Abstract
BackgroundMiRNAs act as negative regulators of gene expression through target mRNA degradation or inhibition of its translation. In cancer, several miRNAs are upregulated and play crucial roles in tumorigenesis, making the inhibition of these oncomiRs an interesting therapeutic approach. This can be achieved by directly complementary single-stranded anti-miRNA oligonucleotides (antimiRs). A major bottleneck in antimiR therapy, however, is their efficient delivery. The nanoparticle formation with polyethylenimine (PEI) may be particularly promising, based on the PEI’s ability to electrostatically interact with oligonucleotides. This leads to their protection and supports delivery. In the present study, we explore for the first time PEI for antimiR formulation and delivery. We use the branched low molecular weight PEI F25-LMW for the complexation of different antimiRs, and analyse tumor- and metastasis-inhibitory effects of PEI/antimiR complexes in different tumor models.ResultsIn prostate carcinoma, transfection of antimiRs against miR-375 and miR-141 leads to tumor cell inhibition in 2D- and 3D-models. More importantly, an in vivo tumor therapy study in prostate carcinoma xenografts reveals anti-tumor effects of the PEI/antimiR complexes. In advanced melanoma and metastasis, we identify by a microRNA screen miR-150 as a particularly relevant oncomiR candidate, and validate this result in vitro and in vivo. Again, the systemic application of PEI/antimiR complexes inhibiting this miRNA, or the previously described antimiR-638, leads to profound tumor growth inhibition. These effects are associated with the upregulation of direct miRNA target genes. In a melanoma metastasis mouse model, anti-metastatic effects of PEI/antimiR treatment are observed as well.ConclusionsWe thus describe PEI-based complexes as efficient platform for antimiR therapy, as determined in two different tumor entities using in vivo models of tumor growth or metastasis. Our study also highlights the therapeutic relevance of miR-375, miR-141, miR-150 and miR-638 as target miRNAs for antimiR-mediated inhibition.
Highlights
MiRNAs act as negative regulators of gene expression through target mRNA degradation or inhibi‐ tion of its translation
We describe for the first time the use of PEI F25-LMW as an uncomplicated system for antimiR complexation and delivery
Tumor cell‐inhibitory effects of miR‐375/miR‐141 inhibition Based on previous studies on the potential roles of miR375 and miR-141 as oncogenic miRNAs [35,36,37,38], we first assessed the effects of the antimiR-mediated miRNA inhibition in 2D and 3D cell growth in different in vitro models of prostate carcinoma
Summary
MiRNAs act as negative regulators of gene expression through target mRNA degradation or inhibi‐ tion of its translation. Several miRNAs are upregulated and play crucial roles in tumorigenesis, making the inhibition of these oncomiRs an interesting therapeutic approach This can be achieved by directly complementary single-stranded anti-miRNA oligonucleotides (antimiRs). The aberrant overexpression of these oncogenic miRNAs (oncomiRs) and their activity in malignancies, as demonstrated in a plethora of functional studies, underscore the relevance of miRNAs in tumorigenesis and tumor progression, and make them interesting therapeutic targets. For their inhibition, the delivery of miRNA inhibitors including antimiRs, antagomirs, miRNA decoys or miRNA sponges has been employed. The miRNA:antimiR hybridization leads to inactivation of the mature miRNA primarily through steric hindrance [7]
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