Abstract
Caerulein-induced acute pancreatitis accelerates the progression of pancreatic intraepithelial neoplasia (PanIN) lesions in a pancreas-specific KrasG12D mouse model. The purpose of this study was to explore whether serum microRNAs (miRNAs) can serve as sensitive biomarkers to detect occult PanIN in the setting of acute pancreatitis. Serum miRNA profiles were quantified by an array-based method and normalized by both Variance Stabilization Normalization (VSN) and invariant methods. Individual miRNAs were validated by TaqMan real-time PCR with synthetic spike-in C. elegans miRNAs as external controls. Serum miRNA profiles distinguished KrasG12D mice with pancreatitis from wild-type mice without pancreatitis, but failed to differentiate KrasG12D mice with pancreatitis from wild-type mice with pancreatitis. Most individual miRNAs that increased in KrasG12D mice with pancreatitis were not significantly different between KrasG12D mice without pancreatitis and wild-type mice without pancreatitis. Mechanistically, Gene Set Enrichment Analysis (GSEA) of the mRNA array data and immunohistochemical assays showed that caerulein-induced acute pancreatitis involved acinar cell loss and immune cell infiltration, which might contribute to serum miRNA profile changes. This study highlighted the challenges in using sensitive serum miRNA biomarker screening for the early detection of pancreatic malignancies during acute pancreatitis.
Highlights
Pancreatic cancer is a leading cause of death in both the United States, with an estimated 53,070 new cases and 41,780 deaths annually [1], and in the People’s Republic of China [2]
We used a KrasG12D mouse model to assess the practicality of distinguishing the presence or absence of Pancreatic intraepithelial neoplasia (PanIN) in mice with acute pancreatitis
The data indicated that serum miRNAs cannot serve as sensitive biomarkers for detecting PanIN lesions in the setting of acute pancreatitis
Summary
Pancreatic cancer is a leading cause of death in both the United States, with an estimated 53,070 new cases and 41,780 deaths annually [1], and in the People’s Republic of China [2]. Despite advances in cancer therapy in recent decades, the five-year survival rate for pancreatic cancer is only 7.2% [3]; the five-year survival is higher (27.1%) for patients with localized disease at the time of diagnosis, highlighting the necessity of diagnosing pancreatic cancer early. Pancreatic intraepithelial neoplasia (PanIN) lesions represent a pre-malignant step during pancreatic tumourigenesis [4]. A recent study showed that acute pancreatitis was associated with an www.impactjournals.com/oncotarget increased risk of pancreatic cancer, and the lag period was approximately two years [5]. Patients with a history of pancreatitis are at high risk for subsequent pancreatic cancer [6,7,8].
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