DOCSLIB.ORG

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Published OnlineFirst December 12, 2014; DOI: 10.1158/1535-7163.MCT-14-0492 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression Feng-qi Nie1, Ming Sun2, Jin-song Yang3, Min Xie2, Tong-peng Xu1, Rui Xia2, Yan-wen Liu2, Xiang-hua Liu2, Er-bao Zhang2, Kai-hua Lu1, and Yong-qian Shu1 Abstract Recent evidence highlights long noncoding RNAs (lncRNA) was increased in NSCLC tissues, and its expression level was as crucial regulators of cancer biology that contribute to essen- significantly correlated with tumor–node–metastasis stages and tial cancer cell functions such as cell proliferation, apoptosis, tumor size. Moreover, patients with high levels of ANRIL and metastasis. In non–small cell lung cancer (NSCLC), several expression had a relatively poor prognosis. In addition, taking lncRNAs' expressions are misregulated and have been nomi- advantage of loss-of-function experiments in NSCLC cells, we nated as critical actors in NSCLC tumorigenesis. LncRNA ANRIL found that knockdown of ANRIL expression could impair cell was first found to be required for the PRC2 recruitment to and proliferation and induce cell apoptosis both in vitro and vivo. silencing of p15INK4B, the expression of which is induced by the Furthermore, we uncover that ANRIL could not repress p15 ATM–E2F1 signaling pathway. Our previous study showed that expression in PC9 cells, but through silencing of KLF2 and P21 ANRIL was significantly upregulated in gastric cancer, and it transcription. Thus, we conclusively demonstrate that lncRNA could promote cell proliferation and inhibit cell apoptosis by ANRIL plays a key role in NSCLC development by associating silencing of miR99a and miR449a transcription. However, its its expression with survival in patients with NSCLC, providing clinical significance and potential role in NSCLC is still not novel insights on the function of lncRNA-driven tumorigenesis. documented. In this study, we reported that ANRIL expression Mol Cancer Ther; 14(1); 268–77. Ó2014 AACR. Introduction in the development, progression, and spread of the NSCLC is essential for the developing of specificdiagnosticmethodsand Lung cancer is the most common type of cancer and the designing of more individualized and effective therapeutic primary cause of cancer-related death worldwide (1). Non– strategies. small cell lung cancer (NSCLC) accounts for 80% of all lung Recently, studies using the great advances in genomic tech- cancer cases, represents the most prevalent class of this cancer nologies have revealed the majority of the human genome is type, and includes several histologic subtypes such as squa- transcribed, whereas only 2% of the transcribed genome codes mous cell carcinoma (SCC), adenocarcinoma and large cell for protein (5). Meanwhile, it is becoming increasingly appar- carcinoma (LCC; refs. 2, 3). Despite current advances in the ent that the large majority of genome is transcribed into treatments for NSCLC, including surgical therapy, chemother- noncoding RNAs (ncRNAs), including microRNAs and long apy, and molecular targeting therapy, the overall 5-year sur- ncRNAs (lncRNAs; ref. 6). The ENCODE Consortium has vival rate for patients with NSCLC has not been markedly elucidated the prevalence of thousands of human lncRNAs, improved over years and remains as low as 15% (4). Therefore, but only very few of them have been assigned with any biologic a greater understanding of the molecular mechanisms involved function (7). To date, studies showed that miRNAs play impor- tant roles in the posttranscriptional regulation of gene expres- sion; however, the lncRNAs counterpart of ncRNA is not well 1Department of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China. 2Department of Bio- characterized (8). Although very few are characterized in detail, chemistry and Molecular Biology, Nanjing Medical University, Nanjing, LncRNAs are involved in a large range of biologic processes, 3 People's Republic of China. Department of Oncology, Nanjing First including modulation of apoptosis and invasion, reprogram- Hospital, Nanjing Medical University, People's Republic of China. ming stem cell pluripotency, and parental imprinting through Note: Supplementary data for this article are available at Molecular Cancer the regulation of gene expression by chromatin remodeling, Therapeutics Online (http://mct.aacrjournals.org/). histone protein modification, regulation of mRNA splicing, and F.-q. Nie, M. Sun, and J.-s. Yang contributed equally and are joint first authors to acting as sponges for microRNAs (9–12). this article. In the past decade, lots of evidence have linked the dysregula- Corresponding Authors: Kai-hua Lu, Department of Oncology, First Affiliated tion of lncRNAs with diverse human diseases, in particular cancers Hospital, Nanjing Medical University, Han Zhong Road 140#, Nanjing 210029, (13–15). Therefore, identification of cancer-associated lncRNAs China. Phone/fax: 25-8686-2728; E-mail: [email protected]; and Yong-qian Shu, and investigation of their molecular and biologic functions are [email protected] important in understanding the molecular biology of NSCLC doi: 10.1158/1535-7163.MCT-14-0492 development and progression. Our previous study showed that Ó2014 American Association for Cancer Research. lncRNA ANRIL was significantly upregulated in gastric cancer, 268 Mol Cancer Ther; 14(1) January 2015 Downloaded from mct.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst December 12, 2014; DOI: 10.1158/1535-7163.MCT-14-0492 ANRIL Promotes Proliferation in NSCLC and increased ANRIL promoted gastric cancer cells prolifera- cells proliferation and apoptosis partly via silencing of KLF2 tion and inhibited apoptosis by epigenetic silencing of miR99a and P21 transcription. This study advances our understanding and miR449a transcription (16). Moreover, ANRIL can bind of the role of lncRNAs, such as a regulator of pathogenesis of to and recruits PRC2 to repress the expression of p15INK4B locus, NSCLC and facilitates the development of lncRNA-directed which resulted in increased cell proliferation (17, 18). However, diagnostics and therapeutics. the ANRIL clinical significance and potential role in NSCLC development and progression is still not documented. In this study, we found that lncRNA ANRIL expression was Materials and Methods increased in NSCLC tissues compared with adjacent normal Tissue collection tissues. Its expression level was significantly correlated with We obtained 68 paired NSCLC and adjacent nontumor lung tumor–node–metastasis (TNM) stages and tumor size. More- tissues from patients who underwent surgery at Jiangsu Province over, patients with higher level of ANRIL expression had a Hospital between 2010 and 2011, and were diagnosed with relatively poor prognosis. Furthermore, we investigated the NSCLC based on histopathologic evaluation. Clinicopathologic effects of ANRIL expression on NSCLC cell phenotype in vitro characteristics, including TNM staging, were recorded. No local or and in vivo with the loss-of-function study. Moreover, we also systemic treatment was conducted in these patients before sur- showed that ANRIL could bind to PRC2 to repress KLF2 and gery. All collected tissue samples were immediately snap-frozen in P21 transcription, but not regulate P15INK4 expression in liquid nitrogen and stored at À80 C until required. Our study was NSCLC PC9 cells, which indicated that ANRIL affected NSCLC approved by the Research Ethics Committee of Nanjing Medical A 50 B 50 Low ANRIL expression High ANRIL expression 40 40 30 30 20 20 10 10 Relative ANRIL expression (fold change) (fold Relative ANRIL expression Relative ANRIL expression (fold change) (fold Relative ANRIL expression 0 0 CD 1.0 1.0 Low ANRIL expression 0.8 Low ANRIL expression 0.8 0.6 0.6 0.4 0.4 Cum. survival Cum. High ANRIL expression High ANRIL expression survival Cum. 0.2 P < 0.001 0.2 P = 0.019 0.0 0.0 .00 10.00 20.00 30.00 40.00 .00 10.00 20.00 30.00 40.00 Months after surgery PFS Months after surgery overall survival Figure 1. Relative ANRIL expression in NSCLC tissues and its clinical significance. A, relative expression of ANRIL in NSCLC tissues (n ¼ 68) compared with corresponding nontumor tissues (n ¼ 68). ANRIL expression was examined by qPCR and normalized to GAPDH expression. Results are presented as the fold change in tumor tissues relative to normal tissues. B, ANRIL expression was classified into two groups. C and D, Kaplan–Meier DFS and OS curves according to ANRIL expression levels. www.aacrjournals.org Mol Cancer Ther; 14(1) January 2015 269 Downloaded from mct.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst December 12, 2014; DOI: 10.1158/1535-7163.MCT-14-0492 Nie et al. University, China. Written informed consent was obtained from early apoptotic cells, and apoptotic cells, and then the relative all patients. ratio of early apoptotic cells were compared with control trans- fectant from each experiment. Cells for cell–cycle analysis were Cell lines stained with PI using the CycleTEST PLUS DNA Reagent Kit (BD Five NSCLC adenocarcinoma cell lines (PC9, SPC-A1, NCI- Biosciences) following the protocol and analyzed by FACScan. H1975, H1299, and H358), and one NSCLC squamous carcino- The percentage of the cells in G0–G1, S, and G2–M phase were mas cell lines (H520) were purchased from the Institute of counted and compared. Biochemistry and Cell Biology of the Chinese Academy of Sciences (Shanghai, China). A549, H1975, H1299, and H520 Tumor formation assay in a nude mouse model cells were cultured in RPMI-1640; 16HBE, PC9, and SPC-A1 cells Female athymic BALB/c nude mice (4-weeks-old) were main- were cultured in DMEM (GIBCO-BRL) medium supplemented tained under pathogen-free conditions and manipulated with 10% FBS, 100 U/mL penicillin and 100 mg/mL streptomycin according to protocols approved by the Shanghai Medical o (Invitrogen, Carlsbad) at 37 C/5% CO2. All cell lines were Experimental Animal Care Commission.
Load more

Recommended publications
  • Increased HOXA5 Expression Provides a Selective Advantage for Gain of Whole Chromosome 7 in IDH Wild-Type Glioblastoma
    Downloaded from genesdev.cshlp.org on May 11, 2018 - Published by Cold Spring Harbor Laboratory Press Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma Patrick J. Cimino,1,2,17 Youngmi Kim,1,17 Hua-Jun Wu,3,4,5 Jes Alexander,1 Hans-Georg Wirsching,1,6 Frank Szulzewsky,1 Ken Pitter,7 Tatsuya Ozawa,1,8 Jiguang Wang,9,10,16 Julio Vazquez,11 Sonali Arora,1 Raul Rabadan,9,10 Ross Levine,12 Franziska Michor,3,4,5,13,14,15 and Eric C. Holland1 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2Department of Pathology, Division of Neuropathology, University of Washington, Seattle, Washington 98104, USA; 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02215, USA; 4Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA; 5Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA; 6Department of Neurology, University Hospital Zurich, Zurich 8091, Switzerland; 7Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; 8Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan; 9Department of Biomedical Informatics, Columbia University, New York, New York 10027, USA; 10Department of Systems Biology, Columbia University, New York,
    [Show full text]
  • Functional Genomics Atlas of Synovial Fibroblasts Defining Rheumatoid Arthritis
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.16.20248230; this version posted December 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability Xiangyu Ge1*, Mojca Frank-Bertoncelj2*, Kerstin Klein2, Amanda Mcgovern1, Tadeja Kuret2,3, Miranda Houtman2, Blaž Burja2,3, Raphael Micheroli2, Miriam Marks4, Andrew Filer5,6, Christopher D. Buckley5,6,7, Gisela Orozco1, Oliver Distler2, Andrew P Morris1, Paul Martin1, Stephen Eyre1* & Caroline Ospelt2*,# 1Versus Arthritis Centre for Genetics and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK 2Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland 3Department of Rheumatology, University Medical Centre, Ljubljana, Slovenia 4Schulthess Klinik, Zurich, Switzerland 5Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK 6NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK 7Kennedy Institute of Rheumatology, University of Oxford Roosevelt Drive Headington Oxford UK *These authors contributed equally #corresponding author: [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.12.16.20248230; this version posted December 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • SUPPLEMENTARY MATERIAL Bone Morphogenetic Protein 4 Promotes
    www.intjdevbiol.com doi: 10.1387/ijdb.160040mk SUPPLEMENTARY MATERIAL corresponding to: Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells SUMIYO MIMURA, MIKA SUGA, KAORI OKADA, MASAKI KINEHARA, HIROKI NIKAWA and MIHO K. FURUE* *Address correspondence to: Miho Kusuda Furue. Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. Tel: 81-72-641-9819. Fax: 81-72-641-9812. E-mail: [email protected] Full text for this paper is available at: http://dx.doi.org/10.1387/ijdb.160040mk TABLE S1 PRIMER LIST FOR QRT-PCR Gene forward reverse AP2α AATTTCTCAACCGACAACATT ATCTGTTTTGTAGCCAGGAGC CDX2 CTGGAGCTGGAGAAGGAGTTTC ATTTTAACCTGCCTCTCAGAGAGC DLX1 AGTTTGCAGTTGCAGGCTTT CCCTGCTTCATCAGCTTCTT FOXD3 CAGCGGTTCGGCGGGAGG TGAGTGAGAGGTTGTGGCGGATG GAPDH CAAAGTTGTCATGGATGACC CCATGGAGAAGGCTGGGG MSX1 GGATCAGACTTCGGAGAGTGAACT GCCTTCCCTTTAACCCTCACA NANOG TGAACCTCAGCTACAAACAG TGGTGGTAGGAAGAGTAAAG OCT4 GACAGGGGGAGGGGAGGAGCTAGG CTTCCCTCCAACCAGTTGCCCCAAA PAX3 TTGCAATGGCCTCTCAC AGGGGAGAGCGCGTAATC PAX6 GTCCATCTTTGCTTGGGAAA TAGCCAGGTTGCGAAGAACT p75 TCATCCCTGTCTATTGCTCCA TGTTCTGCTTGCAGCTGTTC SOX9 AATGGAGCAGCGAAATCAAC CAGAGAGATTTAGCACACTGATC SOX10 GACCAGTACCCGCACCTG CGCTTGTCACTTTCGTTCAG Suppl. Fig. S1. Comparison of the gene expression profiles of the ES cells and the cells induced by NC and NC-B condition. Scatter plots compares the normalized expression of every gene on the array (refer to Table S3). The central line
    [Show full text]
  • UC Riverside UC Riverside Electronic Theses and Dissertations
    UC Riverside UC Riverside Electronic Theses and Dissertations Title The Role of AMPK and miR-92a in the Shear Stress Regulation of KLF2 Permalink https://escholarship.org/uc/item/25z876bc Author Wu, Wei Publication Date 2010 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA RIVERSIDE The Role of AMPK and miR-92a in the Shear Stress Regulation of KLF2 A Dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Cellular, Molecular and Developmental Biology by Wei Wu December 2010 Dissertation Committee: Dr. John Shyy, Chairperson Dr. Ameae Walker Dr. Kathryn Defea Copyright by Wei Wu 2010 ii The Dissertation of Wei Wu is approved: ------------------------------------------ ------------------------------------------ ------------------------------------------ Committee Chairperson University of California, Riverside iii Acknowledgements It is a pleasure to thank those who made this dissertation possible. First of all, I would like to thank CMDB program for giving me the opportunity to pursue my Ph.D degree in UCR. A hearty thanks to Dr. Anthony W. Norman, Dr. Helen Henry and the professors who taught and encouraged me in these past years. I owe my deepest gratitude to my major professor, Dr. John Y-J. Shyy, for his guidance and support. I am also grateful to Dr. Ameae M. Walker and Dr. Kathryn Defea for their valuable discussions and constructive suggestions. I am thankful to all of my colleagues and friends for their generous help and precious discussion on my work. My parents and parents-in-law, thanks for your support and unconditional love. Even though we are thousand of miles away, you were always there whenever I needed you.
    [Show full text]
  • Role of HOX Genes in Stem Cell Differentiation and Cancer
    Thomas Jefferson University Jefferson Digital Commons Kimmel Cancer Center Papers, Presentations, and Grand Rounds Kimmel Cancer Center 7-22-2018 Role of HOX Genes in Stem Cell Differentiation and Cancer. Seema Bhatlekar Helen F. Graham Cancer Center and Research Institute; University of Delaware Jeremy Z Fields CATX Inc. Bruce M. Boman Thomas Jefferson University; Helen F. Graham Cancer Center and Research Institute; University of Delaware; CATX Inc. Follow this and additional works at: https://jdc.jefferson.edu/kimmelgrandrounds Part of the Oncology Commons Let us know how access to this document benefits ouy Recommended Citation Bhatlekar, Seema; Fields, Jeremy Z; and Boman, Bruce M., "Role of HOX Genes in Stem Cell Differentiation and Cancer." (2018). Kimmel Cancer Center Papers, Presentations, and Grand Rounds. Paper 62. https://jdc.jefferson.edu/kimmelgrandrounds/62 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Kimmel Cancer Center Papers, Presentations, and Grand Rounds by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Hindawi Stem Cells International Volume 2018, Article ID 3569493, 15 pages https://doi.org/10.1155/2018/3569493 Review Article Role of HOX Genes in Stem Cell Differentiation and Cancer 1,2 3 1,2,3,4 Seema Bhatlekar , Jeremy Z.
    [Show full text]
  • The Expression of Genes Contributing to Pancreatic Adenocarcinoma Progression Is Influenced by the Respective Environment – Sagini Et Al
    The expression of genes contributing to pancreatic adenocarcinoma progression is influenced by the respective environment – Sagini et al Supplementary Figure 1: Target genes regulated by TGM2. Figure represents 24 genes regulated by TGM2, which were obtained from Ingenuity Pathway Analysis. As indicated, 9 genes (marked red) are down-regulated by TGM2. On the contrary, 15 genes (marked red) are up-regulated by TGM2. Supplementary Table 1: Functional annotations of genes from Suit2-007 cells growing in pancreatic environment Categoriesa Diseases or p-Valuec Predicted Activation Number of genesf Functions activationd Z-scoree Annotationb Cell movement Cell movement 1,56E-11 increased 2,199 LAMB3, CEACAM6, CCL20, AGR2, MUC1, CXCL1, LAMA3, LCN2, COL17A1, CXCL8, AIF1, MMP7, CEMIP, JUP, SOD2, S100A4, PDGFA, NDRG1, SGK1, IGFBP3, DDR1, IL1A, CDKN1A, NREP, SEMA3E SERPINA3, SDC4, ALPP, CX3CL1, NFKBIA, ANXA3, CDH1, CDCP1, CRYAB, TUBB2B, FOXQ1, SLPI, F3, GRINA, ITGA2, ARPIN/C15orf38- AP3S2, SPTLC1, IL10, TSC22D3, LAMC2, TCAF1, CDH3, MX1, LEP, ZC3H12A, PMP22, IL32, FAM83H, EFNA1, PATJ, CEBPB, SERPINA5, PTK6, EPHB6, JUND, TNFSF14, ERBB3, TNFRSF25, FCAR, CXCL16, HLA-A, CEACAM1, FAT1, AHR, CSF2RA, CLDN7, MAPK13, FERMT1, TCAF2, MST1R, CD99, PTP4A2, PHLDA1, DEFB1, RHOB, TNFSF15, CD44, CSF2, SERPINB5, TGM2, SRC, ITGA6, TNC, HNRNPA2B1, RHOD, SKI, KISS1, TACSTD2, GNAI2, CXCL2, NFKB2, TAGLN2, TNF, CD74, PTPRK, STAT3, ARHGAP21, VEGFA, MYH9, SAA1, F11R, PDCD4, IQGAP1, DCN, MAPK8IP3, STC1, ADAM15, LTBP2, HOOK1, CST3, EPHA1, TIMP2, LPAR2, CORO1A, CLDN3, MYO1C,
    [Show full text]
  • Respiratory Adaptations to Lung Morphological Defects in Adult Mice Lacking Hoxa5 Gene Function
    0031-3998/04/5604-0553 PEDIATRIC RESEARCH Vol. 56, No. 4, 2004 Copyright © 2004 International Pediatric Research Foundation, Inc. Printed in U.S.A. Respiratory Adaptations to Lung Morphological Defects in Adult Mice Lacking Hoxa5 Gene Function RICHARD KINKEAD, MICHELLE LEBLANC, ROUMIANA GULEMETOVA, MÉLANIE LALANCETTE-HÉBERT, MARGOT LEMIEUX, ISABEL MANDEVILLE, AND LUCIE JEANNOTTE Département de Pédiatrie [R.K., R.G.], Centre Hospitalier Universitaire de Québec, Centre de recherche de l’Hôpital St-François d’Assise, Québec, Canada, G1L 3L5, Centre de recherche en cancérologie de l’Université Laval [M.LeB., M.L.-H., M.Lem., I.M., L.J.], Centre Hospitalier Universitaire de Québec, L’Hôtel-Dieu de Québec, Québec, Canada, G1R 2J6 ABSTRACT The Hoxa5 mutation is associated with a high perinatal ventilation increase seen during hypoxia was similar for both mortality rate caused by a severe obstruction of the laryngotra- groups of mice; however, the dynamics of the frequency re- cheal airways, pulmonary dysmorphogenesis, and a decreased sponse was genotype-dependent. The hypercapnic ventilatory production of surfactant proteins. Surviving Hoxa5-/- mutant response did not differ between genotypes. These findings reveal mice also display lung anomalies with deficient alveolar septa- the strategies allowing survival of Hoxa5-/- mice facing morpho- tion and areas of collapsed tissue, thus demonstrating the impor- logic anomalies leading to a significant deficit in gas exchange tance of Hoxa5 throughout lung development and maturation. capacity. (Pediatr Res 56: 553–562, 2004) Here, we address the functional consequences of the Hoxa5 mutation on respiration and chemoreflexes by comparing the Abbreviations -/- breathing pattern of Hoxa5 mice to that of wild-type animals FICO2, fractional concentration of carbon dioxide in the under resting conditions and during exposure to moderate ven- inspired gas tilatory stimuli such as hypoxia and hypercapnia.
    [Show full text]
  • Cbx3 Maintains Lineage Specificity During Neural Differentiation
    Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION et al. 2013). However, Cbx3 is also enriched at promoters Cbx3 maintains lineage of mouse embryonic fibroblast (MEF)-derived pre-iPSCs specificity during neural (preinduced pluripotent stem cells), where it does not cor- relate with H3K9 methylation (Sridharan et al. 2013). differentiation RNAi knockdown of Cbx3 promotes reprogramming of fi- broblasts to iPSCs (Sridharan et al. 2013). Chengyang Huang,1,2 Trent Su,1 Yong Xue,1 1 3 1 Cbx3 plays important roles in developmental processes Chen Cheng, Fides D. Lay, Robin A. McKee, (Morikawa et al. 2013). In model systems, Cbx3 promotes Meiyang Li,2 Ajay Vashisht,1 James Wohlschlegel,1 neuronal maturation, kidney development, differentia- Bennett G. Novitch,4 Kathrin Plath,1 tion of ESCs to smooth muscle in culture, and embryonic Siavash K. Kurdistani,1 and Michael Carey1 arteriogenesis (Xiao et al. 2011; Dihazi et al. 2015; Oshiro et al. 2015). Little is known of how Cbx3 functions in dif- 1Department of Biological Chemistry, Eli and Edythe Broad ferentiation, but its promoter localization suggested that Center for Regenerative Medicine and Stem Cell Research, David it might directly affect transcription through the preinitia- Geffen School of Medicine, University of California at Los tion complex (PIC) (Grunberg and Hahn 2013; Allen and Angeles, Los Angeles California 90095, USA; 2Department of Taatjes 2015). The PIC is assembled in response to activa- Neurobiology, Shantou University Medical College, Shantou tors and requires the Mediator coactivator complex to re- 515041, China; 3Department of Molecular, Cell, and cruit the general transcription factors and Pol II (Chen Developmental Biology, University of California at Los Angeles, et al.
    [Show full text]
  • Post-Transcriptional Gene Regulation by Hur Promotes a More Tumorigenic Phenotype
    Oncogene (2008) 27, 6151–6163 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc ORIGINAL ARTICLE Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype K Mazan-Mamczarz1, PR Hagner1, S Corl1, S Srikantan2, WH Wood3, KG Becker3, M Gorospe2, JD Keene4, AS Levenson5 and RB Gartenhaus1 1Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA; 2Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; 3Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; 4Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC, USA and 5Northwestern University, Feinberg School of Medicine, Department of Urology and Robert H Lurie Comprehensive Cancer Center, Chicago, IL, USA In a breast tumor xenograft model, the MCT-1 oncogene Introduction increases the in vivo tumorgenicity ofMCF7 cells by promoting angiogenesis and inhibiting apoptosis. In- In a human xenograft model, the MCT-1/MCTS-1 creases in the tumor microvascular density are accom- (multiple copies in T-cell lymphoma 1) oncogene, panied by a strong reduction in the levels ofthe hereafter named MCT-1 (Prosniak et al., 1998), angiogenesis inhibitor thrombospondin-1 (TSP1), but the promotes the transition to a more aggressive phase in mechanisms underlying this process are unknown. We breast cancer progression by enhancing invasiveness and show that TSP1 expression is controlled, at least in part, decreasing apoptosis (thereby promoting the formation by post-transcriptional events. Using RNA interference to of larger tumors), and increases angiogenesis by redu- knock down the expression ofthe RNA-binding protein cing the expression of the angiogenesis inhibitor TSP1/ HuR in MCF7 cells as well as HuR overexpression, we THBS-1 (thrombospondin 1; Levenson et al., 2005), demonstrate that HuR plays an important role in hereafter named TSP1.
    [Show full text]
  • Gene Expression Profiling of Nfatc1-Knockdown In
    cells Article Gene Expression Profiling of NFATc1-Knockdown in RAW 264.7 Cells: An Alternative Pathway for Macrophage Differentiation Roberta Russo , Selene Mallia, Francesca Zito and Nadia Lampiasi * Institute of Biomedicine and Molecular Immunology “Alberto Monroy”, National Research Council, Via Ugo La Malfa 153, 90146 Palermo, Italy; [email protected] (R.R.); [email protected] (S.M.); [email protected] (F.Z.) * Correspondence: [email protected]; Tel.: +39-091-680-9513 Received: 13 December 2018; Accepted: 5 February 2019; Published: 7 February 2019 Abstract: NFATc1, which is ubiquitous in many cell types, is the master regulator of osteoclastogenesis. However, the molecular mechanisms by which NFATc1 drives its transcriptional program to produce osteoclasts from macrophages (M) remains poorly understood. We performed quantitative PCR (QPCR) arrays and bioinformatic analyses to discover new direct and indirect NFATc1 targets. The results revealed that NFATc1 significantly modified the expression of 55 genes in untransfected cells and 31 genes after NFATc1-knockdown (≥2). Among them, we focused on 19 common genes that showed changes in the PCR arrays between the two groups of cells. Gene Ontology (GO) demonstrated that genes related to cell differentiation and the development process were significantly (p > 0.05) affected by NFATc1-knockdown. Among all the genes analyzed, we focused on GATA2, which was up-regulated in NFATc1-knockdown cells, while its expression was reduced after NFATc1 rescue. Thus, we suggest GATA2 as a new target of NFATc1. Ingenuity Pathway Analysis (IPA) identified up-regulated GATA2 and the STAT family members as principal nodes involved in cell differentiation.
    [Show full text]
  • Identification of Key Differentially Expressed Genes and Gene
    Zhu et al. World Journal of Surgical Oncology (2020) 18:52 https://doi.org/10.1186/s12957-020-01820-z RESEARCH Open Access Identification of key differentially expressed genes and gene mutations in breast ductal carcinoma in situ using RNA-seq analysis Congyuan Zhu*, Hao Hu, Jianping Li*, Jingli Wang, Ke Wang and Jingqiu Sun Abstract Background: The aim of this study was to identify the key differentially expressed genes (DEGs) and high-risk gene mutations in breast ductal carcinoma in situ (DCIS). Methods: Raw data (GSE36863) were downloaded from the database of Gene Expression Omnibus (GEO), including three DCIS samples (DCIS cell lines MCF10.DCIS, Sum102, and Sum225) and one normal control sample (normal mammary epithelial cell line MCF10A). The DEGs were analyzed using NOIseq and annotated via DAVID. Motif scanning in the promoter region of DEGs was performed via SeqPos. Additionally, single nucleotide variations (SNVs) were identified via GenomeAnalysisTK and SNV risk was assessed via VarioWatch. Mutant genes with a high frequency and risk were validated by RT-PCR analyses. Results: Finally, 5391, 7073, and 7944 DEGs were identified in DCIS, Sum102, and Sum22 cell lines, respectively, when compared with MCF10A. VENN analysis of the three cell lines revealed 603 upregulated and 1043 downregulated DEGs, including 16 upregulated and 36 downregulated transcription factor (TF) genes. In addition, six TFs each (e.g., E2F1 and CREB1) were found to regulate the core up- and downregulated DEGs, respectively. Furthermore, SNV detection results revealed 1104 (MCF10.DCIS), 2833 (Sum102), and 1132 (Sum22) mutation sites. Four mutant genes (RWDD4, SDHC, SEPT7, and SFN) with high frequency and risk were identified.
    [Show full text]
  • Three-Dimensional Regulation of HOXA Cluster Genes by a Cis-Element in Hematopoietic Stem Cell and Leukemia
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.16.017533; this version posted April 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Three-dimensional regulation of HOXA cluster genes by a cis-element in hematopoietic stem cell and leukemia. Xue Qing David Wang1, Haley Gore1, Pamela Himadewi1, Fan Feng2, Lu Yang3, Wanding Zhou1,5, Yushuai Liu1, Xinyu Wang4, Chun-wei Chen3, Jianzhong Su4, Jie Liu2, Gerd Pfeifer1,*, Xiaotian Zhang1,* 1. Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan 2. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan. 3. Department of System Biology, City of Hope Cancer Center, California 4. Institute of Biomedical Big Data, Wenzhou Medical University, Wenzhou, China 5. Current address: Children Hospital of Philadelphia, University of Pennsylvania *. These authors jointly supervise this project Correspondence should be addressed to Xiaotian Zhang: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.04.16.017533; this version posted April 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract: Proper gene regulation is crucial for cellular differentiation, and dysregulation of key genes can lead to diseased states such as cancer. The HOX transcription factors play such a role during hematopoiesis, and aberrant expression of certain HOXA genes is found in certain acute myeloid leukemias (AMLs).
    [Show full text]