1,721,171 research outputs found
Role of variations within microRNA-binding sites in cancer.
No full textOver 2000 microRNA (miRNA) sequences from different species have been submitted to the miRBase, the central online repository for miRNAs, making a total of 5071 miRNA loci, expressing 5922 distinct mature miRNA sequences. In this review, we have addressed the importance of the genetic variations in humans affecting miRNAs, their target genes and the genes involved in miRNA processing for individual risk of cancer, with particular emphasis on colorectal cancer. In fact, the number of studies suggesting that individual predisposition to cancer is modulated by genetic polymorphisms affecting the biogenesis of miRNA and the interaction between miRNAs and targets has risen steeply in the last few years. We also report the first evidence that variant alleles of single-nucleotide polymorphisms (SNPs) within miRNA genes and miRNA targets, previously associated with the risk of cancer, behave differently when tested in functional studies. The SNPs belonging to the miRNA world are certainly contributing to new insights in the field of the genetic predisposition to disease
Bona fide targets of deregulated microRNAs in non-small cell lung cancer as tool to identify novel therapeutic targets. A review.
Full text linkBACKGROUND:
Non-small-cell lung cancer (NSCLC) is an aggressive neoplasm with a poor survival and novel therapies are urgently needed. The study of deregulated micro-RNAs (dereg-miRs) could constitute a strategy helping to detect specific genes playing a relevant role in the disease. Thus, the oncoproteins encoded by these genes could be exploited as novel therapeutic targets to be inhibited by small molecules, aptamers, or monoclonal antibodies.
METHODS:
The present review is focused on candidate genes having convincing biological evidences to be both bona fide targets for dereg-miRs and playing a role in NSCLC progression. These genes were evaluated according to the molecular pathway they belong. Moreover, in the attempt to provide an even broader list of candidate therapeutic targets for NSCLC, the full list of genes was analyzed using the online tool Interactome DB.
RESULTS:
Among the identified targets, some of them belong to p53 or MAP kinase signaling pathways, and others include caspases, MCL1, and BCL2L2 (playing a role in apoptosis), ZEB1, ZEB2, and USP25 (epithelial-to-mesenchymal transition), EZH2, SOX9, and HOXA5 (differentiation), Paxillin, LIMK1 and MTDH (cytoskeleton remodeling), and HDGF (angiogenesis). In addition, other targets, such as TIMP-2, PIM-1, and components of the IGF-signaling pathways were suggested following the interactome analysis.
CONCLUSION:
Studies on dereg-miRs helped to identify a set of genes whose encoded proteins could constitute candidates for future therapeutic approaches
MicroRNA binding site polymorphisms as biomarkers in cancer management and research.
No full textMicroRNAs (miRNAs) are important regulators of eukaryotic gene expression. They have been implicated in a broad range of biological processes, and miRNA-related genetic alterations probably underlie several human diseases. Single nucleotide polymorphisms of transcripts may modulate the posttranscriptional regulation of gene expression by miRNAs and explain interindividual variability in cancer risk and in chemotherapy response. On the basis of recent association studies published in the literature, the present review mainly summarizes the potential role of miRNAs as molecular biomarkers for disease susceptibility, diagnosis, prognosis, and drug-response prediction in tumors. Many clues suggest a role for polymorphisms within the 3' untranslated regions of KRAS rs61764370, SET8 rs16917496, and MDM4 rs4245739 as SNPs in miRNA binding sites highly promising in the biology of human cancer. However, more studies are needed to better characterize the composite spectrum of genetic determinants for future use of markers in risk prediction and clinical management of diseases, heading toward personalized medicine
Single tube genotyping of GSTM1, GSTT1 and TP53 polymorphisms by multiplex PCR
No full textGlutathione S-transferases (GST) are enzymes involved in the conjugation of a number of human carcinogens, while p53 tumour suppressor gene is the most frequently mutated gene identified till now in human neoplasias. Typically, GSTM1 and GSTT1 genotyping are performed together, with several different protocol described and sometimes with the risk of misclassification due to "false negative", depending on the internal positive control employed. Here, we report a modification of the classical multiplex polymerase chain reaction (PCR) method, allowing the genotyping of GSTM1, GSTT1, together with a polymorphism within the intron 3 of TP53 tumour suppressor gene (a 16 base pairs (bp) duplication) in a single tube, with an appropriate internal positive control. To test the applicability of the method, the frequencies of the deleted alleles of GSTM1 and GSTT1 (null genotypes), and the 16 bp duplication of TP53 gene were assayed in a series of Caucasian DNA samples
A review of strategies based on primer extension (PEX) technology
No full textin primer extension (PEX) reaction, a DNA polymerase is used to extend specifically a primer that anneals immediately adjacent to the variant nucleotide. The reaction allows highly specific detection of point mutations and single nucleotide polymorphisms (SNPs). Because all SNPs can be analyzed with high specificity at the same reaction conditions, PEX is a promising reaction principle for multiplex high-throughput genotyping assays. This review discusses the possible applications of PEX and different approaches of primer extension reactions
COMPASSS (COMplex PAttern of Sequence Search Software), a simple and effective tool for mining complex motifs in whole genomes
No full textMOTIVATION: The complete sequencing of the human genome shows that only 1% of the entire genome encodes for proteins. The major part of the genome is made up of non-coding DNA, regulatory elements and junk DNA. Transcriptional regulation plays a central role in a multitude of critical cellular processes and responses, and it is a central force in the development and differentiation of multicellular organisms. Identifying regulatory elements is one of the major tasks in this challenge. To accomplish this task, we developed a solid and simple suite that allows direct access to genomic database and immediate result check. We introduce COMPASSS (COMplex PAttern of Sequence Search Software), a simple and effective tool for motif search in entire genomes. Motifs can be partially degenerated and interrupted by spacers of variable length.
RESULTS: We demonstrate through real biological data mining the simplicity and robustness of this tool. The test was performed on two well-known protein domains and a highly variable cis-acting element. COMPASSS successfully identifies both protein domains and cis-acting semi-conserved elements.
AVAILABILITY: The COMPASSS suite is available for Windows free of charge from our web sites: compasss.sourceforge.net/; www.stefanolandi.eu
Platelet phenolsulphotransferase activity, monoamine oxidase activity and peripheral-type benzodiazepine binding in demented patients
No full textBlood platelet phenolsulphotransferase and monoamine oxidase activities, as well as platelet peripheral-type benzodiazepine binding have been studied in several neuropsychiatric disorders, in order to identify biochemical markers for altered brain functioning. In the present work, we determined platelet phenolsulphotransferase and monoamine oxidase activities in demented patients: they showed significantly higher phenolsulphotransferase and monoamine oxidase activities than controls. A significant positive correlation was found between enzyme activities and severity of illness. In the same subjects, we evaluated platelet peripheral-type benzodiazepine binding: a significant reduction of Bmax values was observed in demented patients, whereas Kd values did not substantially differ between the two subject groups. These findings are discussed with reference to central nervous system biochemical abnormalities of demented subjects: it may be that in Dementia of Alzheimer type either some central biochemical changes are reflected in certain peripheral tissues (such as platelets), or a systemic derangement occurs together with a cerebral involvement
A database of single-nucleotide polymorphisms and a genotyping microarray for genetic epidemiology of lung cancer
No full textThe authors set up a database of 105 genes potentially related to lung cancer susceptibility and 464 of their polymorphisms. The database is based on extensive literature searches, and includes genes likely to influence the internal dose of genotoxic compounds that reach the lungs, following exposure to environmental insults, such as tobacco smoke. The authors selected a subset of 250 single-nucleotide polymorphisms with appreciable frequency in at least one major ethnic group and/or a clear functional role, which represent the best candidates as lung cancer risk factors. They developed a microarray for genotyping these polymorphisms, based on arrayed primer extension (APEX)
T-lymphocyte peripheral-type benzodiazepine binding in parkinsonian patients
No full textuman peripheral blood cells, especially lymphocytes and platelets, are being studied increasingly in neuropsychiatric research both as tools for investigating systemic disturbances in neuropsychiatric disorders, and as peripheral models for getting information on central nervous system biochemistry. In this study, we determined T lymphocyte peripheral-type benzodiazepine binding in parkinsonians and controls: significantly reduced B(max) values were found in patients compared with healthy controls, whereas K(d) values were similar. These data argue for an immune response disturbance and a cell energy metabolism impairment in parkinsonian patients, since cell surface peripheral-type benzodiazepine receptors are related with the immune function, and mitochondrial binding sites with energy metabolic pathways
A Catalog of Polymorphisms Falling in MicroRNA-Binding Regions of Cancer Genes
No full textRecent evidence indicates that small, nonprotein-coding RNA molecules, called microRNAs (miRNAs), control cell growth, differentiation, and apoptosis, and are also involved in tumorigenesis. miRNAs can bind to the 3' untranslated regions (3'UTRs) of messenger RNAs and interfere with their translation. We hypothesized that common polymorphisms within their genes or within their targets could have an important impact for an individual's risk to develop complex diseases. In this study, we selected the 3'UTRs of 129 genes involved in pathways commonly acknowledged as important for cancer, and we identified putative miRNA-binding sites by means of specialized algorithms (PicTar, DIANA-MicroT, miRBase, miRanda, TargetScan, and MicroInspector). Then we investigated 79 single-nucleotide polymorphisms (SNPs) within the putative binding sites for their ability to affect or impair the binding with the miRNA by assessing the DeltaDeltaG, the variation of DeltaG (Gibbs free energy), through comparing the wild-type and their corresponding variant alleles. Moreover, we reported seven identified SNPs in seven pre-miRNA hairpin regions and one SNP in the mature sequence of miR-608. Considering the validation status of the SNPs and their frequencies, we found at least 23 candidate polymorphisms of biological relevance that we propose for further investigation in case-control association studies
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