Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer?

• Published in: Pancreas Vol. 51; no. 9; p. 1118
• Main Authors: Huber, Matthew A, Nadella, Sandeep, Cao, Hong, Kallakury, Bhaskar, Tucker, Robin D, Gay, Martha D, Shivapurkar, Narayan, Edmondson, Elijah F, Yue, Yuanzhen, Dou, Wenyu, Fang, Hong-Bin, Smith, Jill P
• Format: Journal Article
• Language: English
• Published: United States 01.10.2022
• Subjects: Animals; Humans; Mice; Mice, Transgenic; Pancreas - metabolism; Pancreatic Neoplasms; Pancreatic Neoplasms - chemically induced; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Proton Pump Inhibitors - adverse effects
• ISSN: 1536-4828
• DOI: 10.1097/MPA.0000000000002145

To analyze whether use of proton pump inhibitors increase the risk for pancreatic cancer in a mouse model and human clinical cohorts. p48-Cre/LSL-KrasG12D mice that develop precancerous pancreatic intraepithelial neoplasia (PanINs) were treated with low- or high-dose proton pump inhibitors (PPIs) orally for 1 and 4 months. The mechanism for the cholecystokinin receptor 2 (CCK-2R) activation was investigated in vitro. Two resources were employed to analyze the risk of pancreatic cancer in human subjects with PPI use. Serum gastrin levels were increased 8-fold (P < 0.0001) in mice treated with chronic high-dose PPIs, and this change correlated with an increase (P = 0.02) in PanIN grade and the development of microinvasive cancer. The CCK-2R expression was regulated by microRNA-148a in the p48-Cre/LSL-KrasG12D mice pancreas and in human pancreatic cancer cells in vitro. Proton pump inhibitor consumption in human subjects was correlated with pancreatic cancer risk (odds ratio, 1.54). A validation analysis conducted using the large-scale United Kingdom Biobank database confirmed the correlation (odds ratio, 1.9; P = 0.00761) of pancreatic cancer risk with PPI exposure. This investigation revealed in both murine models and human subjects, PPI use is correlated with a risk for development of pancreatic cancer.