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Journal ArticleDOI

MiR-101 induces senescence and prevents apoptosis in the background of DNA damage in MCF7 cells.

29 Oct 2014-PLOS ONE (Public Library of Science)-Vol. 9, Iss: 10

TL;DR: It is concluded that a threshold range of over-expressed miR-101, capable of inducing mild/moderate DNA damage, is sensed by cells to become senescent, and this observation derives further support from in-silico protein-protein network analysis where the two novel targets showed their involvement in senescence pathway.

AbstractModerately increased DNA damage due to the exogenous miR-101 (4 fold) over-expression in MCF7 cells was substantiated by an increase in the number of γ-H2AX foci, correlating with a simple-to-do Halo-assay. miR-101 induced mild/moderate DNA damage favoured senescence rather than apoptosis. An experimental support emanated from the induced mild/moderate DNA damage with 1 µM/5 µM etoposide in MCF7 cells, which resulted in an endogenous miR-101 over-expression (10/4 fold, respectively), followed by senescence. On the other hand, the severe DNA damage induced with 10 µM etoposide, resulted in a low (<1 fold) endogenous expression of miR-101 and an elevated percentage of apoptotic cells. Using bioinformatics tools along with in-vitro and in-vivo validations, miR-101 was found to target and downregulate the mRNA expression of UBE2N and SMARCA4, involved in DNA damage repair (DDR) pathways. Recovery of the expression of the two novel targets in anti-miR-101 transfection validated the results. We conclude that a threshold range of over-expressed miR-101, capable of inducing mild/moderate DNA damage, is sensed by cells to become senescent. The observation derives further support from in-silico protein-protein network analysis where the two novel targets showed their involvement in senescence pathway.

Topics: DNA damage (63%), Senescence (57%), Endogeny (53%), Cell aging (52%), Transfection (52%)

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Citations
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Journal ArticleDOI
TL;DR: The results encourage the use of Citrus peels, which is wasted in huge amounts, as cancer preventive food additives and as anticancer agents, without any conspicuous toxic symptoms.
Abstract: Background: Citrus comprises the largest fruit sector worldwide, and its fruit peels are the dominant ‘residue’ of the industry. Though not profitable, Citrus peels are industrially used for making some byproducts (cattle feed, molasses, ethanol, fiber) and for the extraction of bioactives (flavonoids, essential oils, d -limonene). Still huge amounts of peels are wasted by Citrus industries, juice and other vending sectors. Purpose: The biological potentials of these unutilized or ‘wasted’ Citrus peels are least exploited. Here we tested the anticancer potentials of Citrus medica (2 morphotypes), C. sinensis, C. maxima, C. limon and C. reticulata peels by in vitro assays and in vivo cancer models. Methods: Chemical profiles of Citrus peel oils and peel extracts were analyzed by gas chromatographic techniques (GC-FID, GC–MS) and HPTLC-densitometry, respectively. Anticancer potentials of Citrus peels (Citrus medica 2 morphotypes, C. sinensis, C. maxima, C. limon and C. reticulata) were evaluated by various in vitro assays (MTT assay, morphological observations, fast halo assay, flow cytometric analysis) and in vivo cancer models. Results: C. reticulata peels (extracts, essential oils) showed significant activity against DLA cell line in MTT assay. We found C. reticulata peel water extract inducing cell cycle arrest of DLA in G0/G1 phase followed by nuclear condensation, membrane blebbing, formation of apoptotic bodies and DNA damage leading to apoptosis. In in vivo experiments, C. reticulata peel extract pre-treated mice were significantly (50%) protected from DLA compared to post-treated mice (33%), without any conspicuous toxic symptoms. Citrus peels have volatiles (essential oils, limonoids) and non-volatiles (mainly polymethoxy flavones) as their bioactive/anticancer constituents. Conclusion: Our results encourage the use of Citrus peels, which is wasted in huge amounts, as cancer preventive food additives and as anticancer agents.

32 citations


Journal ArticleDOI
TL;DR: How microRNA-101 (miR-101) regulates two independent processes of cellular metastasis by targeting pro-metastatic upstream regulatory transcription factors, ZEB1 and ZEB2, and downstream effector-actin modulators, RHOA and RAC1 is shown, providing a single target for therapeutic intervention.
Abstract: Regulation of metastasis continues to remain enigmatic despite our improved understanding of cancer. Identification of microRNAs associated with metastasis in the recent past has provided a new hope. Here, we show how microRNA-101 (miR-101) regulates two independent processes of cellular metastasis by targeting pro-metastatic upstream regulatory transcription factors, ZEB1 and ZEB2, and downstream effector-actin modulators, RHOA and RAC1, providing a single target for therapeutic intervention. Further, we depict how down-regulation of miR-101 by extracellular signal-regulated kinase-2 (ERK2) is vital for MAP kinase pathway induced cellular migration and mesenchymal transition. Importantly, EKR2 induced expression of ZEB1 seems essential for down-regulation of miR-101-1 and induction of EMT. Given the role of EMT in metastasis, we also observe a significant correlation between miR-101 expression and lymph node metastasis; and identify the ERK2-ZEB1-miR-101-1 pathway active in breast cancer tissues, with an apparent clinicopathological implication.

25 citations


Cites background or result from "MiR-101 induces senescence and prev..."

  • ...confirmed by us in an earlier report on the involve ment of miR-101 in senescence [23]....

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  • ...Ectopic expression of miR101 has also been shown to enhance the sensitivity of cancer cells to radiation, cisplatin a d etoposide [23; 32; 33; 34]....

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  • ...results in inhibiting proliferation either by induc ing apoptosis or senescence [23; 24; 25; 26; 27]....

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Journal ArticleDOI
TL;DR: It is found that integrating mRNA and microRNA data revealed an integrated mesenchymal subtype that is consistently associated with poor survival in multiple cohorts of patients with serous ovarian cancer, consisting of 8 major miRNAs and 214 mRNAs.
Abstract: Metastasis is the main cause of cancer mortality. One of the initiating events of cancer metastasis of epithelial tumors is epithelial-to-mesenchymal transition (EMT), during which cells dedifferentiate from a relatively rigid cell structure/morphology to a flexible and changeable structure/morphology often associated with mesenchymal cells. The presence of EMT in human epithelial tumors is reflected by the increased expression of genes and levels of proteins that are preferentially present in mesenchymal cells. The combined presence of these genes forms the basis of mesenchymal gene signatures, which are the foundation for classifying a mesenchymal subtype of tumors. Indeed, tumor classification schemes that use clustering analysis of large genomic characterizations, like The Cancer Genome Atlas (TCGA), have defined mesenchymal subtype in a number of cancer types, such as high-grade serous ovarian cancer and glioblastoma. However, recent analyses have shown that gene expression-based classifications of mesenchymal subtypes often do not associate with poor survival. This “paradox” can be ameliorated using integrated analysis that combines multiple data types. We recently found that integrating mRNA and microRNA (miRNA) data revealed an integrated mesenchymal subtype that is consistently associated with poor survival in multiple cohorts of patients with serous ovarian cancer. This network consists of 8 major miRNAs and 214 mRNAs. Among the 8 miRNAs, 4 are known to be regulators of EMT. This review provides a summary of these 8 miRNAs, which were associated with the integrated mesenchymal subtype of serous ovarian cancer.

25 citations


Cites background from "MiR-101 induces senescence and prev..."

  • ...miR-101 may also induce senescence in breast cancer cells by targeting ubiquitinconjugating enzyme E2N (UBE2N)- and SWI/SNF-related, matrixassociated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4 )([57]) and inhibit the G1-to-S phase transition of cervical cancer cells by targeting FBJ murine osteosarcoma viral oncogene homolog (Fos)([58])....

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  • ...Thus, miR-101 may act as a suppressor of tumor progression. miR-101 may suppress tumor proliferation and migration and induce apoptosis by targeting enhancer of zeste homolog 2 (EZH2)[54,55] and Janus kinase 2 (JAK2)[56]. miR-101 may also induce senescence in breast cancer cells by targeting ubiquitinconjugating enzyme E2N (UBE2N)- and SWI/SNF-related, matrixassociated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4 )[57] and inhibit the G1-to-S phase transition of cervical cancer cells by targeting FBJ murine osteosarcoma viral oncogene homolog (Fos)[58]....

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  • ...Chin J Cancer; 2015; Vol. 34 Issue 1 Chinese Journal of Cancer Like most miRNAs, miR-101 acts as a tumor suppressor in cancers by targeting the 3-UTR of multiple genes, including EZH2[54], UBE2N and SMARCA4 [57], mitogen-activated protein kinase 1 (MAPK1) and Fos[59], Kruppel-like factor 6 (KLF6)[60], DNA (cytosine5-)-methyltransferase 3 alpha (DNMT3A)[61], and cyclooxygenase-2 (COX-2)[62]....

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  • ...34 Issue 1 Chinese Journal of Cancer Like most miRNAs, miR-101 acts as a tumor suppressor in cancers by targeting the 3-UTR of multiple genes, including EZH2([54]), UBE2N and SMARCA4 ([57]), mitogen-activated protein kinase 1 (MAPK1) and Fos([59]), Kruppel-like factor 6 (KLF6)([60]), DNA (cytosine5-)-methyltransferase 3 alpha (DNMT3A)([61]), and cyclooxygenase-2 (COX-2)([62])....

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Journal ArticleDOI
TL;DR: An overview on microRNAs that are involved in the Aβ cascade and their inhibitory impact on their target mRNAs whose products participate in Aβ clearance is discussed.
Abstract: Imbalance between amyloid-beta (Aβ) peptide synthesis and clearance results in Aβ deregulation. Failure to clear these peptides appears to cause the development of Alzheimer’s disease (AD). In recent years, microRNAs have become established key regulators of biological processes that relate among others to the development and progression of neurodegenerative diseases, such as AD. This review article gives an overview on microRNAs that are involved in the Aβ cascade and discusses their inhibitory impact on their target mRNAs whose products participate in Aβ clearance. Understanding of the mechanism of microRNA in the associated signal pathways could identify novel therapeutic targets for the treatment of AD.

15 citations


Journal ArticleDOI
10 Aug 2015-Gene
TL;DR: In vitro studies in the presence and absence of anti-cancer drugs, such as docetaxel resulted in a significant decrease in cellular viability even at a 200-fold reduced dose of the drug in combination with hsa-miR-24-2.
Abstract: MicroRNAs the small (18–22 in length) noncoding RNA molecules are negative regulators of gene expression, modulating biological processes of cell differentiation, survival and death. The latter two phenomena are critical in tumour biology. We provide here the results of human genome wide target prediction of one such microRNA, hsa-miR-24-2, shown to target genes essential for initiating cellular stability and cell survival. The protein–protein interaction study showed important nodes which could affect cell cycle progression and differential oncogenesis. An analysis of hsa-miR-24-2 in sporadic breast tumours showed a negative correlation with metastasis and increasing nodes. The conclusion drawn of hsa-miR-24-2 targeting the genes of cell survival correlated with the methylation profile and resultant transcription factor binding site gain or loss in support of absence of cell survival. In order to accentuate the potential of hsa-miR-24-2 to reduce cellular viability under experimental conditions, in vitro studies in the presence and absence of anti-cancer drugs, such as docetaxel resulted in a significant decrease in cellular viability even at a 200-fold reduced dose of the drug in combination with hsa-miR-24-2.

13 citations


Cites background from "MiR-101 induces senescence and prev..."

  • ...In addition, the effect of such a treatment on senescent cells, over-expressing hsamiR-101 (Manvati et al., 2014), was also expedited....

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  • ..., 2007) and hsa-miR-24-2 in combination and also to understand the effect of such a treatment on senescent cells, overexpressing hsa-miR-101, an inducer of senescence (Manvati et al., 2014)....

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References
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TL;DR: Version 2.8 introduces two powerful new features—Custom Node Graphics and Attribute Equations—which can be used jointly to greatly enhance Cytoscape's data integration and visualization capabilities.
Abstract: Summary: Cytoscape is a popular bioinformatics package for biological network visualization and data integration. Version 2.8 introduces two powerful new features—Custom Node Graphics and Attribute Equations—which can be used jointly to greatly enhance Cytoscape's data integration and visualization capabilities. Custom Node Graphics allow an image to be projected onto a node, including images generated dynamically or at remote locations. Attribute Equations provide Cytoscape with spreadsheet-like functionality in which the value of an attribute is computed dynamically as a function of other attributes and network properties. Availability and implementation: Cytoscape is a desktop Java application released under the Library Gnu Public License (LGPL). Binary install bundles and source code for Cytoscape 2.8 are available for download from http://cytoscape.org. Contact: [email protected]

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TL;DR: This work has predicted target sites on the 3′ untranslated regions of human gene transcripts for all currently known 218 mammalian miRNAs to facilitate focused experiments and suggests that miRNA genes, which are about 1% of all human genes, regulate protein production for 10% or more of allhuman genes.
Abstract: MicroRNAs (miRNAs) interact with target mRNAs at specific sites to induce cleavage of the message or inhibit translation. The specific function of most mammalian miRNAs is unknown. We have predicted target sites on the 3′ untranslated regions of human gene transcripts for all currently known 218 mammalian miRNAs to facilitate focused experiments. We report about 2,000 human genes with miRNA target sites conserved in mammals and about 250 human genes conserved as targets between mammals and fish. The prediction algorithm optimizes sequence complementarity using position-specific rules and relies on strict requirements of interspecies conservation. Experimental support for the validity of the method comes from known targets and from strong enrichment of predicted targets in mRNAs associated with the fragile X mental retardation protein in mammals. This is consistent with the hypothesis that miRNAs act as sequence-specific adaptors in the interaction of ribonuclear particles with translationally regulated messages. Overrepresented groups of targets include mRNAs coding for transcription factors, components of the miRNA machinery, and other proteins involved in translational regulation, as well as components of the ubiquitin machinery, representing novel feedback loops in gene regulation. Detailed information about target genes, target processes, and open-source software for target prediction (miRanda) is available at http://www.microrna.org. Our analysis suggests that miRNA genes, which are about 1% of all human genes, regulate protein production for 10% or more of all human genes.

3,413 citations


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TL;DR: A number of new features in HPRD are added, including PhosphoMotif Finder, which allows users to find the presence of over 320 experimentally verified phosphorylation motifs in proteins of interest, and a protein distributed annotation system—Human Proteinpedia.
Abstract: Human Protein Reference Database (HPRD--http://www.hprd.org/), initially described in 2003, is a database of curated proteomic information pertaining to human proteins. We have recently added a number of new features in HPRD. These include PhosphoMotif Finder, which allows users to find the presence of over 320 experimentally verified phosphorylation motifs in proteins of interest. Another new feature is a protein distributed annotation system--Human Proteinpedia (http://www.humanproteinpedia.org/)--through which laboratories can submit their data, which is mapped onto protein entries in HPRD. Over 75 laboratories involved in proteomics research have already participated in this effort by submitting data for over 15,000 human proteins. The submitted data includes mass spectrometry and protein microarray-derived data, among other data types. Finally, HPRD is also linked to a compendium of human signaling pathways developed by our group, NetPath (http://www.netpath.org/), which currently contains annotations for several cancer and immune signaling pathways. Since the last update, more than 5500 new protein sequences have been added, making HPRD a comprehensive resource for studying the human proteome.

2,857 citations


"MiR-101 induces senescence and prev..." refers methods in this paper

  • ...The DDR and senescence pathway proteins were retrieved from wiki pathway [35] and HPRD [36] database used to retrieve interacting protein of SMARCA4 and UBE2N....

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Journal ArticleDOI
01 Oct 2004-RNA
TL;DR: A program is presented, RNA-hybrid, that predicts multiple potential binding sites of miRNAs in large target RNAs and applied this method to the prediction of Drosophila miRNA targets in 3'UTRs and coding sequence.
Abstract: MicroRNAs (miRNAs) are short RNAs that post-transcriptionally regulate the expression of target genes by binding to the target mRNAs. Although a large number of animal miRNAs has been defined, only a few targets are known. In contrast to plant miRNAs, which usually bind nearly perfectly to their targets, animal miRNAs bind less tightly, with a few nucleotides being unbound, thus producing more complex secondary structures of miRNA/target duplexes. Here, we present a program, RNA-hybrid, that predicts multiple potential binding sites of miRNAs in large target RNAs. In general, the program finds the energetically most favorable hybridization sites of a small RNA in a large RNA. Intramolecular hybridizations, that is, base pairings between target nucleotides or between miRNA nucleotides are not allowed. For large targets, the time complexity of the algorithm is linear in the target length, allowing many long targets to be searched in a short time. Statistical significance of predicted targets is assessed with an extreme value statistics of length normalized minimum free energies, a Poisson approximation of multiple binding sites, and the calculation of effective numbers of orthologous targets in comparative studies of multiple organisms. We applied our method to the prediction of Drosophila miRNA targets in 3′UTRs and coding sequence. RNAhybrid, with its accompanying programs RNAcalibrate and RNAeffective, is available for download and as a Web tool on the Bielefeld Bioinformatics Server (http://bibiserv.techfak.uni-bielefeld.de/rnahybrid/).

2,032 citations


Journal ArticleDOI
TL;DR: The idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence is discussed.
Abstract: For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.

1,634 citations


"MiR-101 induces senescence and prev..." refers background in this paper

  • ...It would be interesting to understand in future if such senescent cells with mil/moderate DNA damage, could turn tumorigenic, since senescent cells have been reported to attain this characteristic [24]....

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