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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States and the median overall 5-year survival rate is less than 5% due to the aggressive nature of pancreatic cancer [1,2,3]
We found that the mRNA levels of prorenin receptor (PRR) were significantly increased in the five human pancreatic cancer cell lines (Panc-1, ASPC, BXPC-3, HPAC, and MIAPaCa-2) than that of human normal pancreatic ductal epithelial cells (HPDE) cells (Figure 1B)
These data was consistent with protein levels of PRR that was higher in Panc-1, MIAPaCa-2, HPAC, BXPC-3, and ASPC than that of HPDE (Figure 1C)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States and the median overall 5-year survival rate is less than 5% due to the aggressive nature of pancreatic cancer [1,2,3]. PRR is mainly expressed in kidney, heart, pancreas, brain, blood vessels, macrophages, T cells and granulocytes [8,9,10]. The PRR is highly expressed in the metastasis of pancreatic cancer through activation of the Wnt/β-catenin signaling pathway, while PRR knockdown by siRNA triggers apoptosis of PDAC, and causes decreased cell proliferation [13].
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