DOCSLIB.ORG

Differential Expression of Stress and Immune Response Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Differential Expression of Stress and Immune Response Pathway Published OnlineFirst April 30, 2014; DOI: 10.1158/1541-7786.MCR-13-0623 Molecular Cancer Chromatin, Gene, and RNA Regulation Research Differential Expression of Stress and Immune Response Pathway Transcripts and miRNAs in Normal Human Endothelial Cells Subjected to Fractionated or Single-Dose Radiation Sanjeewani T. Palayoor1, Molykutty John-Aryankalayil1, Adeola Y. Makinde1, Michael T. Falduto2, Scott R. Magnuson2, and C. Norman Coleman1 Abstract Although modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors, thus, reducing overall radiation exposure to normal tissues, moderate dose, and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in human coronary artery endothelial cells using single-dose irradiation (SD, 10 Gy) or multifractionated irradiation (MF, 2Gy 5) regimens. Longitudinal time points were collected after an SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared with SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis to uncover miRs associated with target transcripts from several cellular pathways after irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. In addition, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events, and angiogenesis were revealed. Implications: Radiation-induced alterations in stress and immune response genes in endothelial cells contribute to changes in normal tissue and tumor microenvironment, and affect the outcome of radiotherapy. MolCancerRes;12(7);1002–15. Ó2014 AACR. Introduction to tumor focusing on areas deemed at highest risk (3–5). The Radiation oncology remains a mainstay of cancer therapy newer technology can reduce high doses to normal tissues as both curative and palliative therapy used alone or as a but can increase the amount of tissue receiving daily dose (6). component of combined modality therapy. Routinely, in The incidental radiation exposure of normal tissues is a topic clinical practice, radiation therapy is administered as mul- of concern in radiotherapy (7). tiple fractions of 2 to 2.5 Gy per day for 5 days per week for 1 Recent work from our laboratory showed that prostate to 7 weeks to allow repair, repopulation, and recovery of the carcinoma cells that survive multifractionated (MF) radia- tion exposure have a different genomic signature compared collateral damage to the normal tissue (1, 2). Individualized – radiation therapy with development of modern techniques with the cells exposed to single-dose radiation (SD; refs. 8 10). Exposure to 10 Gy radiation delivered as fractionated such as intensity-modulated radiation therapy and image-   guided radiation therapy can deliver more controlled single irradiation (1 Gy 10 or 2 Gy 5) resulted in more robust or fewer fractions of high-dose radiation (hypofractionation) differential gene expression changes in PC3 and DU145 cells, whereas in LNCaP cells, 10 Gy radiation delivered as a single dose was more effective (9, 10). These studies also Authors' Affiliations: 1Radiation Oncology Branch, Center for Cancer revealed that the mRNA expression profiles following frac- Research, National Cancer Institute, NIH, Bethesda, Maryland; and 2GenUs fl Biosystems, Inc., Northbrook, Illinois tionated irradiation were in uenced by p53 status. In LNCaP cells, harboring wild-type p53 DNA replication/ Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). recombination/repair and cell cycle were the top gene ontology categories affected by radiation, whereas in p53- Corresponding Author: Sanjeewani T. Palayoor, National Cancer Insti- tute, NIH, 9000 Rockville Pike, Building # 10, Room B3B406, Bethesda, MD mutated PC3 cells, genes from IFN, immune, and stress 20892. Phone: 301-496-1401; Fax: 301-480-1434; E-mail: response categories were altered significantly. miRNAs play [email protected] an important role in regulation of gene expression at the doi: 10.1158/1541-7786.MCR-13-0623 posttranscriptional level by base pairing with the comple- 0 Ó2014 American Association for Cancer Research. mentary sequences within 3 -untranslated regions of target 1002 Mol Cancer Res; 12(7) July 2014 Downloaded from mcr.aacrjournals.org on September 29, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst April 30, 2014; DOI: 10.1158/1541-7786.MCR-13-0623 mRNA and miRNA Profiles of Irradiated Endothelial Cells mRNAs, resulting in translational repression or mRNA SD and 6 and 24 hours after the final dose of fractionated degradation (11). As observed for the mRNA expression irradiation. Separate controls were maintained for SD and profiles, in the prostate carcinoma cells, treatment with MF radiation protocols. fractionated irradiation significantly altered more miRNAs as compared with the cells exposed to SD radiation (12). RNA isolation Although normal tissue exposure remains a major con- Cells were pelleted at 6 and 24 hours after an SD and 6 fi cern in radiation therapy, few studies have investigated the and24hoursafterthe nal dose of MF irradiation and molecular effects of various radiation treatment regimens stored in liquid nitrogen. Total RNA including small in normal cells. The purpose of the present study was to RNAs was isolated using phenol/chloroform extraction fi investigate global gene and miRNA alterations in normal followed by puri cation over spin columns (Ambion Cat. cells exposed to radiation protocols simulating hypofrac- No. AM9738). The concentration and purity of total tionated and conventionally fractionated radiation regi- RNA were measured by spectrophotometry at OD260/ mens typically used for radiotherapy in clinic. For this 280, and the quality of the total RNA sample was assessed study, we treated normal human coronary artery endo- using an Agilent Bioanalyzer with the RNA6000 Nano thelial cells (HCAEC) with 10 Gy radiation delivered as a Lab Chip (Agilent Technologies). SDradiationoras5fractionsof2Gyradiation(MF).The mRNA microarray analysis differentially expressed mRNAs and miRNAs were iden- The mRNA microarray analysis was performed using tified by microarray analysis at 6 and 24 hours after an SD Agilent Technologies Human Gene Expression 4  44 K and 6 and 24 hours after the final dose of fractionated V2 microarrays (product number G4845A, design irradiation. These data showed that in HCAEC more ID 026652) designed to target 27,958 Entrez Gene RNAs. mRNAs and miRNAs were differentially expressed by exposure to MF compared with SD, and the magnitude miRNA microarray analysis of changes was higher in MF-irradiated cells. Gene ontol- The miRNA microarray analysis was performed using ogy classification showed that in addition to cell cycle, Agilent Technologies Human miRNA 8  15 K V2 micro- genes regulating DNA replication, DNA damage stimu- arrays (product number G4470B, design ID 019118) with lus, and DNA repair, and genes related to immune probes for 723 human and 76 human viral miRNAs sourced response were significantly altered following exposure to from Sanger miRBase (release 10.1). MF. Using ingenuity target filter program, we identified The mRNA and miRNA microarray data were analyzed miRNAs associated with the target genes from different using Gene Spring Software (Agilent Technologies) as cellular pathways that were differentially expressed in described previously (12). To ensure that mRNAs and response to SD and MF. The present study suggests that miRNAs were reliably measured, ANOVA was used to endothelial cells may play an important role in the out- compare the means of each condition (n ¼ 3). For mRNA come of radiotherapy in the clinical settings. analysis, cutoff ratios of gene expression greater than 2.0 and less than 0.5 and a P value of <0.05 relative to the respective Materials and Methods control group were selected. For miRNA analysis, cutoff Cells ratios greater than 1.5 and less than 0.66 with a P value of Cryopreserved HCAEC and the media were purchased <0.05 relative to the respective control were selected. from Lonza Walkersville Inc. Cells were thawed and main- The mRNA and miRNA microarray data discussed in this tained in EBM-2 basal medium supplemented with FBS and publication have been deposited in NCBI's Gene Expression growth factors (EGM-2 MV BulletKit CC-3202) according Omnibus and are accessible through GEO Series Accession to the supplier's instructions. Cells from passages P1 to P3 No. GSE57059 (http://www.ncbi.nlm.nih.gov/geo/query/ were used. acc.cgi?acc¼GSE57059), and Accession No. GSE56824 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? Radiation acc¼GSE56824), respectively. Cells were irradiated in a PANTAK high-frequency X-ray generator (Precision X-ray Inc.), operated at 300 kV and Real-time RT-PCR 10 mA. The dose rate was 1.6 Gy per minute. Cells were Separate experiments were set up to extract RNA at 6 and plated into T75 cm2 flasks (1–1.5  106 for SD radiation 24 hours after an SD and 6 and 24 hours after the final dose and 0.6–0.8  106 for fractionated radiation). After 24 of fractionated irradiation for real-time RT-PCR analysis. hours, cells were exposed to a total of 10 Gy radiation RNA was isolated using the RNAeasy mini Kit (Cat. No administered either as a SD radiation or as MF radiation 74104; Qiagen) as described previously (12). Purified RNA of 2 Gy  5. These nonisoeffective doses were selected to was reverse transcribed to cDNA and RT-PCR was carried simulate clinical hypofractionated and conventionally frac- out as described previously (13). Alterations in selected tionated radiotherapy regimens. For the MF protocol, cells differentially expressed genes were confirmed using Taq- were exposed to 2 Gy radiation twice a day, at 6-hour Man Custom Express Plate (Part # 4391524; Applied interval.
Load more

Recommended publications
  • Case Report a Fetus with Kabuki Syndrome 2 Detected by Chromosomal Microarray Analysis
    Int J Clin Exp Pathol 2020;13(2):302-306 www.ijcep.com /ISSN:1936-2625/IJCEP0104334 Case Report A fetus with Kabuki syndrome 2 detected by chromosomal microarray analysis Chen-Zhao Lin1, Bi-Ru Qi1, Jian-Su Hu2, Xiu-Qiong Huang3 Departments of 1Obstetrics and Gynecology, 2Ultrasound, 3Laboratory Medicine, Fuzhou Municipal First Hospital Affiliated to Fujian Medical University, Fuzhou 350009, Fujian Province, The People’s Republic of China Received November 1, 2019; Accepted January 26, 2020; Epub February 1, 2020; Published February 15, 2020 Abstract: Background: Kabuki syndrome is a rare multiple congenital anomaly syndrome characterized by distinct facial features, intellectual disability, cardiovascular and musculoskeletal abnormalities, persistence of fetal finger- tip pads, and postnatal growth deficiency. Currently, the diagnosis mainly depends on clinical manifestations and genetic testing. To date, there is no report on the identification Kabuki syndrome in fetuses using chromosomal microarray analysis (CMA). Case presentation: A fetus was identified with growth retardation and cardiovascular abnormality on color Doppler ultrasonography; however, non-invasive prenatal testing (NIPT) revealed a low risk and G-banding karyotyping revealed no abnormal karyotype detected. CMA identified a 1.3 Mb deletion on the X chromosome (Xp11.3) containing KDM6A, DUSP21, MIR222, MIR221 and CXorf36 genes. The fetus was diagnosed with Kabuki syndrome 2, and labor was induced. In addition, CMA detected a 1.3 Mb deletion in the chromosome Xp11.3 in the mother, which contains 5 genes namely KDM6A, DUSP21, MIR222, MIR221 and CXorf36, while no chromosomal abnormality was identified in the father. Conclusions: We report a fetus with Kabuki syndrome 2 detected using CMA.
    [Show full text]
  • High-Throughput Sequencing of Human Plasma RNA by Using Thermostable Group II Intron Reverse Transcriptases
    Downloaded from rnajournal.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press High-throughput sequencing of human plasma RNA by using thermostable group II intron reverse transcriptases YIDAN QIN,1,2,3 JUN YAO,1,2,3 DOUGLAS C. WU,1,2 RYAN M. NOTTINGHAM,1,2 SABINE MOHR,1,2 SCOTT HUNICKE-SMITH,1 and ALAN M. LAMBOWITZ1,2 1Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA 2Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712, USA ABSTRACT Next-generation RNA-sequencing (RNA-seq) has revolutionized transcriptome profiling, gene expression analysis, and RNA-based diagnostics. Here, we developed a new RNA-seq method that exploits thermostable group II intron reverse transcriptases (TGIRTs) and used it to profile human plasma RNAs. TGIRTs have higher thermostability, processivity, and fidelity than conventional reverse transcriptases, plus a novel template-switching activity that can efficiently attach RNA-seq adapters to target RNA sequences without RNA ligation. The new TGIRT-seq method enabled construction of RNA-seq libraries from <1 ng of plasma RNA in <5 h. TGIRT-seq of RNA in 1-mL plasma samples from a healthy individual revealed RNA fragments mapping to a diverse population of protein-coding gene and long ncRNAs, which are enriched in intron and antisense sequences, as well as nearly all known classes of small ncRNAs, some of which have never before been seen in plasma. Surprisingly, many of the small ncRNA species were present as full-length transcripts, suggesting that they are protected from plasma RNases in ribonucleoprotein (RNP) complexes and/or exosomes.
    [Show full text]
  • The Role of Microrna in Human Leukemia: a Review
    Leukemia (2009) 23, 1257–1263 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu SPOTLIGHT REVIEW The role of microRNA in human leukemia: a review S Yendamuri1 and GA Calin2 1Department of Thoracic Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA and 2Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA MicroRNAs (miRNAs or miRs) are 18–22-nucleotide non-coding target. If the sequence is a perfect match, the final result seems RNAs that have emerged as a new paradigm of epigenetic to be target mRNA degradation in a manner similar to siRNA- regulation in both normal development and cellular function, and in the pathogenesis of human disease including cancer. induced gene expression silencing. This seems to be the This review summarizes the current literature of mechanism of predominant mechanism in plants. A less than perfect match gene regulation by miRNA and their role in hematopoiesis and may result in inefficient translation leading to effective down- leukemogenesis. An understanding of these processes sug- regulation of the gene, a mechanism more common in gests further avenues for research to understand gene regula- animals.7–9 Isolated examples of miRNA leading to upregulation tion and miRNA-based therapeutic approaches. of genes have been reported.10 Leukemia (2009) 23, 1257–1263; doi:10.1038/leu.2008.382; The mechanism of translational repression is known only published online 15 January 2009 11 Keywords: microRNA; non-coding RNA; microarray; partially. The mRNA segments that miRNAs bind seem to be mostly in the 30UTRs of genes.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • Development of Novel Therapeutic Agents by Inhibition of Oncogenic Micrornas
    International Journal of Molecular Sciences Review Development of Novel Therapeutic Agents by Inhibition of Oncogenic MicroRNAs Dinh-Duc Nguyen and Suhwan Chang * ID Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea; [email protected] * Correspondence: [email protected] Received: 21 November 2017; Accepted: 22 December 2017; Published: 27 December 2017 Abstract: MicroRNAs (miRs, miRNAs) are regulatory small noncoding RNAs, with their roles already confirmed to be important for post-transcriptional regulation of gene expression affecting cell physiology and disease development. Upregulation of a cancer-causing miRNA, known as oncogenic miRNA, has been found in many types of cancers and, therefore, represents a potential new class of targets for therapeutic inhibition. Several strategies have been developed in recent years to inhibit oncogenic miRNAs. Among them is a direct approach that targets mature oncogenic miRNA with an antisense sequence known as antimiR, which could be an oligonucleotide or miRNA sponge. In contrast, an indirect approach is to block the biogenesis of miRNA by genome editing using the CRISPR/Cas9 system or a small molecule inhibitor. The development of these inhibitors is straightforward but involves significant scientific and therapeutic challenges that need to be resolved. In this review, we summarize recent relevant studies on the development of miRNA inhibitors against cancer. Keywords: antimiR; antagomiR; miRNA-sponge; oncomiR; CRISPR/Cas9; cancer therapeutics 1. Introduction Cancer has been the leading cause of death and a major health problem worldwide for many years; basically, it results from out-of-control cell proliferation. Traditionally, several key proteins have been identified and found to affect signaling pathways regulating cell cycle progression, apoptosis, and gene transcription in various types of cancers [1,2].
    [Show full text]
  • Differential Expression of Micrornas in Adipose Tissue After Long-Term High-Fat Diet-Induced Obesity in Mice
    Differential Expression of MicroRNAs in Adipose Tissue after Long-Term High-Fat Diet-Induced Obesity in Mice Dionysios V. Chartoumpekis1, Apostolos Zaravinos2, Panos G. Ziros1, Ralitsa P. Iskrenova1, Agathoklis I. Psyrogiannis1, Venetsana E. Kyriazopoulou1, Ioannis G. Habeos1* 1 Department of Internal Medicine, Division of Endocrinology, Medical School, University of Patras, Patras, Greece, 2 Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Greece Abstract Obesity is a major health concern worldwide which is associated with increased risk of chronic diseases such as metabolic syndrome, cardiovascular disease and cancer. The elucidation of the molecular mechanisms involved in adipogenesis and obesogenesis is of essential importance as it could lead to the identification of novel biomarkers and therapeutic targets for the development of anti-obesity drugs. MicroRNAs (miRNAs) have been shown to play regulatory roles in several biological processes. They have become a growing research field and consist of promising pharmaceutical targets in various fields such as cancer, metabolism, etc. The present study investigated the possible implication of miRNAs in adipose tissue during the development of obesity using as a model the C57BLJ6 mice fed a high-fat diet. C57BLJ6 wild type male mice were fed either a standard (SD) or a high-fat diet (HFD) for 5 months. Total RNA was prepared from white adipose tissue and was used for microRNA profiling and qPCR. Twenty-two of the most differentially expressed miRNAs, as identified by the microRNA profiling were validated using qPCR. The results of the present study confirmed previous results. The up- regulation of mmu-miR-222 and the down-regulation of mmu-miR-200b, mmu-miR-200c, mmu-miR-204, mmu-miR-30a*, mmu-miR-193, mmu-miR-378 and mmu-miR-30e* after HFD feeding has also been previously reported.
    [Show full text]
  • Micrornas in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine
    cells Review MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine Danyel Fernandes Contiliani 1,2, Yasmin de Araújo Ribeiro 1,2, Vitor Nolasco de Moraes 1,2 and Tiago Campos Pereira 1,2,* 1 Graduate Program of Genetics, Department of Genetics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, Ribeirao Preto 3900, Brazil; [email protected] (D.F.C.); [email protected] (Y.d.A.R.); [email protected] (V.N.d.M.) 2 Department of Biology, Faculty of Philosophy, Sciences and Letters, University of Sao Paulo, Av. Bandeirantes, Ribeirao Preto 3900, Brazil * Correspondence: [email protected]; Tel.: +55-16-3315-3818 Abstract: MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of target tran- scripts. Prion diseases comprise a singular group of neurodegenerative conditions caused by endoge- nous, misfolded pathogenic (prion) proteins, associated with molecular aggregates. In humans, classical prion diseases include Creutzfeldt–Jakob disease, fatal familial insomnia, Gerstmann– Sträussler–Scheinker syndrome, and kuru. The aim of this review is to present the connections between miRNAs and prions, exploring how the interaction of both molecular actors may help understand the susceptibility, onset, progression, and pathological findings typical of such disorders, as well as the interface with some prion-like disorders, such as Alzheimer’s. Additionally, due to the inter-regulation of prions and miRNAs in health and disease, potential biomarkers for non-invasive miRNA-based diagnostics, as well as possible miRNA-based therapies to restore the levels of dereg- Citation: Contiliani, D.F.; Ribeiro, Y.d.A.; de Moraes, V.N.; Pereira, T.C.
    [Show full text]
  • Supplementary Information.Pdf
    Supplementary Information Whole transcriptome profiling reveals major cell types in the cellular immune response against acute and chronic active Epstein‐Barr virus infection Huaqing Zhong1, Xinran Hu2, Andrew B. Janowski2, Gregory A. Storch2, Liyun Su1, Lingfeng Cao1, Jinsheng Yu3, and Jin Xu1 Department of Clinical Laboratory1, Children's Hospital of Fudan University, Minhang District, Shanghai 201102, China; Departments of Pediatrics2 and Genetics3, Washington University School of Medicine, Saint Louis, Missouri 63110, United States. Supplementary information includes the following: 1. Supplementary Figure S1: Fold‐change and correlation data for hyperactive and hypoactive genes. 2. Supplementary Table S1: Clinical data and EBV lab results for 110 study subjects. 3. Supplementary Table S2: Differentially expressed genes between AIM vs. Healthy controls. 4. Supplementary Table S3: Differentially expressed genes between CAEBV vs. Healthy controls. 5. Supplementary Table S4: Fold‐change data for 303 immune mediators. 6. Supplementary Table S5: Primers used in qPCR assays. Supplementary Figure S1. Fold‐change (a) and Pearson correlation data (b) for 10 cell markers and 61 hypoactive and hyperactive genes identified in subjects with acute EBV infection (AIM) in the primary cohort. Note: 23 up‐regulated hyperactive genes were highly correlated positively with cytotoxic T cell (Tc) marker CD8A and NK cell marker CD94 (KLRD1), and 38 down‐regulated hypoactive genes were highly correlated positively with B cell, conventional dendritic cell
    [Show full text]
  • Induction of Micrornas, Mir-155, Mir-222, Mir-424 and Mir-503, Promotes Monocytic Differentiation Through Combinatorial Regulation
    Leukemia (2010) 24, 460–466 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ‘ ORIGINAL ARTICLE Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation ARR Forrest1,2, M Kanamori-Katayama1, Y Tomaru1, T Lassmann1, N Ninomiya1, Y Takahashi1, MJL de Hoon1, A Kubosaki1, A Kaiho1, M Suzuki1, J Yasuda1, J Kawai1, Y Hayashizaki1, DA Hume3 and H Suzuki1 1LSA Technology Development Unit, Omics Science Center, RIKEN Yokohama Institute, Yokohama, Kanagawa, Japan; 2The Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Queensland, Australia and 3The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin, UK Acute myeloid leukemia (AML) involves a block in terminal that might promote differentiation. MicroRNAs are short 21–22 differentiation of the myeloid lineage and uncontrolled prolif- nucleotide RNA molecules that cause translational repression eration of a progenitor state. Using phorbol myristate acetate and degradation of multiple mRNAs by binding target sequences (PMA), it is possible to overcome this block in THP-1 cells 0 5 (an M5-AML containing the MLL-MLLT3 fusion), resulting in in their 3 UTRs. Multiple microRNAs are implicated in differentiation to an adherent monocytic phenotype. As part of differentiation of cell lineages including skeletal muscle, FANTOM4, we used microarrays to identify 23 microRNAs that adipocytes and neurons6–8 and in mammals, the microRNA are regulated by PMA. We identify four PMA-induced micro- subsystem is essential for embryonic development. Dicer RNAs (mir-155, mir-222, mir-424 and mir-503) that when over- is required for differentiation of embryonic stem cells,9 Dicer expressed cause cell-cycle arrest and partial differentiation and (À/À) knockouts are embryonic lethal10 and Ago2 (À/À) when used in combination induce additional changes not seen 11 by any individual microRNA.
    [Show full text]
  • Noncoding Rnas As Novel Pancreatic Cancer Targets
    NONCODING RNAS AS NOVEL PANCREATIC CANCER TARGETS by Amy Makler A Thesis Submitted to the Faculty of The Charles E. Schmidt College of Science In Partial Fulfillment of the Requirements for the Degree of Master of Science Florida Atlantic University Boca Raton, FL August 2018 Copyright 2018 by Amy Makler ii ACKNOWLEDGEMENTS I would first like to thank Dr. Narayanan for his continuous support, constant encouragement, and his gentle, but sometimes critical, guidance throughout the past two years of my master’s education. His faith in my abilities and his belief in my future success ensured I continue down this path of research. Working in Dr. Narayanan’s lab has truly been an unforgettable experience as well as a critical step in my future endeavors. I would also like to extend my gratitude to my committee members, Dr. Binninger and Dr. Jia, for their support and suggestions regarding my thesis. Their recommendations added a fresh perspective that enriched our initial hypothesis. They have been indispensable as members of my committee, and I thank them for their contributions. My parents have been integral to my successes in life and their support throughout my education has been crucial. They taught me to push through difficulties and encouraged me to pursue my interests. Thank you, mom and dad! I would like to thank my boyfriend, Joshua Disatham, for his assistance in ensuring my writing maintained a logical progression and flow as well as his unwavering support. He was my rock when the stress grew unbearable and his encouraging words kept me pushing along.
    [Show full text]
  • Expression and Change of Mirs 145, 221 and 222 in Hypertensive Subjects Treated with Enalapril, Losartan Or Olmesartan
    biomedicines Article Expression and Change of miRs 145, 221 and 222 in Hypertensive Subjects Treated with Enalapril, Losartan or Olmesartan Giuseppe Mandraffino 1,2,3,*,† , Alberto Lo Gullo 4,*,† , Maria Cinquegrani 1, Angela D’Ascola 3, Davide Sinicropi 1, Egidio Imbalzano 1 , Giuseppe Blando 1, Giuseppe Maurizio Campo 3, Carmela Morace 1, Clemente Giuffrida 4, Salvatore Campo 5, Giovanni Squadrito 1,‡ and Michele Scuruchi 2,3,‡ 1 Internal Medicine Unit, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy; [email protected] (M.C.); [email protected] (D.S.); [email protected] (E.I.); [email protected] (G.B.); [email protected] (C.M.); [email protected] (G.S.) 2 Lipid Center, Internal Medicine Unit, University of Messina, 98122 Messina, Italy; [email protected] 3 Laboratory of Clinical Biochemistry, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy; [email protected] (A.D.); [email protected] (G.M.C.) 4 IRCCS Neurolesi Bonino Pulejo, 98123 Messina, Italy; [email protected] 5 Laboratory of Molecular Biology, Department of Biomedical and Dental Sciences and Morphofunctional Images, University of Messina, 98122 Messina, Italy; [email protected] * Correspondence: gmandraffi[email protected] (G.M.); [email protected] (A.L.G.) † These authors equally contributed to this work: co-first authors. ‡ These authors equally contributed to this work: both senior authors. Citation: Mandraffino, G.; Lo Gullo, Abstract: miR profile could be associated to CV risk, and also to prognosis/outcome in response to A.; Cinquegrani, M.; D’Ascola, A.; Sinicropi, D.; Imbalzano, E.; Blando, therapeutic approach. We aimed to evaluate if anti-hypertensive drugs enalapril, losartan or olmesar- G.; Campo, G.M.; Morace, C.; tan have effects on monocyte miR profile in essential hypertensives without target organ involvement.
    [Show full text]
  • Dynamic and Modularized Microrna Regulation and Its Implication in Human Cancers
    www.nature.com/scientificreports OPEN Dynamic and Modularized MicroRNA Regulation and Its Implication in Human Cancers Received: 8 February 2017 Jiang Shu1, Bruno Vieira Resende e Silva1, Tian Gao1, Zheng Xu2,3 & Juan Cui1 Accepted: 26 September 2017 MicroRNA is responsible for the fne-tuning of fundamental cellular activities and human disease Published: xx xx xxxx development. The altered availability of microRNAs, target mRNAs, and other types of endogenous RNAs competing for microRNA interactions refects the dynamic and conditional property of microRNA- mediated gene regulation that remains under-investigated. Here we propose a new integrative method to study this dynamic process by considering both competing and cooperative mechanisms and identifying functional modules where diferent microRNAs co-regulate the same functional process. Specifcally, a new pipeline was built based on a meta-Lasso regression model and the proof-of-concept study was performed using a large-scale genomic dataset from ~4,200 patients with 9 cancer types. In the analysis, 10,726 microRNA-mRNA interactions were identifed to be associated with a specifc stage and/or type of cancer, which demonstrated the dynamic and conditional miRNA regulation during cancer progression. On the other hands, we detected 4,134 regulatory modules that exhibit high fdelity of microRNA function through selective microRNA-mRNA binding and modulation. For example, miR-18a-3p, −320a, −193b-3p, and −92b-3p co-regulate the glycolysis/gluconeogenesis and focal adhesion in cancers of kidney, liver, lung, and uterus. Furthermore, several new insights into dynamic microRNA regulation in cancers have been discovered in this study. Mature microRNAs (miRNAs) are typically 20–25 nucleotides long.
    [Show full text]