miRNAs in pancreatic cancer progression and metastasis

Abstract

Small non-coding RNA or microRNA (miRNA) are critical regulators of eukaryotic cells. Dysregulation of miRNA expression and function has been linked to a variety of diseases including cancer. They play a complex role in cancers, having both tumour suppressor and promoter properties. In addition, a single miRNA can be involved in regulating several mRNAs or many miRNAs can regulate a single mRNA, therefore assessing these roles is essential to a better understanding in cancer initiation and development. Pancreatic cancer is a leading cause of cancer death worldwide, in part due to the lack of diagnostic tools and limited treatment options. The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is characterised by major genetic mutations that drive cancer initiation and progression. The regulation or interaction of miRNAs with these cancer driving mutations suggests a strong link between the two. Understanding this link between miRNA and PDAC progression may give rise to novel treatments or diagnostic tools. This review summarises the role of miRNAs in PDAC, the downstream signalling pathways that they play a role in, how these are being used and studied as therapeutic targets as well as prognostic/diagnostic tools to improve the clinical outcome of PDAC.

Keywords: Diagnostics; Novel therapeutics; Pancreatic ductal adenocarcinoma; microRNA.

Fig. 1

Schematic of the canonical and non-canonical pathways of microRNA (miRNA) biogenesis. Canonical pathway is carried out by 6 steps as follows: 1. miRNA transcription by polymerase II 2. Pri-miRNA cleavage by microprocessors 3. Export of pre-miRNA by Exportin 5 4. Pre-miRNA cleavage by Dicer 5. Guide strand forms a miRNA-induced silencing complex (miRISC) after attachment to AGO 6. Binding of miRISC to target mRNA or export to other cells in extracellular vesicles. Several non-canonical pathways exist, for example beginning with transcription of the miRtrons followed by splicing by debranching enzyme 1 (DBR1) resulting in pre-miRNA that then follows the export as and final cleavage per the canonical pathway steps 3–6

Fig. 2

The progression of PDAC is often associated with mutations of KRAS, CDKN2A, TP53 and SMAD4 expressions, which can be directly modulated by several miRNAs. Certain miRNAs are also found to be increased/decreased in expression during different stages of PDAC development

Fig. 3

Examples of miRNAs involved in PDAC progression

Fig. 4

miRNAs have been shown to be implicated in multiple steps of the metastatic cascade in PDAC including: 1. Cancer cell migration and invasion at the primary tumour 2. Intravasation into the blood and lymphatic systems 3. Survival and transit in the circulation 4. Extravasation from the vessels and invasion at the secondary sites 5. Colonisation and expansion at the secondary sites