Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor
10 Feb 2009-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 106, Iss: 6, pp 1814-1819
TL;DR: This work finds that miR-182, member of a miRNA cluster in a chromosomal locus frequently amplified in melanoma, is commonly up-regulated in human melanoma cell lines and tissue samples and suggests that miRNA silencing may be a worthwhile therapeutic strategy.
Abstract: The highly aggressive character of melanoma makes it an excellent model for probing the mechanisms underlying metastasis, which remains one of the most difficult challenges in treating cancer. We find that miR-182, member of a miRNA cluster in a chromosomal locus (7q31-34) frequently amplified in melanoma, is commonly up-regulated in human melanoma cell lines and tissue samples; this up-regulation correlates with gene copy number in a subset of melanoma cell lines. Moreover, miR-182 ectopic expression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo, whereas miR-182 down-regulation impedes invasion and triggers apoptosis. We further show that miR-182 over-expression promotes migration and survival by directly repressing microphthalmia-associated transcription factor-M and FOXO3, whereas enhanced expression of either microphthalmia-associated transcription factor-M or FOXO3 blocks miR-182's proinvasive effects. In human tissues, expression of miR-182 increases with progression from primary to metastatic melanoma and inversely correlates with FOXO3 and microphthalmia-associated transcription factor levels. Our data provide a mechanism for invasion and survival in melanoma that could prove applicable to metastasis of other cancers and suggest that miRNA silencing may be a worthwhile therapeutic strategy.
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TL;DR: In this paper, the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies are discussed.
Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in cellular processes such as inflammation, cell-cycle regulation, stress response, differentiation, apoptosis, and migration. Thus, miRNAs have been implicated in the regulation of virtually all signaling circuits within a cell, and their dysregulation has been shown to play an essential role in the development and progression of cancer. Here, after a brief description of miRNA genomics, biogenesis, and function, we discuss the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies.
1,899 citations
TL;DR: The data suggest that αsyn may be secreted via different secretory pathways, and hypothesize that exosome-mediated release of αsyn oligomers is a mechanism whereby cells clear toxic α synuclein oligomers when autophagic mechanisms fail to be sufficient.
Abstract: Aggregation of alpha-synuclein (αsyn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinson’s disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of αsyn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted αsyn across membranes. The aim of this study is to characterize the transcellular spread of αsyn oligomers and determine their extracellular location. Using a novel protein fragment complementation assay where αsyn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that αsyn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated αsyn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free αsyn oligomers. Specifically, we determine that αsyn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of αsyn oligomers is strongly influenced by autophagic activity. Our data suggest that αsyn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of αsyn oligomers is a mechanism whereby cells clear toxic αsyn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in αsyn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies.
711 citations
Cites background from "Aberrant miR-182 expression promote..."
...182 Repression of tumor suppressors present in exosomes [39,42]...
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TL;DR: It is shown here thatFOXO1 mRNA is down-regulated in breast tumor samples as compared with normal breast tissue and targeting of FOXO1 by microRNAs may contribute to transformation or maintenance of an oncogenic state in breast cancer cells.
548 citations
TL;DR: Insight is provided into the composition and functional properties of exosomes, and components which could be used to enhance the drug delivery properties of Exosome mimetics are focused on.
Abstract: The identification of extracellular phospholipid vesicles as conveyors of cellular information has created excitement in the field of drug delivery. Biological therapeutics, including short interfering RNA and recombinant proteins, are prone to degradation, have limited ability to cross biological membranes, and may elicit immune responses. Therefore, delivery systems for such drugs are under intensive investigation. Exploiting extracellular vesicles as carriers for biological therapeutics is a promising strategy to overcome these issues and to achieve efficient delivery to the cytosol of target cells. Exosomes are a well studied class of extracellular vesicles known to carry proteins and nucleic acids, making them especially suitable for such strategies. However, the considerable complexity and the related high chance of off-target effects of these carriers are major barriers for translation to the clinic. Given that it is well possible that not all components of exosomes are required for their proper functioning, an alternative strategy would be to mimic these vesicles synthetically. By assembly of liposomes harboring only crucial components of natural exosomes, functional exosome mimetics may be created. The low complexity and use of well characterized components strongly increase the pharmaceutical acceptability of such systems. However, exosomal components that would be required for the assembly of functional exosome mimetics remain to be identified. This review provides insights into the composition and functional properties of exosomes, and focuses on components which could be used to enhance the drug delivery properties of exosome mimetics.
440 citations
TL;DR: A Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis is described, and Targeting miR- 218 may provide a strategy for blocking tumor metastasis.
Abstract: MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis.
425 citations
Cites background from "Aberrant miR-182 expression promote..."
...A large number of microribonucleic acids (microRNAs or miRNAs) have been recently implicated in cancer metastasis [5], including miR-10b, miR-21, miR-126, miR-335, miR-373, miR146, miR-520c, and miR-205 in breast cancer [6–11]; miR-224 and miR-21 in prostate cancer [12,13]; miR-29c in nasopharyngeal carcinomas [14]; miR-10a, miR-222, miR-125b, miR-7, and miR-452 in urothelial carcinomas [15]; miR-182 in melanoma [16]; miR-92b and miR-9/9* in brain tumors [17]; and miR-21 in colorectal cancer [18]....
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References
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TL;DR: Two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events and indicate the existence of multiple RISCs that carry out related but specific biological functions.
Abstract: MicroRNAs are a family of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. The two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Since then, hundreds of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals. MicroRNAs have diverse expression patterns and might regulate various developmental and physiological processes. Their discovery adds a new dimension to our understanding of complex gene regulatory networks.
6,282 citations
Rockefeller University1, University of Basel2, Memorial Sloan Kettering Cancer Center3, Swiss Institute of Bioinformatics4, Sapienza University of Rome5, German Cancer Research Center6, Ludwig Maximilian University of Munich7, University of Freiburg8, Miltenyi Biotec9, J. Craig Venter Institute10, Columbia University11, University of Naples Federico II12, University of Düsseldorf13, University of Bonn14, Semmelweis University15, Yeshiva University16, National Institutes of Health17, Cornell University18
TL;DR: A relatively small set of miRNAs, many of which are ubiquitously expressed, account for most of the differences in miRNA profiles between cell lineages and tissues.
3,687 citations
"Aberrant miR-182 expression promote..." refers background in this paper
...miR-182 has been reported to form a gene cluster with two adjacent miRNAs (miR-96 and miR-183) (12, 13) that share highly homologous 5 -seed sequences (Fig....
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TL;DR: The results indicate that microRNAs are components of the molecular circuitry that controls mouse hematopoiesis and suggest that other micro RNAs have similar regulatory roles during other facets of vertebrate development.
Abstract: MicroRNAs (miRNAs) are an abundant class of ∼22-nucleotide regulatory RNAs found in plants and animals. Some miRNAs of plants, Caenorhabditis elegans, and Drosophila play important gene-regulatory roles during development by pairing to target mRNAs to specify posttranscriptional repression of these messages. We identify three miRNAs that are specifically expressed in hematopoietic cells and show that their expression is dynamically regulated during early hematopoiesis and lineage commitment. One of these miRNAs, miR-181, was preferentially expressed in the B-lymphoid cells of mouse bone marrow, and its ectopic expression in hematopoietic stem/progenitor cells led to an increased fraction of B-lineage cells in both tissue-culture differentiation assays and adult mice. Our results indicate that microRNAs are components of the molecular circuitry that controls mouse hematopoiesis and suggest that other microRNAs have similar regulatory roles during other facets of vertebrate development.
3,307 citations
TL;DR: A large number of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals, and their discovery adds a new dimension to the understanding of complex gene regulatory networks.
Abstract: Nature Reviews Genetics 5, 522–531 (2004) In figure 2, the orientation of some RNA structures was incorrect. The corrected version is shown below. This correction has been made to the online enhanced text and PDF version of this review.
2,555 citations
TL;DR: It is shown that miR-10b is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion, and the workings of an undescribed regulatory pathway, in which a pleiotropic transcription factor induces expression of a specific microRNA, which suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumour cell invasion and metastasis.
Abstract: MicroRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumour suppressors, the role of microRNAs in mediating cancer metastasis remains unexplored. Here we show, using a combination of mouse and human cells, that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Overexpression of miR-10b in otherwise non-metastatic breast tumours initiates robust invasion and metastasis. Expression of miR-10b is induced by the transcription factor Twist, which binds directly to the putative promoter of mir-10b (MIRN10B). The miR-10b induced by Twist proceeds to inhibit translation of the messenger RNA encoding homeobox D10, resulting in increased expression of a well-characterized pro-metastatic gene, RHOC. Significantly, the level of miR-10b expression in primary breast carcinomas correlates with clinical progression. These findings suggest the workings of an undescribed regulatory pathway, in which a pleiotropic transcription factor induces expression of a specific microRNA, which suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumour cell invasion and metastasis.
2,502 citations
"Aberrant miR-182 expression promote..." refers background in this paper
...It is interesting to note that strong evidence of altered miRNAs facilitating invasion and metastasis has been recently presented for breast carcinomas (11, 14)....
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