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

Figures

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  Fig. 1. Levels of transcripts of ATP6AP2 ((P) RR encoding gene) in pan-cancers and corresponding normal tissues. Obviously higher ATP6AP2 expression was found widely exists in tumor (T) tissues of various cancers compared to the corresponding normal (N) tissues, 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). T: tumor tissue; N: normal tissue; n: number; ACC: adrenocortical carcinoma; BLCA: bladder urothelial carcinoma; BRCA: breast invasive carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: cholangiocarcinoma; COAD: colon adenocarcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; GBM: glioblastoma multiforme; HNSC: head and neck squamous cell carcinoma; KICH: kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LAML: acute myeloid leukemia; LGG: brain lower grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma;…

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  Fig. 2. Structure of (P)RR. The (pro) renin receptor ((P)RR) is a single transmembrane protein composed of an extracellular domain containing the N-terminal region, a transmembrane domain and a cytoplasmic domain containing the C-terminal region. The full-length (P) RR (FL(P)RR) protein can be cleaved by furin or ADAM19 into a truncated soluble form containing the N-terminal region (soluble (P)RR; s(P)RR) and a truncated transmembrane form containing the C-terminal region (M8–9 fragment)

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  Fig. 3. Schematic diagram of the roles of (P) RR in pathways that contribute to oncogenesis, as well as cancer progression and metastasis. In the Wnt/β-catenin pathway, (P) RR is an important component of the Wnt receptor complex and acts as an adaptor between LRP6 and V-ATPase, thus facilitates the binding of Wnt ligands (Wnts) to the Wnt receptor complex, internalization of the complex as a signalosome and Wnt signaling transduction. Full-length (P) RR or M8–9 fragment also interacts with the V-ATPase, on both plasma and vesicle membranes, thus assists it to generate a proton gradient across the plasma membrane that is crucial for LRP6 phosphorylation and subsequent β-catenin activation, as well as to acidize of the vesicles. On binding with the prorenin/renin, (P) RR further contributes to signal transduction of the PI3K/AKT/mTOR and MAPK/ERK pathways, directly or through the induction of reactive oxygen species (ROS) formation. The binding of prorenin or renin to (P) RR enhances their enzymatic activity, which further facilitates the catalysis of angiotensinogen (AGT) to angiotensin (Ang) I. Then, Ang I will be acted on by angiotensin-converting enzyme (ACE) to produce Ang II, which…

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  Fig. 4. Bioinformatic analysis of the levels of transcripts of ATP6AP2 ((P) RR encoding gene) in various cancers, the possible cancer-related pathways that (P) RR may be involved in, as well as the correlation between (P) RR and corresponding pathway components, based on data in the TCGA and GTEx databases. a Levels of ATP6AP2 transcripts in tumor tissues of pancreatic adenocarcinoma (PAAD) and normal pancreatic tissues. ATP6AP2 expression is significantly higher in tumor tissues than that in normal tissues, moreover, level of ATP6AP2 expression in PAAD is positively correlated with the expression level of CTNNB1 (β-catenin encoding gene) and Wnt target gene AXIN2. b Levels of ATP6AP2 transcripts in tumor tissues of glioblastoma (GBM) and normal matched tissues. ATP6AP2 expression is higher in tumor tissues than that in normal tissues, moreover, level of ATP6AP2 expression in GBM is positively correlated with those of CTNNB1, CCND1 and AGT.c Levels of ATP6AP2 transcripts in tumor tissues of colon adenocarcinoma (COAD) and normal matched tissues. ATP6AP2 expression is higher in tumor tissues than that in normal tissues, moreover, level of ATP6AP2 transcripts in COAD is positively…

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  Fig. 5. (P) RR inhibition attenuates the proliferation of CRC cells in vitro. a and b Treatment with (P) RR antibody for 48 h markedly inhibited the proliferation of DLD-1 (a) and HCT116 (b) cells, as measured by a WST-1 assay. The data are expressed as relative values compared to the vehicle-treated group. N.S.: not significant. **P < 0.01. ***P < 0.001. n = 4