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miRNAs

Sunday 18 July 2004

Definition: MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway.

The small RNAs termed microRNAs (miRNAS) play important roles in cell proliferation, apoptosis and differentiation. MicroRNA mechanism is an efficient means to regulate production of a diverse range of proteins.

MicroRNAs are small noncoding RNAs that regulate gene expression by posttranscriptional mechanisms and many microRNAs could be prime suspects for cancer promoters because, on the basis of computer predictions, they have been proposed to regulate many cell cycle control genes.

nimal microRNAs were originally thought to repress target translation, with little or no influence on mRNA abundance, whereas the reverse was thought to be true in plants. Now, however, it is clear that microRNAs can induce mRNA degradation in animals and, conversely, translational repression in plants.

SNPs

Animal microRNAs (miRNAs) regulate gene expression through base pairing to their targets within the 3’ untranslated region (UTR) of protein-coding genes. Single-nucleotide polymorphisms (SNPs) located within such target sites can affect miRNA regulation.

Biomarkers

MicroRNAs (miRNAs) are a new class of biomarkers. They represent a group of small, noncoding RNAs that regulate gene expression at the posttranslational level by degrading or blocking translation of messenger RNA (mRNA) targets.

miRNAs are important players when it comes to regulating cellular functions and in several diseases, including cancer (Cancer Res 66:7390-7394, 2006; Nature 435:834-838, 2005). So far, miRNAs have been extensively studied in tissue material.

Only recently, it was found that miRNAs also exist in a broad range of body fluids (Clin Chem 56:1733-1741, 2010).

A major challenge still is the efficient and specific detection of miRNAs. The short length of miRNAs, with only 17-27 base pairs, comes with technical difficulties for analysis.

Furthermore, individual miRNAs, especially members of a miRNA family (e.g., the let-7 family), show high sequence homology, with sequences differing by as little as a single base pair.

Although miRNAs are abundant in higher copy numbers compared to mRNAs, miRNAs lack a common feature like a poly-A tail that eases detection in a complex background of other RNA species.

Besides qPCR, in situ hybridization, and next-generation sequencing, microarrays are versatile tools for high-throughput analysis of already known miRNAs (PLoS One 12:e9685, 2010; Nat Genet 38:S2-S7, 2006; Nature Methods 50:298-301, 2010).

Different assay formats have been proposed for expression analysis of miRNAs on microarrays, of which most employed prelabeled RNA molecules.

As a modification, the so-called RAKE assay was developed that combined the use of unlabeled RNA with on-chip enzymatic labeling by exonuclease cleavage and polymerase primer extension (RNA 12:187-191, 2006; Nature Methods 1:155-161, 2004; Genome Res 16:1289-1298, 2006).

Microfluidic primer extension assay can be used with starting material as low as 30 ng of total RNA. This technique has been extensively used for identifying specific sets of miRNAs (miRNA signatures) for diagnosis of cancer and cardiovascular or inflammatory diseases from blood samples of patients (Br J Cancer 103:693-700, 2010; BMC Cancer 9:353, 2009; PLoS One 4:e7440, 2009; BMC Cancer 10:262, 2010; Basic Res Cardiol 106(1):13-23, 2011).

miRNAs and cancer

MicroRNA (miRNA) alterations are involved in the initiation and progression of human cancer. The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery.

MiRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. Profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target protein-coding genes involved in cancer.

Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes. miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.

For example, the precursor miR155/BIC was recently reported to be up-regulated in cells of Hodgkin lymphoma. Bic was originally identified by retroviral insertional mutagenesis in chickens, as a locus specifically activated by viral insertions and collaborating with c-myc inlymphomagenesis. Although the causal relationship has not yet been tested in a suitable animal model, miR-155 appears to be a prime candidate for a microRNA acting as a proto-oncogene.

The microRNA genes miR15 and miR16 are reportedly down-regulated in two-thirds of analyzed cases of chronic lymphocytic leukemia (Calin et al. 2002), and a genome-wide survey of 186 human microRNAs genes has revealed that microRNAs genes are nonrandomly distributed in the genome and frequently locate to known fragile sites and loci involved in cancer (Calin et al. 2004).

Furthermore, small noncoding RNAs are involved in the silencing of repetitive DNA elements, such as retrotransposons, and in the nucleation of heterochromatin silencing and may thereby be important for genome stability and integrity.

Conceivably, the emerging connections between the RNAi machinery and gene regulation will reveal fundamental biological knowledge of importance for the understanding of both normal and neoplastic cells.

p53 and miRNAs

non-coding RNAs are key players in tumour development by placing miRNAs in a central role in a well-known tumour-suppressor network.

Several recent studies have found a conserved microRNA (miRNA) family, the miR-34s, to be direct transcriptional targets of p53.

miR-34 activation can recapitulate elements of p53 activity, including induction of cell-cycle arrest and promotion of apoptosis, and loss of miR-34 can impair p53-mediated cell death.

See also

- small RNAs
- miRNAs in tumors
- miRTRAP

Videos

- The Life Cycle of a Micro RNA

Reviews

- The widespread regulation of microRNA biogenesis, function and decay. Krol J, Loedige I, Filipowicz W. Nat Rev Genet. 2010 Sep;11(9):597-610. PMID: #20661255#

- Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Huntzinger E, Izaurralde E. Nat Rev Genet. 2011 Feb;12(2):99-110. PMID: #21245828#

- miRTRAP, a computational method for the systematic identification of miRNAs from high throughput sequencing data. Hendrix D, Levine M, Shi W. Genome Biol. 2010 Apr 6;11(4):R39. PMID: #20370911#

- Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Brown BD, Naldini L. Nat Rev Genet. 2009 Aug;10(8):578-85. PMID: #19609263#

- MicroRNAs in clinical oncology: at the crossroads between promises and problems. Metias SM, Lianidou E, Yousef GM. J Clin Pathol. 2009 Sep;62(9):771-6. PMID: #19734473#

- Takuno S, Innan H. Evolution of complexity in miRNA-mediated gene regulation systems. Trends Genet. 2008 Feb;24(2):56-9. PMID: #18192068#

- van Rooij E, Liu N, Olson EN. MicroRNAs flex their muscles.Trends Genet. 2008 Apr;24(4):159-66. PMID: #18325627#

- Gardner PP, Vinther J. Mutation of miRNA target sequences during human evolution. Trends Genet. 2008 May 8. PMID: #18472179#

- Callis TE, Wang DZ. Taking microRNAs to heart. Trends Mol Med. 2008 May 3. PMID: #18457996#

- Cui Q, Yu Z, Purisima EO, Wang E. MicroRNA regulation and interspecific variation of gene expression. Trends Genet. 2007 Aug;23(8):372-5. PMID: #17482307#

- He L, He X, Lowe SW, Hannon GJ. microRNAs join the p53 network—another piece in the tumour-suppression puzzle. Nat Rev Cancer. 2007 Nov;7(11):819-22. PMID: #17914404#

- Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM. MicroRNA expression and function in cancer. Trends Mol Med. 2006 Dec;12(12):580-7. PMID: #17071139#

- Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006 Nov;6(11):857-66. PMID: #17060945#

- Kim VN, Nam JW. Genomics of microRNA. Trends Genet. 2006 Mar;22(3):165-73. PMID: #16446010#

- Hammond SM. MicroRNA therapeutics: a new niche for antisense nucleic acids. Trends Mol Med. 2006 Mar;12(3):99-101. PMID: #16473043#

- Yi R, O’carroll D, Pasolli HA, Zhang Z, Dietrich FS, Tarakhovsky A, Fuchs E. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat Genet. 2006 Feb 5; PMID: #16462742#

- Harfe BD. MicroRNAs in vertebrate development. Curr Opin Genet Dev. 2005 Aug;15(4):410-5. PMID: #15979303#

- Miska EA. How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev. 2005 Oct;15(5):563-8. PMID: #16099643#

- Yi R, O’carroll D, Pasolli HA, Zhang Z, Dietrich FS, Tarakhovsky A, Fuchs E. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs.
Nat Genet. 2006 Feb 5; PMID: #16462742#

- Hammond SM. MicroRNAs as oncogenes. Curr Opin Genet Dev. 2006 Feb;16(1):4-9. PMID: #16361094#

- Smalheiser NR, Torvik VI. Mammalian microRNAs derived from genomic repeats. Trends Genet. 2005 Jun;21(6):322-6. PMID: #15922829#

- Pasquinelli AE, Hunter S, Bracht J. MicroRNAs: a developing story. Curr Opin Genet Dev. 2005 Apr;15(2):200-5. PMID: #15797203#

- Tomari Y, Zamore PD. MicroRNA Biogenesis: Drosha Can’t Cut It without a Partner. Curr Biol. 2005 Jan 26;15(2):R61-4. PMID: #15668159#

- Xu P, Guo M, Hay BA. MicroRNAs and the regulation of cell death. Trends Genet. 2004 Dec;20(12):617-24. Review. PMID: #15522457#

- He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004 Jul;5(7):522-31. PMID: #15211354#

- Nakahara K, Carthew RW. Expanding roles for miRNAs and siRNAs in cell regulation. Curr Opin Cell Biol. 2004 Apr;16(2):127-33. PMID: #15196554#

References

- Microfluidic primer extension assay. Beier M, Boisguérin V. Methods Mol Biol. 2012;822:143-52. PMID: #22144197#