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(Pro)Renin Receptor (PRR) Expression in Renal Tumours

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(Pro)Renin Receptor (PRR) Expression in Renal Tumours diagnostics Article Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal Tumours Jon Danel Solano-Iturri 1,2,3, Enrique Echevarría 4, Miguel Unda 5, Ana Loizaga-Iriarte 5, Amparo Pérez-Fernández 5, Javier C. Angulo 6, José I. López 3,7 and Gorka Larrinaga 3,4,8,* 1 Department of Pathology, Donostia University Hospital, 20014 Donostia/San Sebastian, Spain; [email protected] 2 Department of Medical-Surgical Specialities, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain 3 Biocruces-Bizkaia Health Research Institute, 48903 Barakaldo, Spain; [email protected] 4 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; [email protected] 5 Department of Urology, Basurto University Hospital, University of the Basque Country (UPV/EHU), 48013 Bilbao, Spain; [email protected] (M.U.); [email protected] (A.L.-I.); [email protected] (A.P.-F.) 6 Clinical Department. Faculty of Medical Sciences. European University of Madrid, 28905 Getafe, Spain; [email protected] 7 Department of Pathology, Cruces University Hospital, 48903 Barakaldo, Spain 8 Department of Nursing, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain * Correspondence: [email protected] Citation: Solano-Iturri, J.D.; Abstract: (1) Background: Renal cancer is one of the most frequent malignancies in Western countries, Echevarría, E.; Unda, M.; with an unpredictable clinical outcome, partly due to its high heterogeneity and the scarcity of Loizaga-Iriarte, A.; Pérez-Fernández, reliable biomarkers of tumour progression. (Pro)renin receptor (PRR) is a novel receptor of the A.; Angulo, J.C.; López, J.I.; Larrinaga, renin–angiotensin system (RAS) that has been associated with the development and progression G. Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal of some solid tumours by RAS-dependent and -independent mechanisms. (2) Methods: In this Tumours. Diagnostics 2021, 11, 272. study, we analysed the immunohistochemical expression of PRR at the centre and border in a series https://doi.org/10.3390/ of 83 clear-cell renal cell (CCRCCs), 19 papillary (PRCC) and 7 chromophobe (ChRCC) renal cell diagnostics11020272 carcinomas, and the benign tumour renal oncocytoma (RO, n = 11). (3) Results: PRR is expressed in all the tumour subtypes, with higher mean staining intensity in ChRCCs and ROs. A high expression Academic Editor: of PRR at the tumour centre and at the infiltrative front of CCRCC tissues is significantly associated Michelangelo Fiorentino with high grade, tumour diameter, local invasion and stage, and with high mortality risk by UCLA integrated staging system (UISS) scale. (4) Conclusions: These findings indicate that PRR is associated Received: 7 December 2020 with the development and progression of renal tumours. Its potential as a novel biomarker for RCC Accepted: 8 February 2021 diagnosis/prognosis and as a promising therapeutic target should be taken into account in the future. Published: 10 February 2021 Keywords: renal cell carcinoma; (Pro)renin receptor; renin–angiotensin system; prognosis Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Renal cell carcinoma (RCC) is one of the most common malignancies in Western Coun- tries [1–3]. Nearly half of all cases of RCC are diagnosed in people more than 65 years old [2,4]. The incidence of RCC has been steadily increasing in recent decades, and it is expected that Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. this trend will continue in the future due to the aging population of developed countries [4]. This article is an open access article Clear-cell renal cell carcinoma (CCRCC) is by far the most frequent histological sub- distributed under the terms and type of RCCs, accounting for approximately 75–80% of cases, followed by papillary renal conditions of the Creative Commons cell carcinoma (PRCC) (10–15%) and chromophobe renal cell carcinoma (ChRCC) (5%) [5]. Attribution (CC BY) license (https:// The most commonly accepted origin of CCRCC and PRCC is the proximal convoluted creativecommons.org/licenses/by/ tubule of the nephron. ChRCC shares a common lineage with benign tumor renal on- 4.0/). cocytoma (RO) (5%) and both seem to originate from the intercalated cells of the distal Diagnostics 2021, 11, 272. https://doi.org/10.3390/diagnostics11020272 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 272 2 of 13 nephron [6]. CCRCC is the most aggressive of the RCCs; 30% of patients are metastatic at diagnosis and another 30% of patients with localized disease eventually progress to metastatic disease [5]. A close correlation between some specific genomic signatures and clinical aggressiveness has been detected in recent studies [7], but an easier identification of changes linked to tumour behaviour and clinical outcome is necessary to reach an efficient improvement in the management of CCRCC patients [8]. With this regard, in recent years, novel prognostic biomarkers and therapeutic approaches have been explored. Thus, study of the components of the renin–angiotensin system (RAS) in the context of renal neoplasms and the potential usefulness of drugs that target this peptidergic system has become a promising research field for RCC [9]. The RAS has been traditionally described as a circulating hormone system that reg- ulates cardiovascular and renal function [10]. However, RAS is also locally expressed in several organs and tissues and its paracrine, autocrine, and intracrine signals can regulate long-term biologic processes such as cell growth [9,11]. Thus, the discovery of intrarenal RAS has been crucial to understanding its involvement in non-neoplastic chronic kidney disease [9,12]. For years, angiotensin-converting enzyme (ACE) and angiotensin-II recep- tor (AT1R) inhibitors (ACEis and ARBs) have been widely used in the management of this pathology. The mechanism of action of these drugs is based on the inhibition of the ACE/Ang-II/AT1R axis, which induce cell proliferation, fibrosis and inflammation [9,12]. These phenomena are also part of neoplastic processes and, therefore, the study of RAS and the potential of RAS-targeting therapies has received considerable attention in research into renal cancer [9,11]. Thus, imbalances in components of the intrarenal RAS, such as the up-regulation of AT1Rs in RCC cells and ACE in tumour vessels, have been associated with renal cancer development and progression [13–15]. Besides, the use of the abovementioned RAS inhibitors (RASis) has been associated with better response to current treatments and better outcomes of patients with metastatic RCC [16–18]. The (pro)renin receptor (PRR) is a novel component of the RAS that was first described in the past decade [19] and that is expressed in several organs and tissues, including the kidney [12]. The most well-known function of this protein is the activation of RAS. 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 initi- ation, 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 ac- count 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 (accessed on 5 February 2021)) de- scribed 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. In this study, we analysed PRR immunohistochemical expression in a series of 120 kid- ney tumours. The series included three subtypes of RCC (CCRCC, PRCC and ChRCC) and the benign tumour RO. Both the centre of the tumour and the infiltration front was analysed to test the possible heterogeneity of PRR expression in these tumours. Since CCRCC is the most frequent RCC [5], we analysed the association between PRR and tumour progression and its impact on the prognosis of CCRCC patients. Diagnostics 2021, 11, 272 3 of 13 2. Materials and Methods The present study, including all its experiments, comply with current Spanish and European Union legal regulations. The Basque Biobank for Research (OEHUN) (www. biobancovasco.org (accessed on 5 February 2021)) was the source of samples, and the data from employed patients could possibly be used for research purposes. Each patient signed a specific document which was approved by the Ethical and Scientific Committees of the Basque Country Public Health System (Osakidetza) (PI + CES-BIOEF 2018-04). 2.1. Patients A total of 120 renal tumours, surgically removed at Basurto University Hospital between 2012 and 2016, were collected for the study: 83 CCRCCs (mean age: 61.9 years, 58 males and 25 females), 19 PRCCs (mean age: 53.5 years, 15 males and 4 females), 7 ChRCCs (63.9 years, 6 males and 1 female) and 11 ROs (mean age: 63.4 years, 4 males and 7 females).
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