MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that function in regulation of gene expression. Compelling evidences have demonstrated that miRNA expression is dysregulated in human cancer through various mechanisms, including amplification or deletion of miRNA genes, abnormal transcriptional control of miRNAs, dysregulated epigenetic changes and defects in the miRNA biogenesis machinery. MiRNAs may function as either oncogenes or tumor suppressors under certain conditions. The dysregulated miRNAs have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, activating invasion and metastasis, and inducing angiogenesis. An increasing number of studies have identified miRNAs as potential biomarkers for human cancer diagnosis, prognosis and therapeutic targets or tools, which needs further investigation and validation. In this review, we focus on how miRNAs regulate the development of human tumors by acting as tumor suppressors or oncogenes.

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The role of MicroRNAs in human cancer

Small RNA molecules regulate eukaryotic gene expression during development and in response to stresses including viral infection. Specialized ribonucleases and RNA-binding proteins govern the production and action of small regulatory RNAs. After initial processing in the nucleus by Drosha, precursor microRNAs (pre-miRNAs) are transported to the cytoplasm, where Dicer cleavage generates mature microRNAs (miRNAs) and short interfering RNAs (siRNAs). These double-stranded products assemble with Argonaute proteins such that one strand is preferentially selected and used to guide sequence-specific silencing of complementary target mRNAs by endonucleolytic cleavage or translational repression. Molecular structures of Dicer and Argonaute proteins, and of RNA-bound complexes, have offered exciting insights into the mechanisms operating at the heart of RNA-silencing pathways.

Molecular Mechanisms of RNA Interference

In vivo delivery of miRNAs for cancer therapy: challenges and strategies.

Many RNA species have been identified as important players in the development of chronic diseases, including cancer. Over the past decade, numerous studies have highlighted how regulatory RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play crucial roles in the development of a disease state. It is clear that the aberrant expression of miRNAs promotes tumor initiation and progression, is linked with cardiac dysfunction, allows for the improper physiological response in maintaining glucose and insulin levels, and can prevent the appropriate integration of neuronal networks, resulting in neurodegenerative disorders. Because of this, there has been a major effort to therapeutically target these noncoding RNAs. In just the past 5 years, over 100 antisense oligonucleotide-based therapies have been tested in phase I clinical trials, a quarter of which have reached phase II/III. Most notable are fomivirsen and mipomersen, which have received FDA approval to treat cytomegalovirus retinitis and high blood cholesterol, respectively. The continued improvement of innovative RNA modifications and delivery entities, such as nanoparticles, will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. Here we summarize the latest promises and challenges of targeting noncoding RNAs in disease.

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Targeting noncoding RNAs in disease

Aberrant Regulation and Function of MicroRNAs in Cancer

MicroRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression. MicroRNAs are transcribed by RNA polymerases II and III, generating precursors that undergo a series of cleavage events to form mature microRNA. The conventional biogenesis pathway consists of two cleavage events, one nuclear and one cytoplasmic. However, alternative biogenesis pathways exist that differ in the number of cleavage events and enzymes responsible. How microRNA precursors are sorted to the different pathways is unclear but appears to be determined by the site of origin of the microRNA, its sequence and thermodynamic stability. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC). MicroRNA assembles into RISC, activating the complex to target messenger RNA (mRNA) specified by the microRNA. Various RISC assembly models have been proposed and research continues to explore the mechanism(s) of RISC loading and activation. The degree and nature of the complementarity between the microRNA and target determine the gene silencing mechanism, slicer-dependent mRNA degradation or slicer-independent translation inhibition. Recent evidence indicates that P-bodies are essential for microRNA-mediated gene silencing and that RISC assembly and silencing occurs primarily within P-bodies. The P-body model outlines microRNA sorting and shuttling between specialized P-body compartments that house enzymes required for slicer –dependent and –independent silencing, addressing the reversibility of these silencing mechanisms. Detailed knowledge of the microRNA pathways is essential for understanding their physiological role and the implications associated with dysfunction and dysregulation.

MicroRNA: Biogenesis, Function and Role in Cancer.

Basic fibroblast growth factor (FGF2) is a potent wide-spectrum mitogen whose overexpression is associated with immortalization and unregulated cell proliferation in many tumors. The FGF2 gene locus is bi-directionally transcribed to produce FGF2 mRNA from the “sense” strand and a cis-antisense RNA (NUDT6) from the NUDT6 gene on the “antisense” strand. The NUDT6 gene encodes a nudix motif protein of unknown function, while its mRNA has been implicated in the post-transcriptional regulation of FGF2 expression. FGF2 and NUDT6 are co-expressed in rat C6 glioma cells, and ectopic overexpression of NUDT6 suppresses cellular FGF2 accumulation and cell cycle progression. However, the role of the endogenous antisense RNA in regulation of FGF2 is unclear. In the present study, we employed siRNA-mediated gene knockdown to examine the role of the endogenous NUDT6 RNA in regulation of FGF2 expression and cell cycle progression. Knockdown of either FGF2 or NUDT6 mRNA was accompanied by a significant (>3 fold) increase in the complementary partner RNA. Similar reciprocal effects were observed at the protein level, indicating that these two transcripts are mutually regulatory. Remarkably, knockdown of either FGF2 or NUDT6 significantly reduced cell proliferation and inhibited S-phase re-entry following serum deprivation, implicating both FGF2 and NUDT6 in the regulation of cell transformation and cell cycle progression.

https://www.mdpi.com/2073-4425/3/3/505/pdf

Leigh Ann MacFarlane

Papers

MicroRNA: Biogenesis, Function and Role in Cancer.

Regulation of Fibroblast Growth Factor-2 Expression and Cell Cycle Progression by an Endogenous Antisense RNA