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Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer?
Matthew A Huber1, Sandeep Nadella1, Hong Cao1
1From the Department of Medicine.
Objectives:
To analyze whether use of proton pump inhibitors increase the risk for pancreatic cancer in a mouse model and human clinical cohorts.
Methods:
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.
Results:
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.
Conclusions:
This investigation revealed in both murine models and human subjects, PPI use is correlated with a risk for development of pancreatic cancer.
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