Abstract
Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can develop into pancreatic ductal adenocarcinoma (PDAC). Although there is an increasing incidence of IPMN diagnosis, the mechanisms of formation and progression into invasive cancer remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs, repressors of mRNA translation, and promising diagnostic biomarkers for IPMN and PDAC. Functional information on the role of early-altered miRNAs in this setting would offer novel strategies for tracking the IPMN-to-PDAC progression. In order to detect mRNAs that are likely to be under miRNA regulation in IPMNs, whole transcriptome and miRNome data from normal pancreatic tissue (n = 3) and IPMN lesions (n = 4) were combined and filtered according to negative correlation and miRNA-target prediction databases by using miRComb R package. Further comparison analysis with PDAC data allowed us to obtain a subset of miRNA-mRNA pairs shared in IPMN and PDAC. Functional enrichment analysis unravelled processes that are mainly related with cell structure, actin cytoskeleton, and metabolism. MiR-181a appeared as a master regulator of these processes. The expression of selected miRNA-mRNA pairs was validated by qRT-PCR in an independent cohort of patients (n = 40), and then analysed in different pancreatic cell lines. Finally, we generated a cellular model of HPDE cells stably overexpressing miR-181a, which showed a significant alteration of actin cytoskeleton structures accompanied by a significant downregulation of EPB41L4B and SEL1L expression. In situ hybridization of miR-181a and immunohistochemistry of EPB41L4B and SEL1L in pancreatic tissues (n = 4 Healthy; n = 3 IPMN; n = 4 PDAC) were also carried out. In this study, we offer insights on the potential implication of miRNA alteration in the regulation of structural and metabolic changes that pancreatic cells experience during IPMN establishment and that are maintained in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is currently the seventh leading cause of cancer-related deaths worldwide and the fourth in Europe and United States, with a five-year survival rate of only 10% [1,2]
The validation of candidate miRNA-mRNA couples was done by qRT-PCR in an independent set of 40 surgical samples (14 pancreatic ductal adenocarcinoma (PDAC), nine Intraductal papillary mucinous neoplasms (IPMN), 17 Healthy) from individuals that were prospectively included in Hospital Clínic of Barcelona between 2008 and 2013
314 significantly upregulated and 248 significantly downregulated mRNAs were found to be significantly altered between IPMN and healthy tissues (Figure 1B)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is currently the seventh leading cause of cancer-related deaths worldwide and the fourth in Europe and United States, with a five-year survival rate of only 10% [1,2]. Are cystic neoplasms of the pancreas that can lead to cancer either concomitantly or after resection, and they are considered a risk factor for PDAC development [3]. They harbour genomic, transcriptomic, and epigenomic aberrations that are related with the gain of potentially malignant characteristics. Evidences support that IPMN arise from ductal epithelial cells [4], and can progress to PDAC through a range of dysplastic changes [5,6]. Specific interactions between miRNAs and mRNAs are endogenously tuning a wide range of biological processes altered during tumour initiation and progression, such as cellular differentiation, metabolism, or epithelial-to-mesenchymal transition, in the context of pancreatic neoplasia [8]
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