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

Abstract

Background: The (pro) renin receptor ((P)RR) plays important roles in various pathways, such as the Wnt/β-catenin, renin-angiotensin system (RAS), MAPK/ERK and PI3K/AKT/mTOR pathways, that are involved in a wide range of physiological and pathological processes incorporating the tumorigenesis. However, our knowledge about (P) RR was mostly limited to its roles in cardiovascular and renal physiological functions and diseases. In the past 5 years, however, compelling evidence has revealed that (P) RR is aberrantly expressed in and contributes to the development of various cancers by different means. For instance, (P) RR was recently demonstrated to induce the oncogenesis of pancreatic, colorectal and brain cancers via the Wnt signaling, while promote the endometrial cancer and glioblastoma through the RAS. Methods: Combining with the deep analysis of big data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, this review updates and summarizes the recent studies about the newly recognized roles of (P) RR in the pathophysiological processes of cancer development and its detailed functions through related pathways, as well as the novel research progress of (P) RR in related fields including the development and application of soluble (P) RR detection kit and monoclonal (P) RR antibody. Results: This review provides an overview of the essential roles of (P) RR in the tumorigenesis and progression of various cancers and offers a translational outlook for the future research and clinical practices. Conclusion: (P) RR in the tumor tissues and/or body fluids of patients may be a novel and promising biomarker and potential therapeutic target for diagnosis, treatment and prognosis prediction in various cancers.

Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal Tumours

“…Besides this, the staining of this protein was more intense in CCRCCs with high histological grade, diameter and stage, and was associated with a higher risk of mortality according to the UISS scale. These results agree with studies carried out in other solid tumours, showing the potential of PRR as a biomarker of worse prognosis [21]. Furthermore, we reported recently that PRR staining was not very different in the centre and front of colorectal cancers [27], a result that was repeated in RCCs.…”

“…The mechanism by which PRR upregulation could affect the progression of kidney could be RAS-dependent or -independent [12,21]. It is known that under pathologic conditions, PRR induces AngII/AT1R-dependent secretion of pro-fibrotic and pro-inflammatory cytokines in cells from the proximal and distal nephron [12].…”

“…PRR binds renin enzyme and its inactive precursor prorenin, which enhances their activity and the production of angiotensin I, which is converted by ACE in angiotensin II, leading to AT1R-mediated signals. PRR is also activated after the binding of (pro)renin, which leads to PI3/AKT/mTOR and MAPK/ERK signalling [12,20,21]. Besides this, PRR is considered to function as a hinge molecule between the Wnt receptor and the V-ATPase that mediates Wnt receptor internalization and the subsequent Wnt/β-catenin signaling [12,21].…”

“…These RAS-dependent and -independent signalling pathways contribute to cancer initiation, so it was expected that PRR expression could be altered in tumour tissues [21]. Thus, increases in this protein have been described in pancreatic ductal adenocarcinoma [22,23], glioma [24,25], colorectal [26,27], breast [28] and endometrial cancer [29].…”

“…Taking into account that PRR exerts important functions in kidney physiology and that it takes part in inflammatory and fibrotic processes of this organ [12], changes in this protein can also be expected in kidney neoplasms. The Cancer Genome Atlas (TCGA) described high mRNA levels of PRR in RCCs when compared with the uninvolved part of the kidney [21]. The Human Protein Atlas (https://www.proteinatlas.org) described PRR staining in RCCs; however, the analyses were limited to only 11 cases, which was insufficient to understand the association between this protein and tumour progression.…”