Reg proteins promote acinar-to-ductal metaplasia and act as novel diagnostic and prognostic markers in pancreatic ductal adenocarcinoma

Abstract

// Qing Li 1, * , Hao Wang 2, * , George Zogopoulos 3, 4 , Qin Shao 5 , Kun Dong 6 , Fudong Lv 6 , Karam Nwilati 1 , Xian-yong Gui 7 , Adeline Cuggia 4 , Jun-Li Liu 1 , Zu-hua Gao 5 1 Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada 2 Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China 3 Department of Surgery, McGill University Health Centre, Montreal, QC, Canada 4 Quebec Pancreas Cancer Study, McGill University Health Centre, Montreal, QC, Canada 5 Department of Pathology, McGill University Health Centre, Montreal, QC, Canada 6 Department of Pathology, You An Hospital, Capital Medical University, Beijing, China 7 Department of Pathology, University of Calgary, Calgary, AB, Canada * These authors have contributed equally Correspondence to: Zu-hua Gao, email: zu-hua.gao@mcgill.ca Jun-Li Liu, email: jun-li.liu@mcgill.ca Keywords: Reg family proteins, pancreatic ductal adenocarcinoma, acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia, cholangiocarcinoma Received: March 01, 2016     Accepted: October 13, 2016     Published: October 24, 2016 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.