Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality. Considering its very poor prognosis, novel treatment options are urgently needed. MicroRNAs (miRNAs) are
involved in the regulation of various physiological and pathological processes. In tumors, aberrant
downregulation of given miRNAs may result in pathological overexpression of oncogenes, rendering
miRNA replacement as a promising therapeutic strategy. In different tumor entities, miRNA-506-3p
(miR506-3p) has been ambivalently described as tumor suppressing or oncogenic. In PDAC, miR-506
is mainly considered as a tumor-suppressing miRNA. In this study, we extensively analyze the
cellular and molecular effects of miRNA-506-3p replacement in different PDAC cell lines. Beyond
profound antiproliferation and induction of cell death and autophagy, we describe new cellular
miR506-3p effects, i.e., induction of senescence and reactive oxygen species (ROS), as well as alterations in mitochondrial potential and structure, and identify multiple underlying molecular effects. In
a preclinical therapy study, PDAC xenograft-bearing mice were treated with nanoparticle-formulated
miRNA-506 mimics. Profound tumor inhibition upon systemic miRNA-506 administration was
associated with multiple cellular and molecular effects. This demonstrates miRNA replacement as a
potential therapeutic option for PDAC patients. Due to its broad mechanisms of action on multiple
relevant target genes, miR506-3p is identified as a particularly powerful tumor-inhibitory miRNA.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:87882 |
| Date | 03 November 2023 |
| Creators | Borchardt, Hannes, Kogel, Alexander, Kalwa, Hermann, Weirauch, Ulrike, Aigner, Achim |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1692 |
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