Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis
The role of miR-345 in lung cancer was studied by Zhang et al, where they showed that prominent downregulation was associated with the patient poor prognosis in nonsmall-cell lung carcinoma (NSCLC) tissue specimens [70]
The study conducted by Assao et al, to check expression levels of miR-181b, miR-21, miR-31, and miR-345 in actinic cheilitis with and without epithelial dysplasia and with lower lip squamous cell carcinomas (LLSCC), revealed that increased expression of miR345, miR-181b, and miR-31 was found in actinic cheilitis without epithelial dysplasia, in comparison with that of actinic cheilitis with epithelial dysplasia and LLSCC (Figure 1)
Summary
There is an urgent need to identify novel diagnostic/therapeutic targets for the effective management of highly malignant PC [18]. miRNAs have received significant attention as a new class of non-coding-RNAs engaged in the regulation of gene expression. Srivastava et al showed that miR-345 can induce apoptosis in caspase-dependent and -independent mechanisms in PC cells They observed downregulated miR-345 expression in PC tissues and cell lines. They further demonstrated that the overexpression of miR-345 disrupted mitochondrial membrane potential in PC cells, resulting in the release of cytochrome C (Cyt c) to the cytosol from the mitochondria, causing the activation of Caspase 3 and 7 with subsequent cleavage of poly [ADP-ribose] polymerase 1 (PARP-1). Another study by Mou et al showed that the downregulated expression of miR-345 in PDAC tissues and cells, and the overexpression of miR-345 in PANC1 and SW1990 cell lines in vitro inhibited proliferation and metastasis by inactivating the nuclear factor κB (NFκB) signaling pathway and further suppressed PC progression [49]. MiR-345 is an excellent candidate for diagnostic/prognostic and therapeutic targets in PC
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