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SHR Neuro Cancer Cardio Lipid Metab Microb

Prinz, F; Jonas, K; Balihodzic, A; Klec, C; Reicher, A; Barth, DA; Riedl, J; Gerger, A; Kiesslich, T; Mayr, C; Rinner, B; Kargl, J; Pichler, M.
MicroRNA mimics can distort physiological microRNA effects on immune checkpoints by triggering an antiviral interferon response.
RNA Biol. 2022; 19(1):1305-1315 Doi: 10.1080/15476286.2022.2152978 [OPEN ACCESS]
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Leading authors Med Uni Graz
Pichler Martin
Prinz Felix
Co-authors Med Uni Graz
Balihodzic Amar
Barth Dominik Andreas
Gerger Armin
Jonas Katharina
Kargl Julia
Klec Christiane
Reicher Andreas
Riedl Jakob
Rinner Beate
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Abstract:
The microRNA-200 family has wide-ranging regulatory functions in cancer development and progression. Above all, it is strongly associated with the epithelial-to-mesenchymal transition (EMT), a process during which cells change their epithelial to a mesenchymal phenotype and acquire invasive characteristics. More recently, miR-200 family members have also been reported to impact the immune evasion of cancer cells by regulating the expression of immunoinhibitory immune checkpoints (ICs) like PD-L1. Therefore, we aimed to comprehensively characterize this miR-200 family as a regulatory interface between EMT and immune evasion mechanisms in biliary tract cancer. Initial correlation analyses and transient overexpression experiments using miRNA mimics suggested miR-200c-3p as a putative regulator of ICs including PD-L1, LGALS9, and IDO1. However, these effects could not be confirmed in stable miR-200c-3p overexpression cell lines, nor in cells transiently transfected with miR-200c-3p mimic from an independent manufacturer. By shifting our efforts towards dissecting the mechanisms leading to these disparate effects, we observed that the initially used miR-200c-3p mimic triggered a double-stranded (ds)RNA-dependent antiviral response. Besides upregulating the ICs, this had substantial cellular consequences including an induction of interferon type I and type III expression, increased levels of intracellular dsRNA sensors, and a significantly altered cellular growth and apoptotic activity.Our study highlights the capability of miRNA mimics to non-specifically induce a dsRNA-mediated antiviral interferon response. Consequently, phenotypic alterations crucially distort physiological miRNA functions and might result in a major misinterpretation of previous and future miRNA studies, especially in the context of IC regulation.

Find related publications in this database (Keywords)
MicroRNA mimics
miR-200c-3p
non-specific effects
dsRNA sensing
antiviral response
interferons
immune checkpoints
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