(Pro)renin receptor promotes colorectal cancer through the Wnt/beta-catenin signalling pathway despite constitutive pathway component mutations

Abstract

BackgroundAlthough constitutive activating mutations in the Wnt/β-catenin signalling pathway are important for colorectal cancer development, canonical signalling through Wnt ligands is essential for β-catenin activation. Here, we investigated the role of (pro)renin receptor ((P)RR), a component of the Wnt receptor complex, in the pathogenesis of colorectal cancer.Methods(P)RR silencing was performed in human colorectal cancer cells containing constitutive activating mutations in the Wnt/β-catenin pathway. (P)RR overexpression was induced in normal colon epithelial cells. Protein and mRNA levels of pathway components were detected, and Wnt signalling activity was measured using a β-catenin reporter. Cell proliferative activity and apoptosis were evaluated using WST-1 assay and flow cytometry. Xenografts were induced in nude mice.Results(P)RR expression was greater in colorectal cancer tissues and cells than in normal colorectal samples. Patients with strong (P)RR expression took more proportion in groups with poorly-differentiated, advanced and rapidly-progressing cancers. (P)RR silencing attenuated the pathway in colorectal cancer cells, impaired their proliferation in vitro and vivo. (P)RR overexpression enhanced the pathway and proliferation of normal colon epithelial cells.ConclusionsAberrant (P)RR expression promotes colorectal cancer through the Wnt/β-catenin signalling pathway despite constitutive pathway-activating mutations. (P)RR is a potential diagnostic and therapeutic target for colorectal cancer.

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.…”

“…The above findings suggest that Wnts can further stimulate a mutated Wnt/ β-catenin pathway with constitutively hyperactivated signaling activity. More recently, we have published the data that demonstrated, for the first time, that (P) RR promotes CRC through the Wnt/β-catenin pathway despite constitutive activating mutations in APC or β-catenin [10]. To further verify those results in big data, we have compared the levels of ATP6AP2 transcripts in tumor tissues of colon adenocarcinoma (COAD) and normal matched tissues, based on the data in the TCGA and GTEx databases.…”

“…4c). In addition, we further summarized the relationship between (P) RR expression levels, detected through the immunohistochemistry and evaluated by 3 independent pathologists as previously described [10], in primary tumor tissues and a series of detailed pathophysiological characteristics of 60 CRC patients (information collected from Kagawa University Hospital, Japan). We found that higher (P) RR expression levels are more commonly observed in patients with the following characteristics: male sex, early age at onset, poorly differentiated lesions, advanced cancer stage, distant metastasis, rapid progression, lower 5-year survival rate and shorter recurrence-free survival time (Table 1).…”

“…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.…”