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microRNAs (miRNAs) are small (19-24 nt), endogenous highly conserved noncoding RNAs with important regulatory functions. They negatively regulate gene expression through binding to the 3'-untranslated region (3'-UTR) of the target mRNAs and causing mRNA degradation or translational repression. Therefore, they are involved in post-transcriptional gene silencing and are predicted to target about 30% of the protein-coding genes. miRNAs play an important role in a variety of biological processes, including embryogenesis, developmental timings, cell differentiation, organogenesis, metabolism, apoptosis, and various diseases.
There is a significant body of evidence to suggest that miRNA dysregulation is deeply involved in tumor occurrence and progression, affecting the expression of key genes implicated in cancer processes such as invasion, migration and metastasis, and resistance to cell death. Similarly, genes encoding mRNAs may be divided into oncogenes and tumor suppressor genes according to their function in cancer, miRNAs can also be classified based on exhibiting tumor-promoting functions (oncomiRs, metastamiRs) or tumor suppressive miRNAs. However, due to the more and more research focus on miRNAs, it is now known that several well-characterized miRNAs can have either oncogenic or tumor suppressive functions, depending on the cell type in which the miRNA is expressed, in much the same way as many mRNAs and proteins. For example, miR-221 and -222 target at least four tumor suppressor genes (CDKN1B, CDKN1C, PTEN, and TIMP3), thus, functioning as oncogenic miRNAs to inhibit these tumor suppressor genes in solid tumors, while in erythroblastic cells, they function as tumor suppressors by targeting the oncogene KIT to suppress the growth of erythoblastic leukaemia.
Figure 1. Several miRNAs in cancer progression. (He B, et al., 2020)
In the last decade, the major advances have focused on designing novel targeted therapy capable of targeting specifically the malignant cells in a more reasonable way. The emergence of miRNAs provides an additional layer of gene regulation on a broad spectrum of biological pathways by fine-tuning protein expression levels. The ability of miRNAs to regulate cellular processes, their inherent role in carcinogenesis as oncogenes or tumor suppressor genes, and the aberrant dysregulation of their expression levels in cancer illustrate the potential of miRNA modulation as a feasible therapeutic strategy and a powerful intervention tool. Due to their ability to target multiple protein-coding genes and their aberrant perturbations in a wide range of cancers, miRNAs have emerged to be promising novel therapeutic targets and intervention tools.
In cancer therapeutics, miRNAs can be used to degrade the anti-apoptotic genes or can be silenced to up-regulate the tumor suppressor genes. For example, the restoration of miR-34 suppressed tumor formation while antagonizing miR-21 using anti-sense oligonucleotides causes pro-apoptotic response. The anti-sense oligonucleotides used to correct the interaction between miRNA and mRNA needs to be modified chemically for stability and cellular uptake. There are several approaches currently being explored for miRNA modulation.
Table 1. miRNA-based therapeutics approaches. (Shah M Y, Calin G A. 2014)
|Method||Definition||Mechanism of Action|
|AMOs||A single-stranded, RNA molecule designed to be complementary to a selected miRNA||Competitive inhibition of mature miRNA by Watson–Crick binding|
|2'-O-modified AMOs||Modification of 2'-OH to 2'-O-methyl- and 2'-O-methoxyethyl- groups||Competitive inhibition of mature miRNA by Watson–Crick binding|
|Antagomirs||AMOs modified to have a phosphonothioate backbone and conjugated with cholesterol||Competitive inhibition of mature|
miRNA; detailed mechanisms still unclear
|LNA anti-miRNAs||Addition of an extra methylene bridge connecting the 2'-O atom and the 4'-C atom 'locks' the ribose ring in a C3'-endo or C2'-endo conformation||High-affinity Watson–Crick hybridization with their RNA target molecules—inhibition|
|miRNA sponges||RNA transcripts with multiple tandem repeats of miRNA-binding sites for an endogenous miRNA||Stably interact with corresponding miRNA and prevent its interaction with its target mRNAs|
|miRNA masks||Single-stranded 2'-O-methyl-modified antisense oligonucleotides with entire complementary to the miRNA-binding sites in the 3'-UTR of the target mRNA||‘Mask’ the target mRNA from the endogenous miRNA and thus prevent its suppression|
|Small-molecule inhibitors of miRNAs (SMIRs)||Small-molecule chemical compounds that interfere with miRNA biogenesis or maturation||Block specific miRNAs by structure-based docking onto the precursor or mature form of the miRNAs|
|miRNA expression vectors||Expression vectors that express a specific type of miRNA||Restoration of the expression and function of a specific miRNA|
|miRNA mimics||Small, chemically modified (2'-O-methoxy) RNA duplexes that can be loaded into RISC and achieve the downstream inhibition of the target mRNAs||Assist the miRNA function|
A comprehensive understanding of the role of miRNAs in complex regulatory networks involved in cancer may help with designing combinatorial therapeutic strategies. The goal of the IntegrateRNA is to support basic and applied research in RNA biology to generate new and novel insights into the role of RNA in health and disease and provide new tools and targets for RNA research, diagnostics and therapies. For further information, please feel free to contact us.