Abstract
Simple SummaryCancer is a complex disease associated with deregulation of numerous genes. In addition, redundant cellular pathways limit efficiency of monotarget drugs in cancer therapy. MicroRNAs are a class of gene expression regulators, which often function by targeting multiple genes. This feature makes them a double-edged sword (a) as attractive targets for anti-tumor therapy and concomitantly (b) as risky targets due to their potential side effects on healthy tissues. As for conventional antitumor drugs, nanocarriers have been developed to circumvent the problems associated with miRNA delivery to tumors. In this review, we highlight studies that have established the pre-clinical proof-of concept of miRNAs as relevant therapeutic targets in oncology. Particular attention was brought to new strategies based on nanovectorization of miRNAs as well as to the perspectives for their applications.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.
Highlights
MicroRNAs are highly conserved small non-coding RNAs, which regulate gene expression through imperfect base pairing to the 3 -untranslated region (3 -UTR) of target mRNA
Intensive analysis of the Cancer Genome Atlas (TCGA) data revealed a large panel of miRNA deregulations in the three ovarian cancer (OvCa) subtypes
The pleiotropic action of miRNAs suggests that targeting these molecules could efficiently reverse phenotypes of multifactorial pathologies like cancer
Summary
MicroRNAs (miRNAs) are highly conserved small non-coding RNAs, which regulate gene expression through imperfect base pairing to the 3 -untranslated region (3 -UTR) of target mRNA. The resulting small RNA duplex is assembled into AGO (Argonaute) protein within the RNA-Induced Silencing Complex (RISC) where the guide strand is selected to exert its effect on the target transcript [3] Given their small size of ~22 nucleotides, miRNAs can regulate various genes, in a developmental and tissue-specific manner [4]. MiR-27b and miR-892a were found to respectively target and downregulate CYP1B1 and CYP1A1 expression in breast cancer [21,22] and to impair the benzo(a)pyrene-mediated decrease in cancer cell viability [22] All these findings reinforce the idea that subsets of miRNAs may have clinical relevance as therapeutics agents. Doses and side effects are monitored for FDA approval and treatment scale-up
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