gliomas independent of IDH1 R132H mutation. Moreover, by detecting the tissue samples of 31 patients, they found that the (P) RR expression level was positively correlated with the WHO grade and Ki-67 labelling index (r = 0.8080, P < 0.0001), and negatively associated with the glioma patients' survival times (r = − 0.6499, P < 0.0002) [13]. At the cellular level, (P) RR promoted the proliferation of human glioma cells through the Wnt/β-catenin pathway and inhibited cell apoptosis by attenuating caspase-3 activation [13].…”

“…Moreover, by detecting the tissue samples of 31 patients, they found that the (P) RR expression level was positively correlated with the WHO grade and Ki-67 labelling index (r = 0.8080, P < 0.0001), and negatively associated with the glioma patients' survival times (r = − 0.6499, P < 0.0002) [13]. At the cellular level, (P) RR promoted the proliferation of human glioma cells through the Wnt/β-catenin pathway and inhibited cell apoptosis by attenuating caspase-3 activation [13]. Consistent with these findings, Juillerat-Jeanneret et al [38] also reported a high expression level of (P) RR in human glioblastoma (GBM) (WHO grade IV), the most malignant type of glioma [39], and indicated that attenuation of renin activity in glioblastoma cells could decrease cell proliferation and induce apoptosis.…”

“…The first link between (P) RR and the Wnt/β-catenin pathway was clarified by Cruciat et al [3], who indicated that (P) RR is an important component of the Wnt receptor complex and acts as an adaptor between LRP6 and the V-ATPase independent of the RAS, thus facilitating the binding of Wnts to the Wnt receptor complex [3]. Based on this evidence, further studies convincingly revealed that (P) RR promotes pancreatic [11], brain [13] and colorectal [10] cancers through the Wnt/β-catenin pathway. Interestingly, research also suggests that (P) RR not only serves as a membrane adaptor protein but also exists in the cytoplasm and positively affects the protein expression level of Wnt2 in glioma cells [13] as well as that of Wnt3 and total LRP6 in CRC cells [10].…”

“…Considering these connections, scientists asked the following question "Does (P) RR play a role in cancer development through one or several of these mechanisms?" In the past 5 years, compelling evidence has revealed that (P) RR expression is significantly increased in many human cancers and benign tumors, such as colorectal cancer (CRC) [10], pancreatic ductal adenocarcinoma (PDAC) [11,12], glioma [13], breast carcinoma [14] and aldosterone-producing adenoma [15], in comparison to that in normal tissues. Consistently, we have compared the levels of ATP6AP2 transcripts in tumor tissues of different cancers and corresponding matched normal tissues, based on the data provided in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and found that obviously higher ATP6AP2 expression widely exists in various cancers, especially in the lymphoid neoplasm diffuse large B-cell Lymphoma (DLBC), kidney renal clear cell carcinoma (KIRC), pancreatic adenocarcinoma (PAAD), stomach adenocarcinoma (STAD), testicular germ cell tumors (TGCT) and thymoma (THYM) (Fig.…”