The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by promoting acquisition of cancer hallmark traits. The multi-target action of miRNAs, which enable regulation of entire signaling networks, makes them attractive tools for the development of anti-cancer therapies. Hence, supplementing downregulated miRNA by synthetic oligonucleotides or silencing overexpressed miRNAs through artificial antagonists became a common strategy in cancer research. However, the ultimate success of miRNA therapeutics will depend on solving pharmacokinetic and targeted delivery issues. The development of a number of nanocarrier-based platforms holds significant promises to enhance the cell specific controlled delivery and safety profile of miRNA-based therapies. In this review, we provide among the most comprehensive assessments to date of promising nanomedicine platforms that have been tested preclinically, pertaining to the treatment of selected solid tumors including lung, liver, breast, and glioblastoma tumors as well as endocrine malignancies. The future challenges and potential applications in clinical oncology are discussed.

Adrenocortical carcinoma (ACC) is a rare malignancy with dismal prognosis. Deregulated microRNA (miRNA) expression has been implicated in ACC aggressiveness. Nevertheless, the mechanisms underlying such deregulations remain unknown. Aberrant Wnt/β-Catenin signaling has been reported in about 40% of ACC and is associated with poor outcome. Here, we investigated the link between constitutive activation of Wnt/β-Catenin pathway and miRNA expression alterations in ACC. Inducible shRNA-mediated gene silencing of β-Catenin (β-Cat) was performed in ACC cells expressing constitutively active β-Catenin. The miRnome of ACC cells was analyzed using RNA-Sequencing. Selected miRNAs and mRNAs were validated using quantitative PCR and functional experiments with an emphasis on miR-139-5p, its host gene phosphodiesterase 2A (PDE2A) and its target gene N-Myc Downstream-Regulated Gene 4 (NDRG4). Prognostic values of Wnt/β-Catenin pathway components or mutational status and their correlations with miRNA/mRNA expressions were determined in COMETE-ENSAT and TCGA cohorts. We carried out the first miRnome analysis in β-Catenin-deficient (β-Cat-) ACC cells. Twelve upregulated miRNAs and 42 downregulated miRNAs among which miR-139-5p and miRNAs of the 14q32 locus were identified in β-Cat- cells. Downregulation of selected poor prognosis-associated miRNAs was confirmed using RT-qPCR. Remarkably, the expression of the intronic miR-139-5p was decreased by 90% in β-Cat- cells with a concomitant repression of its host gene PDE2A and upregulation of its target gene NDRG4. In ACC patients, miR-139-5p levels were highly correlated with the levels of PDE2A and anti-correlated with those of NDRG4. MiR-139-5p and PDE2A expressions were higher in patients with mutations in components of Wnt/β-Catenin signaling pathway or high expression of LEF1, with LEF1 proving a better predictor of prognosis than Wnt/β-Catenin signaling pathway mutational status. Our findings indicate that in addition to inducing protein-coding genes in ACC, constitutively active Wnt/β-Catenin signaling upregulates the expression of a subset of miRNAs involved in tumour aggressiveness and poor clinical outcome.