Targeting the (pro)renin receptor in cancers: from signaling to pathophysiological effects

Abstract

Cancer is a major public health problem, currently affecting hundreds of millions of people worldwide, and its clinical results are unpredictable, partly due to the lack of reliable biomarkers of cancer progression. Recently, it has been reported that (pro)renin receptor (PRR), as a new biomarker, plays an important role in different types of cancer, such as colorectal cancer, breast cancer, glioma, aldosterone-producing adenoma, endometrial cancer, urothelial cancer, and pancreatic ductal adenocarcinoma. In order to comprehensively and systematically understand the relationship and role of PRR with various cancers, this review will summarize the current research on targeting PRR in cancer from signaling to pathophysiological effects, including the correlation between PRR/sPRR expression level and different cancers, potential mechanisms regulated by PRR in the progress of cancers, and PRR in cancer treatment. PRR can be a novel and promising biomarker and potential therapeutic target for diagnosis, treatment, and prognosis in cancer, which is worthy of extensive development and application in clinics.

Introduction

Cancer is a world recognized refractory disease with high mortality, low survival rate and poor prognosis. According to the GLOBOCAN 2020 by the International Agency for Research on Cancer, it is estimated that there were 19.3 million new cancer cases (18.1 million cases, excluding nonmelanoma skin cancer) and nearly 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred worldwide for 36 cancers in 185 countries in 2020 (Sung et al. 2021). Moreover, cancer as an example of premature death worldwide is increasing (Bray et al. 2021). As mentioned above, cancer is a very serious disease for human beings and has become a hot and difficult issue in the medical field. In addition, assuming that the latest incidence rate trend of major cancer types continues to increase, some scholars predict that by 2070, the incidence rate of all cancers will double that of 2020 (Soerjomataram and Bray 2021). Therefore, strengthening cancer research is a very urgent issue.

In recent years, cancer research has made some new progress. The academic community has focused on the relationship between renin–angiotensin system (RAS) and cancer, and has made certain achievements. RAS is an important humoral regulation system of the human body, which includes prorenin, renin, (pro)renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin II (AngII), AngII receptors (AT1R, AT2R), etc. Initially, our understanding of RAS was limited to its effect on regulating water and electrolyte balance and blood pressure stability in the human body (Peach 1977; Ziaja et al. 2021). As the research develops in-depth, researchers have further realized that the role of RAS should be attached great importance in the development and progression of cancer. Wegman-Ostrosky T et al. reported that RAS has been widely associated with the progression of various cancer (Wegman-Ostrosky et al. 2015). Downward J indicated that targeting the RAS pathways might inhibit tumor growth, survival and spread (Downward 2003). Now, emerging research has shown that RAS inhibitors commonly used in hypotension have anti-tumor functions (Lonati and Morganti 2015; Huang et al. 2017; Perini et al. 2020; Afsar et al. 2021).

As an important member of RAS, PRR was initially discovered and successfully cloned in 2002 by Nguyen et al. (2002). PRR, a single transmembrane protein consisting of 350 amino acids, is encoded by the ATP6AP2 gene located on the X chromosome (Nguyen et al. 2002). Therefore, there is another name for it, that is, ATP6AP2 (adenosine triphosphatase H⁺ transporting accessory protein 2). The PRR undergoes intracellular processing to generate three different molecular forms, such as full-length integral transmembrane protein (full-length PRR), soluble PRR (sPRR), and truncated form composed of transmembrane and cytoplasmic domains associated with the vacuolar H⁺-adenosine triphosphatase (V-ATPase) (Cousin et al. 2009; Kinouchi et al. 2010). Interestingly, PRR is expressed ubiquitously in the human body (Nguyen et al. 2002), which was also confirmed by Morimoto S et al. study. Studies have shown that PRR is expressed in the cytoplasm and membrane in almost all organs, as assessed by immunohistochemistry (Morimoto et al. 2021). Now, PRR plays a key role in the normal development and maintenance of vital organs (Ichihara and Yatabe 2019). However, PRR dysfunction is associated with various diseases. For example, activation of PRR leads to cardiovascular diseases, kidney injury, hypertension, diabetes and its complications, and preeclampsia (Tamada et al. 2019; Arthur et al. 2021; Xu et al. 2022). At present, the application of PRR in cancer has also attracted much attention. Many studies have shown that, compared to normal tissues, the expression of PRR is significantly elevated in many cancers, such as colorectal cancer (Wang et al. 2019), breast carcinoma (Ohba et al. 2014), glioma (Kouchi et al. 2017), aldosterone-producing adenoma (Yamamoto et al. 2013), and pancreatic ductal adenocarcinoma (Shibayama et al. 2015). Most importantly, initial PRR overexpression is associated with the early stages of tumorigenesis (Munro et al. 2017; Zhao et al. 2020). Therefore, using PRR for early screening can promote early detection, early diagnosis, and early intervention for cancers, which will be of great practical significance.

In order to comprehensively and systematically understand the relationship and role of PRR with cancer, this review will comprehensively summarize the current research on targeting the PRR in cancers from signaling to pathophysiological effects.

(Pro)renin receptor and cancers: clinical evidences

PRR

In order to express clearly the relationship between PRR and the occurrence and development of tumors in clinical tumor tissue samples, we listed tumor types, detection method, PRR expression levels, and the correlation with cancer-related indicators, and added references, as shown in Table 1.

Table 1.

The expression of PRR in different tumor tissue specimens

Tumor type	Detection method	PRR level	Association with cancer-related indicators	References
Breast cancer (BC)	Immunohistochemistry and western blot analysis	↑	PRR was expressed in 4 types of human breast carcinoma cell lines (MCF-7, T47D, SK- BR-3, and MDA-MD-231)	Ohba et al. (2014)
Lung adenocarcinoma (LA)	Gene expression analysis	↑ (Nonsignificant)	Increased PRR in LA tissue is no statistical significance	Goldstein et al. (2017)
LA	Western blot, immunocytochemistry, and one-step reverse transcription quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA)	↑	The intensity of PRR immunoreactivity was significantly associated with Ki-67 (a proliferation marker)	Ohba et al. (2020)
Colorectal cancer (CRC)	Immunohistochemistry, real-time PCR, western blotting, and immunoprecipitation	↑	Aberrant PRR expression promotes CRC through the Wnt/β-catenin signaling pathway despite constitutive pathway-activating mutations	Wang et al. (2019)
CRC	Immunohistochemistry	↑	PRR expression was gradually augmented along the uninvolved mucosa-adenoma-adenocarcinoma sequence	Beitia et al. (2019)
Glioma	Immunohistochemical analysis and western blotting	↑	PRR expression was higher in human glioblastoma cell lines (U251MG, U87MG, and T98G) than in human astrocytes	Kouchi et al. (2017)
Glioblastoma multiforme (GBM)	3,3-Diaminobenzidine immunohistochemical staining, western blotting, and immunofluorescent immunohistochemical staining	↑	The expression of PRR by the cancer stem cells (CSCs) marker, SOX2 CSCs population	Bradshaw et al. (2016)
Aldosterone-producing adenoma (APA)	Immunocytochemistry, western blot analysis, and real-time RT-PCR	↑	Elevated PRR was found in APAs, particularly in compact cells; PRR protein levels were higher in tumor tissues of APAs than in attached non-neoplastic adrenal tissues of APAs; PRR mRNA levels were increased in APAs	Yamamoto et al. (2013)
APA	Digital-droplet real-time PCR, immunoblotting, confocal, and immunogold electron microscopy	↑	A high PRR-to-porphobilinogen deaminase ratio in both the normal adrenal cortex and APAs; marked expression of the PRR gene and protein was found in HAC15 cells	Recarti et al. (2015)
APA	Real-time RT-qPCR and western blot analysis	↑	PRR colocalized with CYP11B2 (an aldosterone synthase) and expression levels of PRR were positively associated with those of CYP11B2 in APA tissues	Watanabe et al. (2020)
Renal cell carcinoma (RCC)	Immunohistochemistry	↑	PRR is expressed in all the tumor subtypes, including clear-cell renal cell (CCRCCs), papillary (PRCC), chromophobe (ChRCC) renal cell carcinomas, and the benign tumor renal oncocytoma	Solano-Iturri et al. (2021)
RCC	Immunohistochemical staining, western blotting, and RT-qPCR	↑	Expression of PRR in 13 out of 15 renal clear-cell carcinoma samples	Siljee et al. (2021)
Urothelial cancer (UC)	Tissue microarray construction and immunohistochemical staining	↑	PRR was expressed in 77.3% of the primary UC and 70% of positive lymph nodes	Larrinaga et al. (2021)

sPRR

In order to better understand the correlation between the level of sPRR in the serum/plasma of clinical tumor patients and the diagnosis of tumor, the tumor type, detection method, level of sPRR expression, association with cancer-related indicators, and reference are listed in Table 2, respectively.

Table 2.

The expression of sPRR in serum/plasma of different tumor patients

Tumor type	Detection method	sPRR level	Association with cancer-related indicators	References
BC	Western blotting, RT-qPCR, sPRR ELISA, immunostaining and fluorescence, and polysome profiling	↑	The concentration of sPRR was elevated in the plasma of patients with BC and correlated with tumor burden in HER2-enriched cancers	Mohammad et al. (2020)
Epithelial ovarian cancer (EOC)	ELISA	=	No correlations of sPRR levels with neither clinicopathological factors nor prognostic data; the distribution of sPRR in patients and controls was normal	Kreienbring et al. (2016)
Pancreatic ductal adenocarcinoma (PDAC)	ELISA, immunohistochemistry, transient gene transfection by siRNA and plasmid DNA, and western blot analysis	↑	Plasma sPRR levels were significantly (P < 0.0001) higher in patients with PDAC than in healthy matched controls	Shibayama et al. (2015)
CRC	ELISA	=	Plasmatic sPRR levels were not associated with CRC aggressiveness	Beitia et al. (2019)
APA	Real-time RT-qPCR and western blot analysis	=	Serum sPRR concentration failed to show any significant relationship with adrenal PRR expression in APA tissues	Watanabe et al. (2020)

Potential mechanisms regulated by (pro)renin receptor in the progress of cancers

The process of stimulating PRR to promote cancer development is extremely complex. It has lots of possible pathways. According to the current research, there are mainly six signaling pathways. Among these pathways, the association between each pathway, PRR, and cancer is shown in Fig. 1.

Fig. 1.

An overview of signaling of PRR promoting cancers

Wherein, RAS represents renin–angiotensin system, MAPK represents mitogen-activated protein kinase, ERK represents extracellular signal-regulated kinase, PI3K represents phosphatidylinositol 3-kinase, AKT represents protein kinase B, mTOR represents mammalian target of rapamycin, YAP represents yes-associated protein, V-ATPase represents vacuolar H⁺-adenosine triphosphatase.

Activation of PRR by activating Wnt/β-catenin pathway promotes cancer progression

Numerous studies have shown that Wnt/β-catenin pathway plays an important role in the development of various cancers (Bian et al. 2020; Zhang and Wang 2020; Yu et al. 2021). The first relationship between PRR and the Wnt/β-catenin pathway was clarified by Cruciat et al. (2010), which indicated that PRR is an important component of the Wnt receptor complex and acts as an adaptor between low-density lipoprotein receptor-related protein 6 (LRP6) and the V-ATPase independent of the RAS, facilitating the binding of Wnts to the Wnt receptor complex. Based on the above studies, it is further explained that PRR contributes to the progress of cancers by activating the Wnt/β-catenin pathway.

First, by detecting specimens of gliomas from 31 patients, Kouchi M et al. first confirmed that PRR has an important role in the development of glioma through aberrant activation of the Wnt/β-catenin signaling pathway (Kouchi et al. 2017), which showed that PRR expression was much higher in glioblastoma [the most malignant type of glioma (Ohgaki and Kleihues 2009)] than in normal tissue or lower grade glioma, regardless of isocitrate dehydrogenase 1 with mutations involving arginine 132 (IDH1^R132H) mutation (Kouchi et al. 2017). In addition, it was also higher in human glioblastoma cell lines than in human astrocytes. Moreover, it was positively associated with the Ki-67 labeling index, while negatively correlated with the survival time of glioma patients (Kouchi et al. 2017). Interestingly, treatment with PRR siRNA significantly reduced the activating Wnt/β-catenin signaling, the proliferative capacity, and the cell line apoptosis (Kouchi et al. 2017). Second, Shibayama Y et al. first elucidated that PRR is crucial for Wnt/β-catenin-dependent genesis of pancreatic ductal adenocarcinoma (PDAC) (Shibayama et al. 2015), using human plasma and tissue samples from 20 patients with PDAC and 20 healthy volunteer examinees, which demonstrated that plasma sPRR levels were much higher in PDAC patients than in matched controls (P < 0.0001), and PRR was expressed aberrantly in PanIN and PDAC lesions (Shibayama et al. 2015). Nevertheless, inhibiting or decreasing PRR would attenuate the activation of the Wnt/β-catenin signaling pathway, reduce the proliferative ability of PDAC cells in vitro and in vivo, and induce apoptosis of human PDAC cells (Shibayama et al. 2015). Third, Rahman A et al. demonstrated that monoclonal antibodies (mAbs) against human PRR could suppress PDAC cell proliferation by blocking the activation of the Wnt/β-catenin signaling pathway (Rahman et al. 2020). In addition, it is found that four rat anti-PRR mAbs remarkably decreased proliferation in vitro and Wnt/β-catenin signaling attenuated at the same time (Rahman et al. 2020). In addition, systemic administration of the anti-PRR mAbs to nude mice bearing subcutaneous PK-1 xenografts significantly reduced tumor expression of active β-catenin and the proliferation marker Ki-67, and slowed the growth of tumor (Rahman et al. 2020). Forth, after analyzing tissue samples from 60 patients diagnosed with colorectal cancer (CRC), including both cancer lesions and the matched adjacent normal tissues, Wang J et al. suggested that aberrant PRR expression promotes CRC through the Wnt/β-catenin signaling pathway despite constitutive pathway-activating mutations (Wang et al. 2019), which showed that PRR expression was higher in CRC tissues and cells than in normal samples, and patients with strong PRR expression took more proportion in groups with poorly differentiated, advanced, and rapidly progressing cancers (Wang et al. 2019). In addition, PRR silencing attenuated the activation of Wnt/β-catenin signaling pathway in CRC cells and impaired CRC cells proliferation in vitro and vivo (Wang et al. 2019). In contrast, PRR overexpression can enhance the pathway and proliferation of normal cells (Wang et al. 2019). Fifth, Zhao et al. (2020) utilized data from public datasets and conducted in vitro experiments to explore the potential functions of PRR in breast cancer (BC). In the UALCAN and ONCOMINE analysis, the results indicated that PRR transcript level was much higher in BC tissues than in normal tissues, and PRR was consistently upregulated in BC regardless of age, histologic subtype, and menopause status (Zhao et al. 2020). In GOBO datasets, the luminal type of BC was examined with the highest expression level in BC cell lines (Zhao et al. 2020). Using the cell counting Kit-8 and transwell assays, it is found that PRR knockdown inhibited MCF-7 BC cell invasion and migration ability, which indicated that PRR was capable of promoting BC progression (Zhao et al. 2020). The functional enrichment analysis suggested that PRR regulates several cancer-related pathways, especially the Wnt/β-catenin signaling pathway (Zhao et al. 2020). Sixth, van Schaijik et al. (2019) reported that renin increased infantile hemangioma (IH) cells proliferation through activating the Wnt signaling pathway by PRR, which may contribute to cell accumulation in IH during the proliferative phase of the tumor. On the one hand, NanoString analysis and IHC staining confirmed the transcriptional and translational expression of PRR, which was localized to the non-endothelial and endothelial in IH cell populations (van Schaijik et al. 2019). On the other hand, the MTT assay demonstrated an increased number of viable IH cells by administration of renin (van Schaijik et al. 2019). However, the effect of the Wnt receptor blocker dickkopf-1 was negated (van Schaijik et al. 2019). Lastly, in 2021, Larrinaga G et al. first described PRR and its prognostic role in invasive urothelial cancer (UC) of the bladder (Larrinaga et al. 2021). The immunostaining showed that PRR was expressed in 77.3% of the primary tumors and 70% of invaded lymph nodes, and always restricted to epithelial tumor cells (Larrinaga et al. 2021). The potential tumorigenic effect of PRR observed in the immunohistochemical analysis can be explained by the fact that the overexpression of PRR may trigger an over-activation of the Wnt signaling pathway, leading to the self-renewal of urothelial cancer stem cells and progression of UC and chemoresistance (Larrinaga et al. 2021).

Activation of PRR contributes to the progress of cancers via the activation of RAS

As described in the introduction, PRR is a critical member of RAS. Binding to prorenin or renin, it activates RAS. Once RAS is activated, it enhances the enzymatic activity of these molecules, which further facilitates the catalysis of angiotensinogen (AGT) to angiotensin I (Ang I). Then, Ang I is acted on ACE to produce Ang II, which triggers Ang II receptor-mediated signal transduction, leading to elevate tissue RAS activity (Ichihara et al. 2009).

With respect to RAS, it can perform its normal function in the human body under physiological conditions. For example, previous studies have indicated that healthy human endometrium from women of reproductive age expresses all components of the RAS (Li and Ahmed 1997), including PRR, which is also expressed in the endometrium during pregnancy (Pringle et al. 2011). It is responsible for stimulating angiogenesis, cell proliferation, and migration in the normal endometrium. However, if it is activated abnormally, it will promote abnormal cell growth. Studies have reported that RAS affects cancer cell proliferation, apoptosis inhibition, migration, invasion, and metastasis (George et al. 2010). More importantly, increased RAS activation through both Ang II/AT1R and prorenin/PRR promotes cancer development by stimulating the downstream factors of oncogenesis (Delforce et al. 2017).

In fact, several studies have revealed that PRR plays a role in cancers through the RAS. In endometrial cancer (EC), evidence suggests that local RAS in the female reproductive system is involved in the progression of EC (Li et al. 2020). Delforce SJ et al. measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded cancerous endometrium and their adjacent non-cancerous endometrium to confirm that a dysfunctional RAS aids the growth and spread of EC (Delforce et al. 2017). The results showed that all components of the RAS were expressed in most tumors and adjacent non-cancerous endometrium (Delforce et al. 2017). In addition, transforming growth factor beta-1 (TGF β-1), strongly correlated with the expression of endometrial RAS, was also elevated in EC tissue (P = 0.001) (Delforce et al. 2017). Furthermore, mRNA levels of PRR, AT1R, ACE, and ACE2 were higher in tumor tissue than in adjacent non-cancerous endometrium (P = 0.023, 0.008, 0.004, and 0.046, respectively) (Delforce et al. 2017). These data suggested that PRR may excessively activate the function of RAS, thereby promoting the growth and spread of EC (Delforce et al. 2017). Notably, other experiments by Lumbers et al. demonstrated that the increase in prorenin secretion can stimulate vascular endothelial growth factor (VEGF) expression, since PRR is abundant, activating RAS in human endometrium with decidualisation by stimulating VEGF expression and secretion may be critical in establishing an adequate blood supply (Lumbers et al. 2015). According to the findings of Lumbers et al., it is further indicated that the activation of endometrial PRR to establish an abundant blood supply is very important for the development of cancer (Wang et al. 2020).

Activation of PRR promotes the progress of cancers by stimulating the MAPK/ERK and PI3K/AKT/mTOR pathways

PRR was initially investigated as part of the RAS for its role in the activation of mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway through the binding of RAS to its ligands renin and/or prorenin (Nguyen et al. 2002). Recently, studies have shown that MAPK/ERK signaling pathway regulates cancer cell proliferation, apoptosis, inflammation, angiogenesis, metastasis, and drug resistance (Pashirzad et al. 2021). Remarkably, ERK1/2 activated by MAPK is to increase cell proliferation and upregulate profibrotic factors through the TGF-β1 (Zhang et al. 2008; Huang and Siragy 2009), which mediates the pathogenesis and metastasis of cancer. In addition, mutations and up-regulation of components of the MAPK/ERK signaling pathway, as well as over-activation of this critical signaling pathway, are frequently observed in cancers. For instance, Xie et al. investigated the effect of MAPK in 20 ovarian cancer tissues, and the immunohistochemical investigation of these tissues showed that MAPK levels were significantly elevated in the drug-resistant tumors (Xie et al. 2014). Besides, PRR induces the formation of reactive oxygen species (ROS), which is independent of Ang II, thereby further promoting the MAPK/ERK and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) signal transduction (Peng et al. 2013). The PI3K/AKT/mTOR is a signaling pathway that is involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair (Miricescu et al. 2020). The Components of this pathway have been extensively studied and found to be ubiquitously activated in human cancer (Alzahrani 2019).

To further illustrate that PRR may cause cancer development through the MAPK/ERK and PI3K/AKT/mTOR pathways, some researchers are conducting research. For example, anti-PRR labeled with ¹²⁵I was a promising radiotracer for imaging diagnosis by single-photon emission computed tomography (SPECT)/CT at early stages of PDAC by Arundhathi A et al. which showed that aberrant expression of PRR in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, human PDAC samples, and PDAC cell lines, particularly in Panc-1 cells (Arundhathi et al. 2016). In their study, PRR overexpression contributed to cell proliferation upgrading and apoptosis decreasing, while PRR knockdown caused cell proliferation to decrease and apoptosis to be enhanced in PDAC cells (Arundhathi et al. 2016). Furthermore, PRR overexpression enhanced MAPK and PI3K/AKT signaling pathways in PDAC cells, while PRR knockdown suppressed both pathways (Arundhathi et al. 2016). Most importantly, PRR expression and radioactivity ¹²⁵I accumulation were increased in PDAC-bearing mice at 96 h after injection (Arundhathi et al. 2016). Taken together, these data revealed that PRR may promote the development of PDAC through both pathways. Another study by Ohba et al. (2014) showed for the first time that PRR was expressed in human BC tissues in 69 clinical cases. The immunohistochemistry showed that PRR immunoreactivity was detected in the BC cells of 50 cases, accounting for about 72% of the total amount (Ohba et al. 2014). The analysis of the correlation between PRR immunoreactivity and clinicopathological parameters showed that the number of PRR positive cases was much higher in Ki-67 (a cell proliferation marker) ≥ 10% group than in Ki-67 < 10% group (Ohba et al. 2014). PRR silencing inhibited the proliferation of both MCF-7 (estrogen receptor (ER)α-positive) and SK-BR-3 (ERα-negative) breast cancer cells (Ohba et al. 2014). In contrast, prorenin stimulated ERK1/2 phosphorylation dose- dependently in MCF-7 and SK-BR-3 cells (Ohba et al. 2014). These findings indicate that PRR may stimulate the proliferation of breast carcinoma cells through phosphorylation of ERK1/2 (Ohba et al. 2014).

Activation of PRR promotes the progress of cancers by stimulating YAP pathway

Yes-associated protein (YAP) is the main downstream effector of the Hippo signaling pathway (Guo and Teng 2015). The deactivation of the Hippo pathway and up-regulation of YAP have been reported to occur frequently in many human cancers (Guo and Teng 2015). YAP is a highly related transcriptional regulator that is essential for cancer initiation or growth in most solid tumors (Zanconato et al. 2016, 2019). Its activation induces attributes, proliferation, chemoresistance and metastasis of cancer stem cells (Zanconato et al. 2016).

As for PRR, it is known that the activation of PRR can promote the progression of most cancers, as shown in Table 1. However, the relationship between PRR, YAP pathway and cancer has not been reported. Based on the mentioned above, it can be speculated that PRR activation may promote cancer progression by stimulating the YAP pathway. In order to test the hypothesis, further research and exploration are needed.

PRR controls cancer development by acting as a V-ATPase

One fragment of PRR is known as ATP6AP2 associated with vacuolar V-ATPase which is a multi-subunit proton pump involved in diverse and fundamental aspects of cellular physiology, including receptor-mediated endocytosis and recycling, processing of proteins and signaling molecules, membrane sorting and trafficking, and activation of lysosomal/autophagosomal enzymes (Kinouchi 2011; Bernhard et al. 2012). Meanwhile, the V-ATPase complex is an ATP-driven proton pump that acidifies intracellular compartments, including endosomes and lysosomes, and it is essential for a wide range of oncogenic signaling pathways (Sun-Wada and Wada 2015). Obviously, V-ATPases participate in the development of cancers. Indeed, Sennoune SR et al. reported that V-ATPase was located at the plasma membrane of human breast carcinoma cells, particularly prominent in the highly metastatic cells (Sennoune et al. 2004). Another finding by Cotter et al. also reported that the expression of some V-ATPase subunits was increased in tumor cells (Cotter et al. 2016). In addition, Murakami T et al. proved that the expression of V-ATPases was elevated in cisplatin-resistant cell lines derived from human epidermoid, prostate and ovarian cancer cells (Murakami et al. 2001). Moreover, V-ATPases are functionally expressed in plasma membranes of certain human tumor cells, such as HL-60 human promyelocytic leukemia cells and leiomyosarcoma cells (Marquardt and Center 1991; Martinez-Zaguilan et al. 1993).

Recently, PRR was found to be an adaptor protein between Wnt receptor complex and H(+)-ATPase (V-ATPase) (Cruciat et al. 2010). Nguyen G pointed out that V-ATPase generates a proton gradient on the vesicle membrane through its interaction with PRR, which is crucial for LRP6 phosphorylation and subsequent β-catenin activation (Nguyen 2011). These discussions suggest that PRR controls cancer development by acting as a V-ATPase. Of course, there are some research findings that have reconfirmed this view. For example, Mohammad AH et al. showed that V-ATPase associated PRR was upregulated in prostate cancer after PTEN deletion, in which PRR expression was found to be necessary to promote prostate cancer cells by maintaining V-ATPase function. Lower levels of PRR resulted in attenuated V-ATPase activity and decreased prostate cancer cell proliferation (Mohammad et al. 2019). Ohba K et al. demonstrated that PRR down-regulation inhibited autophagy, possibly by reducing V-ATPase activity and impairing lysosomal acidification, as well as reducing cell proliferation and LA cell migration (Ohba et al. 2020). Kashio-Yokota Y. et al. found that the PRR suppression may result in reducing V-ATPase activity and decreasing the proliferation of cancer cells by neutralizing extracellular pH, and the impairment of lysosomal acidification and autophagy (Kashio-Yokota et al. 2021). Furthermore, to determine the role of elevated PRR on V-ATPase activity, a study by Mohammad AH et al. knocked down PRR in scrambled and PTENsh MCF-7 cells and measured V-ATPase activity (Mohammad et al. 2020). Interestingly, PRR knockdown reversed the increase in V-ATPase activity observed after PTEN knockdown (Mohammad et al. 2020). These observations demonstrated that V-ATPase complex activity is mediated by the expression of PRR. They further proved that the elevation of V-ATPase activity after PTEN deletion was required for the enhancement of oncogenic signaling in BC (Mohammad et al. 2020).

PRR may promote the progress of cancers by promoting neovascularization

In 2002, Judah Folkman initiated the concept of “Angiogenesis” (Folkman 2002). Angiogenesis or neovascularization refers to the formation of new blood vessels from pre-existing vessels, which is essential for the progression and maintenance of diseases involving cellular metabolism and tissue expansion, especially cancer (Folkman 2002; Thairu et al. 2011). Neovascularization is necessary for the growth and metastasis of invasive tumor (Folkman 2002; Li et al. 2019), which are dynamic and complex processes involving multiple mechanisms and are regulated by various molecules (Li et al. 2019). Tumor neovascularization predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis (Lin 2020). Tumor neovascularization significantly impacted hematogenous and lymphogenous metastases in cancers. Therefore, inhibiting neovascularization has been used as a therapeutic target for tumors for decades.

The PRR has been implicated in the development of cancers. The role of PRR in cancer has attracted many researchers to explore and has made some advances in these years. However, there are few studies on whether PRR promotes cancer development by promoting neovascularization. Martin JH et al. investigated the role of PRR in endometrial cancer cell growth and showed that the expression of PRR was expressed overly in human endometrial cancer tissues compared with adjacent unaffected endometrium (Martin et al. 2022), the result of which did not surprise them at all. They explained that PRR promotes angiogenesis, proliferation and migration, all of which are involved in tumourigenesis, the development and progression of endometrial cancer (Martin et al. 2022). Thus, PRR may promote the progress of cancers by promoting neovascularization.

Targeting (pro)renin receptor in cancer treatment

HRP and PRO20

Handle region peptide (HRP) is a PRR blocker and a peptide consisting of 10 amino acids from the prorenin prosegment (Muller et al. 2008). PRO20 is a decoy peptide consisting of the first 20 amino acid residues of the prorenin prosegment used as a PRR antagonist to block the binding of prorenin to the PRR (Qin et al. 2021). If it does not bind to prorenin, it will not activate RAS and further promote the progress of cancers, as described in Activation of PRR contributes to the progress of cancers via the activation of RAS.

Above all, both HRP and PRO20 can block PRR, so they will have anti-cancer effects. Hence, it is meaningful to apply them to cancer treatment. Unfortunately, there are no relevant reports on the treatment of cancer by HRP and PRO20. However, our research group convinces that HRP and PRO20 may be promising therapeutic targets for cancer treatment, which is worthy of further research and exploration.

Anti-PRR antibodies

Anti-PRR antibodies are another idea for targeting PRR in cancer therapy. In these years, the application of anti-PRR antibodies has been studied. These results are satisfying. For example, Rahman A et al. described the development and effects of neutralizing mAbs raised against residues 200–213 in the extracellular domain of PRR (Rahman et al. 2020), which showed that treatment with PRR mAbs markedly suppressed the proliferation of two human PDAC cell lines in vitro, and systemic administration significantly blunted the growth of PK-1 xenografts in athymic mice (Rahman et al. 2020). Thus, anti-PRR antibodies may be a potential novel therapy for PDAC. Another study by Wang J et al. revealed the promising potential anti-colon cancer effect of anti-PRR antibodies (Wang et al. 2020). In their study, the water-soluble tetrazolium salt-1 (WST-1) assay indicated that cell proliferation continued to decline by blocking specific amino acid regions on the extracellular domain of PRR with the mAb (Wang et al. 2020). Compared with treatment with human IgG, treatment with anti-PRR antibody significantly decreased the proliferation of both human CRC DLD-1 and HCT116 cells (Wang et al. 2020).

Conclusion

This review discusses the relationship between PRR and different types of cancer in recent years, from signaling to pathophysiological effects. First, the relationship between PRR expression and tumor development in clinical tumor tissue samples, and the correlation between the sPRR level in serum/plasma of clinical tumor patients and the tumor diagnosis were discussed. Then, the potential mechanisms of regulation in the cancer progression is explained in detail and in depth, which includes six aspects: (1) activating the Wnt/β-catenin pathway, (2) activating RAS, (3) stimulating the MAPK/ERK and PI3K/AKT/mTOR pathways, (4) stimulating the YAP pathway, (5) acting as a V-ATPase, and (6) promoting neovascularization. Finally, targeting PRR in cancer therapy, includes HRP, PRO20, and anti-PRR antibodies. Studies have indicated that PRR can be a novel and promising biomarker and potential therapeutic target for diagnosis, treatment, and prognosis in cancer. Of course, these studies also have some limitations and shortcomings. First, in addition to these types of cancers mentioned in this review, the association and role of PRR with other cancers have not been reported, whether in animal experiments or clinical research. Second, some mechanisms of PRR promoting cancers are less studied, especially the YAP pathway. Third, regarding the role of PRR in a certain cancer, a large-sample and multi-center approach can be conducted to further promote the promotion and application of PRR in the clinic.

Abbreviations

ACE

Angiotensin-converting enzyme

AGT

Angiotensinogen

Ang I

Angiotensin I

Ang II

Angiotensin II

APA

Aldosterone-producing adenoma

AT1R

Type 1 Ang II receptor

AT2R

Type 2 Ang II receptor

ATP6AP2

Adenosine triphosphatase H⁺ transporting accessory protein 2

BC

Breast cancer

CRC

Colorectal cancer

ELISA

Enzyme-linked immunosorbent assay

EOC

Epithelial ovarian cancer

ERK

Extracellular signal-regulated kinase

GBM

Glioblastoma multiforme

HRP

Handle region peptide

IDH1^R132H

Isocitrate dehydrogenase 1 with mutations involving arginine 132

IH

Infantile hemangioma

LA

Lung adenocarcinoma

LRP6

Low-density lipoprotein receptor-related protein 6

mAbs

Monoclonal antibodies

MAPK

Mitogen-activated protein kinase

mTOR

Mammalian target of rapamycin

PanIN

Premalignant pancreatic intraepithelial neoplasia

PDAC

Pancreatic ductal adenocarcinoma

PI3K

Phosphatidylinositol 3-kinase

PRR

(Pro)renin receptor

RAS

Renin–angiotensin system

RCC

Renal cell carcinoma

ROS

Reactive oxygen species

RT-qPCR

Reverse transcription quantitative polymerase chain reaction

SPECT

Single-photon emission computed tomography

sPRR

Soluble (pro)renin receptor

TGF β-1

Transforming growth factor beta-1

UC

Urothelial cancer

V-ATPase

Vacuolar H⁺-adenosine triphosphatase

VEGF

Vascular endothelial growth factor

WST-1

Water-soluble tetrazolium salt-1

YAP

Yes-associated protein

Author contributions

All the authors contributed to the current study. XOY wrote the manuscript; CMX supervised the project and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82160051 and 81660819), Jiangxi “Double thousand plan” (No. jxsq2020101074), Jiangxi Provincial Natural Science Foundation (No. 20212BAB216005), the PhD Start-up Research Fund in Jiangxi University of Chinese Medicine (No. 2020BSZR009), Jiangxi Key Laboratory grant in Science and Technology Department of Jiangxi Province (No. 20202BCD42014), and Key Program for Science and Technology Projects of Jiangxi Province of China (No. GJJ201208).

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent to publish

Not applicable.