Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis

Abstract

Recent studies have implicated the prorenin receptor (PRR) is associated with pancreatic tumorigenesis. We therefore investigated the role of PRR in pancreatic tumorigenesis and assessed whether PRR can serve as a target for imaging diagnosis at early stages of PDAC. Here we show that aberrant expression of PRR in premalignant PanIN lesions, and human PDAC samples, and PDAC cell lines, particularly in Panc-1 cells. Interestingly, PRR expression was positively associated with PDAC progression. Moreover, overexpression of human PRR resulted in increased cell proliferation and decreased apoptosis, while knockdown of human PRR caused decreased cell proliferation and enhanced apoptosis in pancreatic cancer cells. We also observed that overexpression of human PRR enhanced MAPK and PI3K/Akt signaling pathways in PDAC cells, while knockdown of human PRR suppressed both of pathways. The confocal imaging analysis showed that human PRR was highly expressed in Panc-1, ASPC, and Miapaca cells, whereas BXPC-3, and HPAC cells had a significantly lower fluorescent signals. Consistently, the single-photon emission computed tomography (SPET/CT) showed that the uptake of anti-PRR labelled with 125I was higher in Panc-1 and ASPC tumors-bearing mice after 96 hours injection. Importantly, tumors in pancreas of Pdx1-cre; LSL-KrasG12D mice had a significant increased PRR expression and accumulation of radioactivity at 96 h after injection. These data suggest that 125I-anti-PRR can detect the orthotopic tumors in Pdx1-cre; LSL-KrasG12D mice. Therefore, anti-PRR labelled with 125I is a promising radiotracer for imaging diagnosis at early stages of pancreatic cancer.

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

“…Additionally, (P) RR induces reactive oxygen species (ROS) formation, which is independent of Ang II, thus further contributing to MAPK/ERK and PI3K/ AKT/mTOR signal transduction [31]. Consistent with these observations, Arundhathi et al [32] investigated the function of (P) RR in the biological activities of the human pancreatic cancer cell lines Panc-1 and ASPC and found that (P) RR exerts a cancer-promoting effect by enhancing activity in the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. In particular, the data from this group showed that (P) RR overexpression increased the phosphorylation of AKT, ERK1/2, and mammalian target of rapamycin (mTOR) and elevated the level of NF-κB; however, (P) RR silencing downregulated the expression of ERK1/2, AKT and NF-κB [32] in pancreatic cancer cells.…”

“…Consistent with these observations, Arundhathi et al [32] investigated the function of (P) RR in the biological activities of the human pancreatic cancer cell lines Panc-1 and ASPC and found that (P) RR exerts a cancer-promoting effect by enhancing activity in the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. In particular, the data from this group showed that (P) RR overexpression increased the phosphorylation of AKT, ERK1/2, and mammalian target of rapamycin (mTOR) and elevated the level of NF-κB; however, (P) RR silencing downregulated the expression of ERK1/2, AKT and NF-κB [32] in pancreatic cancer cells. Taken together, these findings indicate that (P) RR may contribute to cancer development through the MAPK/ERK and PI3K/AKT/mTOR pathways (Fig.…”

“…Soon after the finding of Shibayama et al, (P) RR was further definitively identified as a potential molecular biomarker for the diagnosis of PDAC by Arundhathi et al [32], who showed that (P) RR mRNA level was positively correlated with TNM stage in human PDAC (patient number = 90, r = 0.688, P < 0.001) [32]. Moreover, anti-(P) RR antibody labelled with iodine-125 ( 125 I) is a promising tracer for imaging diagnosis by singlephoton emission computed tomography (SPECT)/CT in early stages of pancreatic cancer [32]. These findings revealed the essential roles of (P) RR in the molecular diagnosis and severity evaluation of pancreatic cancer.…”

“…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.…”

Cancer stem cell subpopulations in metastatic melanoma to the brain express components of the renin-angiotensin system

“…Renin and its precursor pro-renin bind to pro-renin receptor (PRR) to activate the MAPK signaling cascades. PRR is associated with increased cell proliferation, decreased apoptosis and highly expressed in pancreatic ductal adenocarcinoma [25] . CSC subpopulations in GB [26] and OCSCC of different subsites [27][28][29] express components of RAS.…”