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Abstract
BackgroundMicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated.MethodsTissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets.ResultsWidespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a “seedless” binding site within its 3′UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change.ConclusionsExpression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers.
Highlights
Pancreatic cancer is the 4th commonest cause of cancer-related death accounting for 33,000 deaths per year in the US [1,2,3] and at least 6,000 deaths per year in the UK [4]
In order to distinguish the various types of pancreatic tumor, miRNA expression profiling was performed using total RNA derived from formalin-fixed paraffin embedded (FFPE) tissues of low and high malignant potential benign cystic tumors (BCT) and ductal adenocarcinoma (CEI and pancreatic ductal adenocarcinoma (PDAC))
MiR-16, miR-126 and let-7d modulate the expression of pancreatic cancer oncogenes The current study has revealed that many of the miRNAs found to be down-regulated in PDAC compared to serous microcystic adenomas (SMCA) can potentially regulate the expression of genes which promote malignant transformation
Summary
Pancreatic cancer is the 4th commonest cause of cancer-related death accounting for 33,000 deaths per year in the US [1,2,3] and at least 6,000 deaths per year in the UK [4]. Most patients have locally advanced or metastatic disease at presentation and are not surgical candidates [3,6]; the actual resection rate is less than 10% [7]. Routine imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) are not sensitive enough to detect pancreatic cancer at an early stage [2]. The epithelial benign cystic tumors (BCT) of the pancreas have the potential to transform into invasive pancreatic ductal adenocarcinoma (PDAC) (Figure S1).
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