MicroRNA in Pancreatic Cancer: From Biology to Therapeutic Potential

Abstract

Pancreatic cancer is one of the most aggressive malignancies, accounting for more than 45,750 deaths annually in the U.S. alone. The aggressive nature and late diagnosis of pancreatic cancer, coupled with the limitations of existing chemotherapy, present the pressing need for the development of novel therapeutic strategies. Recent reports have demonstrated a critical role of microRNAs (miRNAs) in the initiation, progression, and metastasis of cancer. Furthermore, aberrant expressions of miRNAs have often been associated with the cause and consequence of pancreatic cancer, emphasizing the possible use of miRNAs in the effective management of pancreatic cancer patients. In this review, we provide a brief overview of miRNA biogenesis and its role in fundamental cellular process and miRNA studies in pancreatic cancer patients and animal models. Subsequent sections narrate the role of miRNA in, (i) cell cycle and proliferation; (ii) apoptosis; (iii) invasions and metastasis; and (iv) various cellular signaling pathways. We also describe the role of miRNA's in pancreatic cancer; (i) diagnosis; (ii) prognosis and (iii) therapeutic intervention. Conclusion section describes the gist of review with future directions.

Keywords: diagnosis; microRNA; pancreatic cancer; potential therapeutic targets; prognosis.

Figure 1

Biogenesis of miRNA and its functions. The miRNA synthesis starts in the nucleus where pri-miRNA transcript 100 to >1000 nucleotides is generated by RNA polymerase II. Subsequently, pri-miRNA is cleaved by Drosha/DGCR8 to form ~70–100 nucleotides long hairpin loop pre-miRNA. Pre-miRNA is then transported from nucleus to cytoplasm through Exportin 5 and Ran-GTP6 wherein it is further processed by RNase activity of Dicer to 19–24 nucleotides double-stranded mature miRNA duplex. The miRNA duplex then loads onto Ago in the RISC complex and undergoes strand separation. The guide strand of the miRNA mediates gene silencing by degrading the target mRNA or interfering with the translational process. The passenger strand gets degraded. Adopted from [29] © 2013 Ranganna K, Mathew OM, Milton SG, Hayes BE under a CC-BY 3.0 license.

Figure 2

The major structures of the pancreatic gland indicating the origin of PDAC. A cataloug of commonly downregulated miRNAs (in green), upregulated miRNAs (in red) and differentially regulated miRNAs (in blue) in PDAC are listed in different colors. Differentially regulated miRNAs refers to either up or down-regulated miRNAs compared to healthy pancreatic tissue.

Figure 3

Schematic illustration of different stages of pancreatic ductal adenocarcinoma (PDAC). The list of miRNAs that are upregulated (in red color) and downregulated (in green color) during initiation and progression stages of PDAC are listed.

Figure 4

Schematic illustration of the role of tumor suppressor miRNAs at different stages of pancreatic ductal adenocarcinoma (PDAC). The figure depicts the interrelationship between pancreatic cancer cells (PCCs), pancreatic stellate cells (PSCs) and cancer stem cells (CSCs). The epithelial pancreatic cells undergo epithelial-mesenchymal transition (EMT) and become mesenchymal cells which bear high propensity to metastasize. EMT could be reversed back to mesenchymal-to-epithelial transition (MET) by the intervention of certain miRNAs. This figure is adopted and modified from [87], © 2015 Chitkara D, Mittal A, Mahato RI. under a CC BY-NC-SA 4.0 license.