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PubMed2007

MicroRNA: past and present.

MicroRNAs (miRNAs) are approximately 22 nucleotide (nt) non-coding RNAs that participate in gene regulation. MiRNAs confer their regulation at a post-transcriptional level, where they either cleave or repress translation of mRNAs. Over 3000 identified mature miRNAs exist in species ranging from plants to humans, suggesting that they are ancient players in gene regulation. A relatively small number of miRNAs have been experimentally tested for their function. Of those tested, functions including cell differentiation, proliferation, apoptosis, anti-viral defense and cancer have been proposed. Improved software programs are now able to predict the targets of miRNAs in a more efficient manner, thus facilitating the elucidation of miRNA function. Furthermore, methods such as real-time PCR and microarray have been enhanced for studying miRNA expression. Using these tools, scientists are able to discover novel functions for miRNAs. It is possible that miRNAs will be revealed as having a role in virtually every aspect of gene regulation. This review guides readers through the biogenesis of miRNAs, their mechanism of action on their target mRNAs, the functional outcomes of their action on mRNAs and the current techniques to investigate these processes.

Animals↗

PubMed2017

MicroRNA‑27a promotes tumorigenesis via targeting AKT in triple negative breast cancer.

Altered microRNA (miRNA/miR) expression regulates tumor development and progression in triple‑negative breast cancer (TNBC). The present study examined the effect of miR‑27a on proliferation, migration and invasion of TNBC cells in vitro and in vivo. An MTT assay was performed to examine the proliferation of MDA‑MB‑231 and MDA‑MB‑468 breast cancer cells with either overexpression of miR‑27a or downregulation of miR‑27a, in the presence or absence of radiation. The migratory and invasive abilities of MDA‑MB‑231 and MDA‑MB‑468 breast cancer cells were assessed by Transwell migration and Matrigel invasion assays. The protein expression levels were examined by western blotting. The caspase‑Glo3/7 assay was performed to examine the effect of miR‑27a on radiation‑induced apoptosis in MDA‑MB‑231 and MDA‑MB‑468 breast cancer cells. A luciferase assay was performed to evaluate the effect of miR‑27a on phosphatase and tensin homolog (PTEN) and B cell lymphoma (Bcl)‑2 associated X, apoptosis regulator (BAX) expression. Immunodeficient nude mice were used to examine tumor growth following injection of MDA‑MB‑231 breast cancer cells. miR‑27a promoted proliferation in vitro and in vivo, and enhanced migration and invasion in TNBC cells. miR‑27a improved the survival of TNBC cells following irradiation. miR‑27a inhibited radiation‑induced apoptosis in TNBC cells by regulation of caspase 3/7 and Bcl‑2 expression. Furthermore, the expression levels of PTEN and phosphorylated protein kinase B in MDA‑MB‑231 and MDA‑MB‑468 cells was altered following overexpression of miR‑27a. The luciferase assay demonstrated that miR‑27a regulated PTEN and BAX expression by binding to 3'‑untranslated regions. Overall, miR‑27a exhibits an essential role in tumor development and progression in TNBC and may be used as a potential biomarker to predict radiotherapy response and prognosis for the disease.

3' Untranslated Regions↗

PubMed2006

MicroRNA trafficking and human cancer.

MicroRNAs (miRNAs) are short endogenous noncoding small RNA molecules with 21 to 25 nucleotides (nt) in length, which negatively regulate gene expression either by degrading specific mRNA or impeding translation at the transcriptional and post-transcriptional level. Recent advances suggest that miRNAs play prominent roles in development, genome organization, viral and transposon defense, and human disease, including neurodegenerative and metabolic diseases. Surprisingly, miRNAs are now linked with a variety of cancers, in which a reduced expression or overexpression may lead to oncogene or tumor suppressor gene-like actions. Here we will overview the miRNA pathway and its regulation with emphasis on the links with human cancer. Finally potential applications of miRNA in tumor diagnosis and therapy will be discussed.

Gene Expression Regulation, Neoplastic↗

PubMed2005

MicroRNAs: critical regulators of development, cellular physiology and malignancy.

MicroRNAs (miRNAs) are 18-24 nucleotide RNA molecules that regulate the stability or translational efficiency of target mRNAs. These regulatory RNAs function by acting as sequence-specific guides which recruit a large protein complex known as the RNA-induced silencing complex, or RISC, to target mRNAs which are subsequently silenced. Diverse functions have been attributed to miRNAs including the regulation of cellular differentiation, proliferation, and apoptosis. Moreover, significant evidence has accumulated implicating a fundamental role for miRNAs in the development of cancer. We recently demonstrated that the oncogenic transcription factor c-Myc regulates a group of miRNAs known as the mir-17 cluster. This represents the first documented example of a mammalian transcription factor that regulates miRNA expression. Moreover, it was independently demonstrated that the mir-17 cluster accelerates c-Myc-induced lymphomagenesis in an in vivo mouse model. Together, these studies support an important role for this group of miRNAs in c-Myc-mediated tumorigenesis. We have also demonstrated that two miRNAs in this cluster regulate the pro-proliferative, pro-apoptotic transcription factor E2F1. Herein, we propose a model in which the mir-17 cluster prevents excessive E2F1 activity, and thereby apoptosis, in response to activation of c-Myc.

3' Untranslated Regions↗

PubMed2006

MicroRNAs: a new insight into cancer genome.

Cancer is a disease involving multi-step dynamic changes in the genome. However, studies on cancer genome so far have focused most heavily on protein-coding genes, and our knowledge on alterations of the functional noncoding sequences in cancer is largely absent. MicroRNAs (miRNA) are approximately 22 nt noncoding RNAs, which regulate gene expression in a sequence-specific manner via translational inhibition or mRNA degradation. Mounting evidence is showing that miRNAs may play important roles in tumor development, and a better understanding of their alteration in cancer genome and oncogenic property should contribute to the diagnosis and treatment of cancer.

Epigenesis, Genetic↗

PubMed2006

Epigenetic activation of tumor suppressor microRNAs in human cancer cells.

MicroRNAs (miRNAs) are small noncoding RNAs that function as endogenous post-transcriptional silencers of target genes. miRNAs are expressed in a tissue specific manner and play important roles in cell proliferation, apoptosis and differentiation during animal development. Recent studies have shown a distinct connection between aberrant expression of miRNAs and the development of cancer, suggesting that miRNAs can be potential therapeutic targets. Our recent study has shown that some miRNAs are controlled by epigenetic alterations such as DNA methylation and histone modification in human cancer cells. Activation of tumor suppressor miRNAs by chromatin modifying drugs may cause downregulation of target oncogenes and could be a novel strategy for the prevention and treatment of human cancer.

Epigenesis, Genetic↗

PubMed2006

The MicroRNA pathway plays a regulatory role in stem cell division.

One of the key characteristics of stem cells is their capacity for self-renewal for long periods of time. In this respect, stem cells are similar to cancer cells, which also have the ability to escape cell cycle stop signals. Therefore, a critical question in stem cell and cancer biology is how cell division is regulated in these cell types. In this review, we summarize recent progress and describe future challenges to understanding the role the microRNA pathway plays in regulating mechanisms controlling stem cell division.

Animals↗

PubMed2006

A new role for microRNA pathways: modulation of degeneration induced by pathogenic human disease proteins.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of target transcript mRNAs. Many miRNAs have been defined, however their roles and the processes influenced by miRNA pathways are still being elucidated. A role for miRNAs in development and cancer has been described. We recently isolated the miRNA bantam (ban) in a genetic screen for modulators of pathogenicity of a human neurodegenerative disease model in Drosophila. These studies showed that upregulation of ban mitigates degeneration induced by the pathogenic polyglutamine (polyQ) protein Ataxin-3, which is mutated in the human polyglutamine disease spinocerebellar ataxia type 3 (SCA3). To address the broader role for miRNAs in neuroprotection, we also showed that loss of all miRNAs, by dicer mutation, dramatically enhances pathogenic polyQ protein toxicity in flies and in human HeLa cells. These studies suggest that miRNAs may be important for neuronal survival in the context of human neurodegenerative disease. These studies provide the foundation to define the miRNAs involved in neurodegenerative disease, and the biological pathways affected.

Animals↗

PubMed2004

miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1.

These studies show that miR-122, a 22-nucleotide microRNA, is derived from a liver-specific noncoding polyadenylated RNA transcribed from the gene hcr. The exact sequence of miR-122 as well as the adjacent secondary structure within the hcr mRNA are conserved from mammalian species back to fish. Levels of miR-122 in the mouse liver increase to half maximal values around day 17 of embryogenesis, and reach near maximal levels of 50,000 copies per average cell before birth. Lewis et al. (2003) predicted the cationic amino acid transporter (CAT-1 or SLC7A1) as a miR-122 target. CAT-1 protein and its mRNA are expressed in all mammalian tissues but with lower levels in adult liver. Furthermore, during mouse liver development CAT-1 mRNA decreases in an almost inverse correlation with miR-122. Eight potential miR-122 target sites were predicted within the human CAT-1 mRNA, with six in the 3'-untranslated region. Using a reporter construct it was found that just three of the predicted sites, linked in a 400-nucleotide sequence from human CAT-1, acted with synergy and were sufficient to strongly inhibit protein synthesis and reduce mRNA levels. In summary, these studies followed the accumulation during development of miR-122 from its mRNA precursor, hcr, through to identification of what may be a specific mRNA target, CAT-1.

Animals↗

PubMed2005

Rational probe optimization and enhanced detection strategy for microRNAs using microarrays.

MicroRNAs (miRNAs) are post-transcriptional regulators participating in biological processes ranging from differentiation to carcinogenesis. We developed a rational probe design algorithm and a sensitive labelling scheme for optimizing miRNA microarrays. Our microarray contains probes for all validated miRNAs from five species, with the potential for drawing on species conservation to identify novel miRNAs with homologous probes. These methods are useful for high-throughput analysis of micro RNAs from various sources, and allow analysis with limiting quantities of RNA. The system design can also be extended for use on Luminex beads or on 96-well plates in an ELISA-style assay. We optimized hybridization temperatures using sequence variations on 20 of the probes and determined that all probes distinguish wild-type from 2 nt mutations, and most probes distinguish a 1 nt mutation, producing good selectivity between closely-related small RNA sequences. Results of tissue comparisons on our microarrays reveal patterns of hybridization that agree with results from Northern blots and other methods.

Animals↗

PubMed2003

Reduced accumulation of specific microRNAs in colorectal neoplasia.

Short non-coding RNAs are known to regulate cellular processes including development, heterochromatin formation, and genomic stability in eukaryotes. Given the impact of these processes on cellular identity, a study was undertaken to investigate possible changes in microRNA (miRNA) levels during tumorigenesis. A total of 28 different miRNA sequences was identified in a colonic adenocarcinoma and normal mucosa, including 3 novel sequences and a further 7 that had previously been cloned only from mice. Human homologues of murine miRNA sequences, miR-143 and miR-145, consistently display reduced steady-state levels of the mature miRNA at the adenomatous and cancer stages of colorectal neoplasia.

Adenocarcinoma↗

PubMed2005

Computational identification of novel family members of microRNA genes in Arabidopsis thaliana and Oryza sativa.

MicroRNAs (miRNAs) are a class of endogenous small RNAs that play important regulatory roles in both animals and plants. miRNA genes have been intensively studied in animals, but not in plants. In this study, we adopted a homology search approach to identify homologs of previously validated plant miRNAs in Arabidopsis thaliana and Oryza sativa. We identified 20 potential miRNA genes in Arabidopsis and 40 in O. sativa, providing a relatively complete enumeration of family members for these miRNAs in plants. In addition, a greater number of Arabidopsis miRNAs (MIR168, MIR159 and MIR172) were found to be conserved in rice. With the novel homologs, most of the miRNAs have closely related fellow miRNAs and the number of paralogs varies in the different miRNA families. Moreover, a probable functional segment highly conserved on the elongated stem of pre-miRNA fold-backs of MIR319 and MIR159 family was identified. These results support a model of variegated miRNA regulation in plants, in which miRNAs with different functional elements on their pre-miRNA fold-backs can differ in their function or regulation, and closely related miRNAs can be diverse in their specificity or competence to downregulate target genes. It appears that the sophisticated regulation of miRNAs can achieve complex biological effects through qualitative and quantitative modulation of gene expression profiles in plants.

Arabidopsis↗

PubMed2005

Synthetic microRNA and double-stranded RNA targeting the 3'-untranslated region of HER-2/neu mRNA inhibit HER-2 protein expression in ovarian cancer cells.

MicroRNA (miRNA) are a class of non-coding RNAs found both in normal tissues and cancer cells. The natural miRNA, which target cancer genes for transcriptional repression are still unknown. Approaches for synthetic miRNA design targeting cancer genes have not yet been established. We designed miRNAs targeting the 3' UTR (nt 4350-4372) of HER-2 proto-oncogene. One miRNA (miR-14U) was designed by introducing a mutation in the nt 14 counting from the 5' end of anti-sense RNA. Two others (miR4350-10GGA and miR4350-11AAGCU) were designed by introducing either loop-forming nucleotides in position 10 or a part of the complementary sequence of the Brd-box consensus sequence, in position 11. miR4350-10GGA was more effective than the anti-sense strand in decreasing the numbers of ovarian tumor SKOV3 cells, which over-expressed HER-2 protein. Its inhibitory effects were lower than that of corresponding double-stranded (ds) RNA4350-4372. Inhibition of HER-2 expression mediated by miRNAs was higher in cells expressing higher levels of HER-2 protein than in cells expressing lower levels of HER-2 protein. This is the first demonstration of inhibition of expression of a constitutively over-expressed tumor protein by designed synthetic miRNA and its cor-responding dsRNA targeting 3' untranslated regions in mRNA. Our results also show that measuring the effects of miRNA and dsRNA in pooled populations of tumor cells, which express various levels of target oncogenes, may reflect the survival responses of siRNA resistant tumors rather than the growth inhibitory responses of siRNA-sensitive tumors.

3' Untranslated Regions↗

PubMed2006

An approach for the identification of microRNA with an application to Anopheles gambiae.

MicroRNAs (miRNAs) are an abundant class of 20-27 nt long noncoding RNAs, involved in post-transcriptional regulation of genes in eukaryotes. These miRNAs are usually highly conserved between the genomes of related organisms and their pre-miRNA transcript, about 60-120 nt long, forms extended stem-loop structure. Keeping these facts in mind miRsearch is developed which relies on searching the homologues of all known miRNAs of one organism in the genome of a related organism allowing few mismatches depending on the phylogenetic distance between them, followed by assessing for the capability of formation of stem-loop structure. The precursor sequences so obtained were then screened through the RNA folding program MFOLD selecting the cut-off values on the basis of known Drosophila melanogaster pre-miRNAs. With this approach, about 91 probable candidate miRNAs along with pre-miRNAs were identified in Anopheles gambiae using known D. melanogaster miRNAs. Out of these, 41 probable miRNAs have 100% similarity with already known D. melanogaster miRNAs and others were found to be at least 85% similar to the miRNAs of various other organisms.

Animals↗

PubMed2006

MicroRNAs: small but potent oncogenes or tumor suppressors.

MicroRNAs (miRNAs) are small, non-coding RNAs that modulate the expression of target mRNA. Many miRNAs are known to be up- or downregulated in a variety of cancers, suggesting a role for miRNAs in tumorigenesis. The correlation between the expression of miRNAs and their effects on target oncogenes, on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidence. For example, the miRNA (miR)-17-92 cluster has been characterized as an oncogene, while let-7 represses Ras and miR-15a/-16-1 represses Bcl-2, thereby acting as tumor suppressors. Thus, an oncogenic or tumor suppressive miRNA may have potential as a therapeutic target to control cancers. This review will discuss the relationship between miRNAs and tumorigenesis, and the potential for modulating miRNAs for the treatment of cancer.

Animals↗

PubMed2006

MicroRNAs of the mammalian eye display distinct and overlapping tissue specificity.

PURPOSE: In mammals, endogenous, noncoding RNAs, designated as microRNAs (miRNAs), inhibit the translation of a target messenger RNA, thereby silencing protein production. MiRNAs have been shown to regulate many aspects of development and differentiation in a wide range of tissues. Surprisingly, little consideration has been directed towards characterizing the expression of miRNAs in mammalian ocular tissues. METHODS: Low molecular weight (LMW) RNA isolated from the adult mouse corneal epithelium, lens/ciliary body, and a retina fractions of the eye was analyzed by miRNA arrays. The validity of the miRNA expression profiles were confirmed by northern blots and the tissue distribution of selected miRNAs was determined by in situ hybridization. RESULTS: MiRNAs exhibited distinct tissue and cell-type specificity in the ocular regions studied. MiRNA (mir)-184 had the highest hybridization signal in the corneal and lens arrays. In situ hybridization analysis revealed that mir-184 was expressed in the basal and immediately suprabasal cells of the corneal epithelium. In contrast, expression of mir-205 was detected throughout the anterior segmental epithelia as well as in the epidermis. Within the lens, expression of mir-184 was more strongly expressed in the epithelial cells of the germinative zone, whereas expression of mir-204 was uniformly expressed in all lens epithelial cells. Mir-181, -182, and -183 were detected in retinal and brain tissues, and their distribution patterns within the retina were both distinct and overlapping. CONCLUSIONS: The tissue and cell specificity of ocular miRNAs suggests that these noncoding RNAs may be regulating aspects of development and differentiation.

Animals↗

PubMedDate not supplied

[Great potential of small RNAs: RNA interference and microRNA].

Double-stranded RNA (dsRNA) induces a sequence-specific silencing in eukaryotic cells. This silencing process beggins when long dsRNA is cleaved to 21 to 26 long small RNA by means of the RNAse III-type enzyme Dicer. These small dsRNA are included into silencing effector complexes, that are targeted to complementary sequences. Small RNA dependent gene silencing can be achieved by distinct mechanisms based depending mainly on the nature of target sequences and on the proteins present in the effector complex. The route of interference RNA (RNAi) begins when Dicer yields small interference RNA (siRNA) that bind to complementary mRNA for its degradation, forming the RISC complex. siRNA are naturally formed from transposons and dsRNA viruses during its replication, as well as from other bidirectional transcribed repetitive sequences. Some of the enzymes thar are part of the RNAi machinery, including Dicer, are encoded by multigene families in many species, that also play a role in other mechanisms of RND-dependent gene silencing. MicroRNA's (miRNA) are other small RNA's that can induce gene silencing at the mRNA level. These are formed in a general manner when Dicer process hairpin structures resulting from the transcription of non-coding sequences from plant and animal genomes. miRNA's are integrated into a RISC-like complex, after which, depending on their degree of complementarity with target mRNA, can either repress translation or induce mRNA degradation. miRNA-dependent silencing is essential for the development of multicellular organisms. Artificial RNAi induction by means of siRNA or miRNA is being used as a tool to inactivate gene expression in culture cells and in living organisms. This review focuses on the progress in the understanding of the mechanisms involved in gene regulation by RNA in animals and details some current efforts to apply theses phenomena as a tool in research and in the therapeutic of human diseases.

Humans↗

PubMedDate not supplied

The emerging world of microRNAs.

MicroRNAs (miRNAs) are a family of naturally occurring, evolutionary conserved, small (approximately 19-23 nucleotides), non-protein-coding RNA molecules that generally negatively regulate post-transcriptional gene expression. miRNAs are estimated to account for >3% of all human genes and to control expression of thousands of target mRNAs, with multiple miRNAs targeting each mRNA. A role for miRNAs has been identified in both normal physiological and pathological conditions, including metabolism, proliferation, cell death, differentiation and development, insulin secretion from pancreatic beta cells, viral infection and cancer. Antisense technologies have been successfully used to control miRNA expression in vitro and in vivo. Further analysis of this interesting class of small RNAs, in normal and pathological conditions, will enable us determine their potential to be exploited as therapeutic targets in disease.

MicroRNAs↗