title: Reg proteins promote acinar-to-ductal metaplasia and act as novel diagnostic and prognostic markers in pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) are both precursor lesions that lead to the development of PDAC. Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries. The aim of this study was to establish a role for Reg proteins in the development of PDAC and their clinical value as biomarkers. We found that Reg1A and Reg3A/G were highly expressed in the ADM tissues by immunohistochemistry. In the 3-dimensional culture of mouse acinar cells, Reg3A promoted ADM formation with concurrent activation of mitogen-acitvated protein kinase. Upregulation of Reg1A and Reg1B levels was observed as benign ductal epithelium progresses from PanIN to invasive PDAC. Patients with PDAC showed significantly higher serum levels of Reg1A and Reg1B than matching healthy subjects. These results were further validated by the quantification of Reg 1A and 1B mRNA levels in the microdissected tissues (22- and 6-fold increases vs. non-tumor tissues). Interestingly, patients with higher levels of Reg1A and 1B exhibited improved survival rate than those with lower levels. Furthermore, tissue expressions of Reg1A, Reg1B, and Reg4 could differentiate metastatic PDAC in the liver from intrahepatic cholangiocarcinoma with 92% sensitivity and 95% specificity. Overall, our results demonstrate the upregulation of Reg proteins during PDAC development. If validated in larger scale, Reg1A and Reg1B could become clinical markers for detecting early stages of PDAC, monitoring therapeutic response, and/or predicting patient's prognosis.
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
authors: Qing
authors: Q
authors: Li
authors: Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China.
authors: Hao
authors: H
authors: Wang
authors: Department of Surgery, McGill University Health Centre, Montreal, QC, Canada.|Quebec Pancreas Cancer Study, McGill University Health Centre, Montreal, QC, Canada.
authors: George
authors: G
authors: Zogopoulos
authors: Department of Pathology, McGill University Health Centre, Montreal, QC, Canada.
authors: Qin
authors: Q
authors: Shao
authors: Department of Pathology, You An Hospital, Capital Medical University, Beijing, China.
authors: Kun
authors: K
authors: Dong
authors: Department of Pathology, You An Hospital, Capital Medical University, Beijing, China.
authors: Fudong
authors: F
authors: Lv
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
authors: Karam
authors: K
authors: Nwilati
authors: Department of Pathology, University of Calgary, Calgary, AB, Canada.
authors: Xian-Yong
authors: XY
authors: Gui
authors: Quebec Pancreas Cancer Study, McGill University Health Centre, Montreal, QC, Canada.
authors: Adeline
authors: A
authors: Cuggia
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
authors: Jun-Li
authors: JL
authors: Liu
authors: Department of Pathology, McGill University Health Centre, Montreal, QC, Canada.
authors: Zu-Hua
authors: ZH
authors: Gao
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D003937:Diagnosis, Differential; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051847:Lithostathine / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D051847:Lithostathine; D000073718:Pancreatitis-Associated Proteins; C497617:REG1A protein, human; C497618:REG1B protein, human; C000612141:REG3A protein, human; C494437:REG3G protein, human; C428528:REG4 protein, human
keywords: acinar-to-ductal metaplasia; cholangiocarcinoma; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; Reg family proteins