scholarly journals The role of microRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment.

2012 ◽  
Vol 59 (4) ◽  
Author(s):  
Paulina Tokarz ◽  
Janusz Blasiak
Keyword(s):  
Colorectal Cancer ◽  
Cancer Prognosis ◽  
Nucleotide Polymorphisms ◽  
Rna Molecules ◽  
Metastatic Colonization ◽  
Wide Range ◽  
Genes Encoding ◽  
Kras Protein ◽  
A Disintegrin And Metalloproteinase

microRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression by targeting specific mRNAs. microRNAs play a role in several physiological processes in the cell, including migration, proliferation, differentiation and apoptosis. Apart from their role in regular metabolism, abnormal profiles of miRNA expression accompany cancer transformation, including colorectal cancer (CRC) metastasis. microRNAs may play a role in each phase of CRC metastasis including angiogenesis, invasion, intravasation, circulation, extravasation and metastatic colonization. microRNA levels may serve as a predictive CRC marker, which was confirmed by the serum level of miR-29a targeting KLF4, a marker of cell stemness, and the plasma level of miR-221 down-regulating c-Kit, Stat5A and ETS1, which are signal transducers and transcription factor, respectively. In turn, the level of miR-143 in CRC cells decreasing the amount of MACC1 (metastasis-associated in colon cancer-1) and oncogenic KRAS protein, may be utilized as a prognostic marker. Also, single nucleotide polymorphisms of genes encoding miRNAs, including miR-423 and miR-608, which correlate with tumor recurrence, may be useful as diagnostic, prognostic and predictive indicators in CRC metastasis. Pre-miR-34a and pre-miR-199a decreased the level of Axl, a tyrosine-protein kinase receptor, so they can be considered as drugs in antimetastatic therapy. On the other hand, miR-222 targeting ADAM-17, a disintegrin and metalloproteinase, and miR-328 interacting with ABCG2, an ABC transporter, may overcome drug resistance of cancer cells. microRNAs may be considered in wide-range application to facilitate CRC metastasis diagnosis, prognosis, prediction and therapy, however, further clinical, epidemiological and in vitro studies should be conducted to verify their utility.

scholarly journals Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties

2020 ◽  
Author(s):  
Jonathan P. Hutchinson ◽  
Ioannis Temponeras ◽  
Jonas Kuiper ◽  
Adrian Cortes ◽  
Justyna Korczynska ◽  
...  
Keyword(s):  
Antigen Processing ◽  
Catalytic Efficiency ◽  
Enzymatic Properties ◽  
Human Populations ◽  
Substrate Affinity ◽  
Antigenic Peptides ◽  
Nucleotide Polymorphisms ◽  
Recombinant Enzymes ◽  
Wide Range

AbstractObjectivePolymorphic variation of immune system proteins can drive variability of individual immune responses. ER aminopeptidase 1 (ERAP1) generates antigenic peptides for presentation by MHC class I molecules. Coding single nucleotide polymorphisms (SNPs) in ERAP1 have been associated with predisposition to inflammatory rheumatic disease and shown to affect functional properties of the enzyme, but the interplay between combinations of these SNPs as they exist in allotypes, has not been thoroughly explored.MethodsWe used phased genotype data to estimate ERAP1 allotype frequency in 2,504 individuals across five major human populations, generated highly pure recombinant enzymes corresponding to the 10 most common ERAP1 allotypes and systematically characterized their in vitro enzymatic properties.ResultsWe find that ERAP1 allotypes possess a wide range of enzymatic activities, up to 60-fold, whose ranking is substrate-dependent. Strikingly, allotype 10, previously associated with Behçet’s disease, is consistently a low-activity outlier, suggesting that a significant percentage of individuals carry a sub-active ERAP1 gene. Enzymatic analysis revealed that ERAP1 allotypes can differ in both catalytic efficiency and substrate affinity, differences that can change intermediate accumulation in multi-step trimming reactions. Alterations in efficacy of an allosteric inhibitor that targets the regulatory site suggest that allotypic variation influences the communication between the regulatory and the active site.ConclusionOur work defines the wide landscape of ERAP1 activity in human populations and demonstrates how common allotypes can induce substrate-dependent variability in antigen processing, thus contributing, in synergy with MHC haplotypes, to immune response variability and to predisposition to chronic inflammatory conditions.

scholarly journals Selection and Recombinant Phenotyping of a Novel CMX001 and Cidofovir Resistance Mutation in Human Cytomegalovirus

2013 ◽  
Vol 57 (7) ◽  
pp. 3321-3325 ◽  
Author(s):  
Scott H. James ◽  
Nathan B. Price ◽  
Caroll B. Hartline ◽  
E. Randall Lanier ◽  
Mark N. Prichard
Keyword(s):  
Dna Polymerase ◽  
Selective Pressure ◽  
Resistance Mutation ◽  
Artificial Chromosome ◽  
Wild Type ◽  
Phenotypic Resistance ◽  
Genotypic Analysis ◽  
Wide Range ◽  
Genes Encoding

ABSTRACTCMX001 is an orally available lipid acyclic nucleotide phosphonate that delivers high intracellular levels of cidofovir (CDV)-diphosphate and exhibits enhancedin vitroantiviral activity against a wide range of double-stranded DNA viruses, including cytomegalovirus (CMV). Mutations in the DNA polymerase of CMV that impart resistance to CDV also render the virus resistant to CMX001. Here, we report a novel resistance mutation that arose under the selective pressure of CMX001. The wild-type CMV strain AD169 was propagated in human foreskin fibroblasts under increasing concentrations of CMX001 over 10 months, and the resulting strain (named CMX001R) was less susceptible to CDV and CMX001 in a plaque reduction assay. Genotypic analysis of virus strain CMX001Rvia conventional sequencing of the genes encoding the CMV DNA polymerase (UL54) and UL97 kinase (UL97) demonstrated one mutation that changed the wild-type aspartate to glutamate at position 542 inUL54. A recombinant virus with this novel D542E mutation was generated via bacterial artificial chromosome-mediated marker transfer experiments. Subsequent phenotypic resistance analysis of the D542E mutant demonstrated reductions in susceptibility of greater than 10-fold to CMX001 and CDV, but no resistance to foscarnet (FOS) or ganciclovir (GCV). Analysis of replicative fitness showed that both strain CMX001Rand the D542E mutant viruses demonstrated a smaller plaque phenotype and slower replication kinetics than their respective parent viruses. These data describe the first resistance mutation generated under the selective pressure of CMX001 and suggest that CMX001 may have a unique resistance profile associated with reduced viral replication and maintenance of sensitivity to FOS and GCV.

scholarly journals Modelling and Development of Electrical Aptasensors, a Short Review

2018 ◽  
Author(s):  
Rosella Cataldo ◽  
Maria Leuzzi ◽  
Eleonora Alfinito
Keyword(s):  
High Performance ◽  
Short Review ◽  
Live Cells ◽  
Computational Framework ◽  
In Vitro Techniques ◽  
Rna Molecules ◽  
Disease Therapy ◽  
Wide Range ◽  
Targeting Ability

Selected by in vitro techniques (SELEX, cell-SELEX), aptamers are strands of DNA or RNA molecules able to bind a wide range of targets, from small molecules to live cells, and even tissues, with high affinity and specificity. Due to their efficient targeting ability, aptamers are extensively used in different fields of applications. For example, they ensure high performance as cancer-related markers or in recognizing cancer cells. Actually, they represent a promising way for early diagnosis (biosensors) and to deliver imaging agents and drugs, in both cancer imaging and therapy (therapeutic aptamers). Aptamer-based biosensors (aptasensors) have attracted particular attention over the last decades, so as the possibility of using aptamers in disease therapy in substitution of monoclonal antibodies. The paper briefly reviews the most recent literature on this topic, both concerning the advances in biomedical applications and in the development of electrical aptasensors. The investigation concerning the bioelectronics features of aptamers, to be implemented in the development of electrical nanobiosensors, is also reviewed. To this aim, some recent results of a theoretical/computational framework for modelling the electrical properties of biomolecules (Proteotronics) are reported.

scholarly journals Sequence, infectivity and replication kinetics of SARS-CoV-2 isolated from COVID-19 patients in Canada

2020 ◽  
Author(s):  
Arinjay Banerjee ◽  
Jalees A. Nasir ◽  
Patrick Budylowski ◽  
Lily Yip ◽  
Patryk Aftanas ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Productive Infection ◽  
Nucleotide Polymorphisms ◽  
Peripheral Blood Mononuclear ◽  
Single Nucleotide ◽  
Infection Models ◽  
Wide Range ◽  
Kinetics Of

ABSTRACTSARS-CoV-2 emerged in December 2019 in Wuhan, China and has since infected over 1.5 million people, of which over 107,000 have died. As SARS-CoV-2 spreads across the planet, speculations remain about the range of human cells that can be infected by SARS-CoV-2. In this study, we report the isolation of SARS-CoV-2 from two COVID-19 patients in Toronto, Canada. We determined the genomic sequences of the two isolates and identified single nucleotide changes in representative populations of our virus stocks. More importantly, we tested a wide range of human immune cells for productive infection with SARS-CoV-2. Here we confirm that human primary peripheral blood mononuclear cells (PBMCs) are not permissive to SARS-CoV-2. As SARS-CoV-2 continues to spread globally, it is essential to monitor small nucleotide polymorphisms in the virus and to continue to isolate circulating viruses to determine cell susceptibility and pathogenicity using in vitro and in vivo infection models.

scholarly journals Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Eunsu Yoo ◽  
Jaehak Lee ◽  
Pattawika Lertpatipanpong ◽  
Junsun Ryu ◽  
Chong-Tai Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Bioactive Compound ◽  
Binding Activity ◽  
In Vitro Assays ◽  
Transcriptional Level ◽  
Wide Range ◽  
Colorectal Cancer Cells

Abstract Background A. oxyphylla extract is known to possess a wide range of pharmacological activites. However, the molecular mechanism of A. oxyphylla and its bioactive compound nootkatone in colorectal cancer is unknown. Methods Our study aims to examine the role of A. oxyphylla and its bioactive compound nootkatone, in tumor suppression using several in vitro assays. Results Both A. oxyphylla extract and nootkatone exhibited antiproliferative activity in colorectal cancer cells. A. oxyphylla displayed antioxidant activity in colorectal cancer cells, likely mediated via induction of HO-1. Furthermore, expression of pro-apoptotic protein NAG-1 and cell proliferative protein cyclin D1 were increased and decreased respectively in the presence of A. oxyphylla. When examined for anticancer activity, nootkatone treatment resulted in the reduction of colony and spheroid formation. Correspondingly, nootkatone also led to increased NAG-1 expression and decreased cyclin D1 expression. The mechanism by which nootkatone suppresses cyclin D1 involves protein level regulation, whereas nootkatone increases NAG-1 expression at the transcriptional level. In addition to having PPARγ binding activity, nootkatone also increases EGR-1 expression which ultimately results in enhanced NAG-1 promoter activity. Conclusion In summary, our findings suggest that nootkatone is an anti-tumorigenic compound harboring antiproliferative and pro-apoptotic activity.

scholarly journals The kallikrein 14 gene is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness

2012 ◽  
Vol 393 (5) ◽  
pp. 403-412 ◽  
Author(s):  
Felicity Lose ◽  
Mitchell G. Lawrence ◽  
Srilakshmi Srinivasan ◽  
Tracy O’Mara ◽  
Louise Marquart ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gleason Score ◽  
Disease Recurrence ◽  
Cancer Prognosis ◽  
Nucleotide Polymorphisms ◽  
Common Genetic Variants ◽  
Patients At Risk ◽  
Androgen Regulation ◽  
Tumour Characteristics

Abstract Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.

scholarly journals The polymorphisms of extracellular matrix-remodeling genes are associated with pelvic organ prolapse

2022 ◽  
Author(s):  
Lei Li ◽  
Yidi Ma ◽  
Hua Yang ◽  
Zhijing Sun ◽  
Juan Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pelvic Organ Prolapse ◽  
Pelvic Organ ◽  
Matrix Remodeling ◽  
Nucleotide Polymorphisms ◽  
Processing Enzymes ◽  
Tissue Inhibitors Of Metalloproteinase ◽  
Genes Encoding ◽  
A Disintegrin And Metalloproteinase ◽  
Adjusted Model

Abstract Introduction and hypothesis Extracellular matrix (ECM) synthesis and metabolism abnormalities may influence the pelvic supporting system and lead to the occurrence and development of pelvic organ prolapse (POP). Genetic polymorphisms of such related genes have been increasingly studied. This study aims to explore the association between the single-nucleotide polymorphisms (SNPs) of genes encoding ECM processing enzymes (a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTSs]), ECM degrading enzymes (matrix metalloproteinases [MMPs]) and their tissue inhibitors of metalloproteinase (TIMPs), and POP. Methods We conducted an association study including 48 women with POP at stages III and IV and 48 women without prolapse in Chinese groups. SNPs were identified using the target region sequencing technique. We performed Fisher’s exact tests to assess the association between SNPs and POP in the unadjusted model and logistic regression analysis in the adjusted model, adjusting for delivery and pregnancy. Results There was a significant association between TIMP2 SNP rs2277698 (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16–0.82; P = 0.015), ADAMTS13 SNP rs149586801 (OR, 0.18; 95% CI, 0.05–0.69; P = 0.012), and ADAMTS1 SNPs rs370850 and rs422803 (OR, 3.71; 95% CI, 1.35–10.15; P = 0.011 for both), rs402007, rs428785, rs434857, and rs445784 (OR, 2.18; 95% CI, 1.05–4.56; P = 0.038 for the four), and POP in the adjusted model. Conclusion TIMP2, ADAMTS13, and ADAMTS1 might be candidate genes for POP. Our results provide preliminarily new evidence for future investigation of these genes in the pathophysiology of POP.

scholarly journals Functional analyses of a low-penetrance risk variant rs6702619/1p21.2 associating with colorectal cancer in Polish population

2019 ◽  
Author(s):  
Malgorzata Statkiewicz ◽  
Natalia Maryan ◽  
Maria Kulecka ◽  
Urszula Kuklinska ◽  
Jerzy Ostrowski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Long Range ◽  
Cancer Biology ◽  
Polish Population ◽  
Nucleotide Polymorphisms ◽  
Chromosome Conformation ◽  
Functional Studies ◽  
Functional Analyses

Several studies employed the genome-wide association (GWA) analysis of single-nucleotide polymorphisms (SNPs) to identify susceptibility regions in colorectal cancer (CRC). However, the functional studies exploring the role of associating SNPs with cancer biology are limited. Herein, using chromatin immunoprecipitation assay (ChIP), reporter assay and chromosome conformation capture sequencing (3C-Seq) augmented with publically available genomic and epigenomic databases we aimed to define the function of rs6702619/1p21.2 region associated with CRC in the Polish population. Using ChIP we confirmed that rs6702619 region is occupied by a CTCF, a master regulator of long-range genomic interactions, and is decorated with enhancer-like histone modifications. The enhancer blocking assay revealed that rs6702619 region acts as an insulator with activity dependent on the SNP genotype. Finally, a 3C-Seq survey indicated more than a hundred loci in the rs6702619 locus interactome, including GNAS gene that is frequently amplified in CRC. Taken together, we showed that the CRC-associated rs6702619 region has in vitro and in vivo properties of an insulator that demonstrates long-range physical interactions with CRC-relevant loci.

scholarly journals Identification and in silico Characterization of Deleterious Single Nucleotide Variations in Human ZP2 Gene

2021 ◽  
Vol 9 ◽  
Author(s):  
Neha Rajput ◽  
Gagandeep Kaur Gahlay
Keyword(s):  
In Silico ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Computational Tools ◽  
Coding Regions ◽  
Wide Range ◽  
Genes Encoding ◽  
In Silico Characterization ◽  
Dbsnp Database

ZP2, an important component of the zona matrix, surrounds mammalian oocytes and facilitates fertilization. Recently, some studies have documented the association of mutations in genes encoding the zona matrix with the infertile status of human females. Single nucleotide polymorphisms are the most common type of genetic variations observed in a population and as per the dbSNP database, around 5,152 SNPs are reported to exist in the human ZP2 (hZP2) gene. Although a wide range of computational tools are publicly available, yet no computational studies have been done to date to identify and analyze structural and functional effects of deleterious SNPs on hZP2. In this study, we conducted a comprehensive in silico analysis of all the SNPs found in hZP2. Six different computational tools including SIFT and PolyPhen-2 predicted 18 common nsSNPs as deleterious of which 12 were predicted to most likely affect the structure/functional properties. These were either present in the N-term region crucial for sperm-zona interaction or in the zona domain. 31 additional SNPs in both coding and non-coding regions were also identified. Interestingly, some of these SNPs have been found to be present in infertile females in some recent studies.

scholarly journals Exosomal microRNAs and other non-coding RNAs as colorectal cancer biomarkers: a review

Mutagenesis ◽  
2019 ◽  
Vol 35 (3) ◽  
pp. 243-260 ◽  
Author(s):  
Antonio Francavilla ◽  
Szimonetta Turoczi ◽  
Sonia Tarallo ◽  
Pavel Vodicka ◽  
Barbara Pardini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Expression Profiles ◽  
Predictive Markers ◽  
Circular Rnas ◽  
Rna Molecules ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Prognostic And Predictive Markers

Abstract The circulating human transcriptome, which includes both coding and non-coding RNA (ncRNA) molecules, represents a rich source of potential biomarkers for colorectal cancer (CRC) that has only recently been explored. In particular, the release of RNA-containing extracellular vesicles (EVs), in a multitude of different in vitro cell systems and in a variety of body fluids, has attracted wide interest. The role of RNA species in EVs is still not fully understood, but their capacity to act as a form of distant communication between cells and their higher abundance in association with cancer demonstrated their relevance. In this review, we report the evidence from both in vitro and human studies on microRNAs (miRNAs) and other ncRNA profiles analysed in EVs in relation to CRC as diagnostic, prognostic and predictive markers. The studies so far highlighted that, in exosomes, the most studied category of EVs, several miRNAs are able to accurately discriminate CRC cases from controls as well as to describe the progression of the disease and its prognosis. Most of the time, the in vitro findings support the miRNA profiles detected in human exosomes. The expression profiles measured in exosomes and other EVs differ and, interestingly, there is a variability of expression also among different subsets of exosomes according to their proteic profile. On the other hand, evidence is still limited for what concerns exosome miRNAs as early diagnostic and predictive markers of treatment. Several other ncRNAs that are carried by exosomes, mostly long ncRNAs and circular RNAs, seem also to be dysregulated in CRC. Besides various technical challenges, such as the standardisation of EVs isolation methods and the optimisation of methodologies to characterise the whole spectrum of RNA molecules in exosomes, further studies are needed in order to elucidate their relevance as CRC markers.

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