(Pro)renin receptor is crucial for Wnt/β-catenin-dependent genesis of pancreatic ductal adenocarcinoma.
Although Wnt/β-catenin signaling is known to be aberrantly activated in PDAC, mutations of CTNNB1, APC or other pathway components are rare in this tumor type, suggesting alternative mechanisms for Wnt/β-catenin activation. Recent studies have implicated the (pro)renin receptor ((P)RR) is related to the Wnt/β-catenin signaling pathway. We therefore investigated the possible role of (P)RR in pancreatic carcinogenesis. Plasma s(P)RR levels were significantly (P < 0.0001) higher in patients with PDAC than in healthy matched controls. We also identified aberrant expression of (P)RR in premalignant PanIN and PDAC lesions and all the PDAC cell lines examined. Inhibiting (P)RR with an siRNA attenuated activation of Wnt/β-catenin signaling pathway and reduced the proliferative ability of PDAC cells in vitro and the growth of engrafted tumors in vivo. Loss of (P)RR induced apoptosis of human PDAC cells. This is the first demonstration that (P)RR may be profoundly involved in ductal tumorigenesis in the pancreas.
Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Yuki
Y
Shibayama
Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Takayuki
T
Fujimori
Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Centre National de la Recherche Scientifique (CNRS) Unités Mixtes de Recherche (UMR) 7241, Institut National de la Santé et de la Recherche Médicale (INSERM) U1050, Paris 75005, France.
Genevieve
G
Nguyen
Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Centre National de la Recherche Scientifique (CNRS) Unités Mixtes de Recherche (UMR) 7241, Institut National de la Santé et de la Recherche Médicale (INSERM) U1050, Paris 75005, France.
Takuo
T
Hirose
Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Sendai 980-8577, Japan.
Kazuhito
K
Totsune
Department of Hypertension and Endocrinology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
Atsuhiro
A
Ichihara
Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Kento
K
Kitada
Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Daisuke
D
Nakano
Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Hiroyuki
H
Kobori
Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Masakazu
M
Kohno
Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Tsutomu
T
Masaki
Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Yasuyuki
Y
Suzuki
1] Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan [2] Division of Refractory Cancer Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Shinichi
S
Yachida
Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Akira
A
Nishiyama
D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000097:blood*; D025262:Vacuolar Proton-Translocating ATPases / Q000097:blood*; D060449:Wnt Signaling Pathway; D000093342:Prorenin Receptor
D011956:Receptors, Cell Surface; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor