Therapeutic miR-506-3p Replacement in Pancreatic Carcinoma Leads to Multiple Effects including Autophagy, Apoptosis, Senescence, and Mitochondrial Alterations In Vitro and In Vivo

Abstract

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.

Nano-drug delivery system for pancreatic cancer: A visualization and bibliometric analysis

“…However, susceptibility to degradation by nucleases, low intracellular absorption rate due to an inherent negative charge and hydrophilic structure, and potential off-target effects limit the application of miRNAs ( Kara et al, 2022 ). MiRNA nanocarriers based on polymers, inorganic materials, and lipids have demonstrated their potential in the treatment of PC ( Arora et al, 2014 ; Gurbuz and Ozpolat, 2019 ; Gokita et al, 2020 ; Wu et al, 2020 ; Borchardt et al, 2022 ). However, it is important to note that therapeutic miRNAs can also accumulate in healthy tissues due to interstitial fluid pressure and shearing stress promoting NPs extravasation, which may lead to their degradation ( Zhang et al, 2019a ), and cause toxic and other adverse reactions ( Kara et al, 2022 ).…”

The Emerging Role of MicroRNAs and Autophagy Mechanism in Pancreatic Cancer Progression: Future Therapeutic Approaches

“…More particularly, miR-30c targets TWF1 and induces arrest of G1-phase of cell cycle and apoptosis, implying its role as a tumor0suppressive miRNA, while in cases where miR-30c was decreased, re-expression led to favorable anti-neoplastic effects [ 71 ]. MiR-340 overexpression is closely associated with the regulation of Bicaudal-D2 (BICD2), leading to the inhibition of pancreatic malignant cell growth and progression, implying the anti-neoplastic potential of miR-340/BICD2 axis [ 72 ].MiRNA-506 constitutes another miRNA that acts as tumor suppressor and significantly reduces the PDAC progression, although this is achieved when it is overexpressed [ 73 ].…”

“…It is reported that the replacement of miR-506-3p in PDAC has various effects on apoptosis, autophagy pathway, and on mitochondrial modifications not only in vitro but also in vivo. Based on the study of various pancreatic cancer entities, miRNA-506-3p was found downregulated in the majority of them (71%), whereas PIM-3 proto-oncogene was found overregulated [ 73 ]. Based on the above data, the downregulation of miR-506 expression was closely related to pancreatic tumor progression, with the less differentiated pancreatic tumors having a lower expression of miR-506, in comparison with moderate and well-differentiated tumors.…”

“…Meanwhile, the levels of reactive oxygen species (ROS), which are related to the mitochondria-induced apoptotic mechanism, were increased in the post-transfection period of 72h. The autophagy pathway was also modified after the transfection of PaTu-8988t, with a 2–3 times higher level of LC3-II/LC3I ratio, implying the increased activation (40%) of autophagy machinery in the transfected cells [ 73 ].…”

“…Tumor Promoters (OncomiRs) miR-143-3p [74] miR-301a-3p [97] miR-203a-3p [75] miR-1469-5p [105] miR-519d-3p [76] miR-17-5p [100] miR-365a-3p [86] miR-186 [89] miR-451a [70] miR-34 [90] miR-30c [71] miR-196b [92] miR-340 [72] miR-506 [93] miR-506 [73] miR-221 [96] miR-375 [77] miR-18a [95] miR-216b [78] miR-21 [91] miR-142 [79] miR-205 [98] miR-455-3p [80] miR-29a [99] Table 1. Cont.…”