DOCSLIB.ORG

A Runaway PRH/HHEX-Notch3 Positive Feedback Loop Drives Cholangiocarcinoma and Determines Response to CDK4/6 Inhibition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Runaway PRH/HHEX-Notch3 Positive Feedback Loop Drives Cholangiocarcinoma and Determines Response to CDK4/6 Inhibition Author Manuscript Published OnlineFirst on December 16, 2019; DOI: 10.1158/0008-5472.CAN-19-0942 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 2 A runaway PRH/HHEX-Notch3 positive feedback loop 3 drives cholangiocarcinoma and determines response to 4 CDK4/6 inhibition. 5 Philip Kitchen1, Ka Ying Lee1, Danielle Clark2, Nikki Lau1, Jomnarong Lertsuwan3, 6 Anyaporn Sawasdichai4, Jutamaad Satayavivad4, Sebastian Oltean5, Simon Afford6, Kevin 7 Gaston7*# and Padma-Sheela Jayaraman1*# 8 9 1. Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, 10 University of Birmingham, UK. 2.Department of Biochemistry, Medical School, University 11 of Bristol, UK 3.Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, 12 Bangkok, Thailand; 4.Laboratory of Pharmacology, Chulabhorn Research Institute, Bangkok, 13 Thailand; 5.Institute of Biomedical & Clinical Sciences, University of Exeter Medical 14 School, Exeter, UK. 6.Institute of Immunology and Immunotherapy, University of 15 Birmingham, Birmingham UK. 7.Division of Cancer and Stem Cells, School of Medicine, 16 University of Nottingham, Nottingham, UK. 17 # joint senior author and *joint corresponding author 18 Running title: PRH drives cholangiocarcinoma and chemotherapeutic response 19 7 figures 20 Email: [email protected] tel. no. +44( 0)121-414-4383 1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 16, 2019; DOI: 10.1158/0008-5472.CAN-19-0942 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 21 Email: [email protected] tel. no. +44(0)115-8231395 22 23 Declaration of Interests 24 The authors declare no competing interests. 25 26 27 2 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 16, 2019; DOI: 10.1158/0008-5472.CAN-19-0942 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 28 Abstract 29 Aberrant Notch and Wnt signalling are known drivers of cholangiocarcinoma (CCA) but the 30 underlying factors that initiate and maintain these pathways are not known. Here we show 31 that the PRH/HHEX transcription factor forms a positive transcriptional feedback loop with 32 Notch3 that is critical in CCA. PRH/HHEX expression was elevated in CCA and depletion of 33 PRH reduced CCA tumour growth in a xenograft model. Overexpression of PRH in primary 34 human biliary epithelial cells was sufficient to increase cell proliferation and produce an 35 invasive phenotype. Interrogation of the gene networks regulated by PRH and Notch3 36 revealed that unlike Notch3, PRH directly activated canonical Wnt signalling. These data 37 indicate that hyperactivation of Notch and Wnt signalling is independent of the underlying 38 mutational landscape and has a common origin in dysregulation of PRH. Moreover, they 39 suggest new therapeutic options based on the dependence of specific Wnt, Notch, and 40 CDK4/6 inhibitors on PRH activity. 41 Significance 42 The PRH/HHEX transcription factor is an oncogenic driver in cholangiocarcinoma that 43 confers sensitivity to CDK4/6 inhibitors. 44 45 Keywords: cholangiocarcinoma, bile duct, biliary epithelial cells, cholangiocyte, HHEX, 46 PRH, Notch, Wnt, epithelial-mesenchymal transition 47 3 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 16, 2019; DOI: 10.1158/0008-5472.CAN-19-0942 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 48 Introduction 49 Cholangiocarcinoma (CCA) is a tumour of the bile duct epithelium with an unmet clinical 50 need as this disease is usually advanced at diagnosis. For non-resectable disease median 51 survival is less than 12 months and 5-year survival is around 2% (1). New treatment options 52 and markers that allow early detection and/or inform personalised cancer treatment are 53 therefore urgently needed. Risk factors for CCA include viral infection (Hepatitis B and C), 54 liver fluke infection, primary sclerosing cholangitis (PSC), cholestasis (loss of bile flow), and 55 exposure to dietary toxins or metabolites, all of which lead to inflammation in and around the 56 biliary tree. Chronic inflammation can provoke uncontrolled wound-healing responses 57 involving the generation of DNA-damaging reactive oxygen and nitrogen species, activation 58 of immune cells (particularly macrophages) and stroma, and aberrant activation of autocrine 59 signalling, as well as activation of signalling pathways that promote epithelial-mesenchymal 60 transition (EMT) and angiogenesis. All these events ultimately lead to cancer development 61 and progression (2). Many of the dysregulated pathways involved in CCA are also involved 62 in embryonic liver morphogenesis, such as the Wnt, TGFβ, Notch, Hedgehog and Hippo 63 pathways. Several of these pathways (including Wnt and Notch) can transiently promote 64 EMT or the acquisition of mesenchymal features, such as increased cell migration and matrix 65 invasion or loss of the epithelial cell-cell adhesion molecule E-cadherin (3, 4). In many 66 cancers including mammary cancers, EMT is associated with an increased proportion of 67 tumour initiating cells (the so-called cancer stem cells or CSC) that show increased self- 68 renewal properties and increased chemoresistance (3). EMT and the CSC phenotype can be 69 induced by any one of a common set of aberrantly expressed EMT transcription factors (e.g. 70 Snail, Twist, Zeb) that, amongst many other things, directly repress the expression of E- 71 cadherin (reviewed (5)). CCA patient samples exhibit decreased E-cadherin expression and 72 contain CSCs (6) suggesting that EMT may also be a feature of CCA. 4 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 16, 2019; DOI: 10.1158/0008-5472.CAN-19-0942 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 73 Canonical Wnt signalling is critical for cell proliferation and contributes to the development 74 of CCA in a mouse CCA carcinogenesis model (7, 8). In canonical Wnt signaling, Wnt 75 ligands activate Frizzled family receptors and stabilise the β-catenin protein which then enters 76 the nucleus and activates transcription of Wnt target genes through interaction with TCF/LEF 77 family transcription factors and co-activators (4). β-catenin, by acting as both a co-activator 78 for TCF/LEF transcription factors and a structural component of adherens junctions via 79 interaction with E-cadherin, facilitates cross-talk between canonical Wnt signalling and cell- 80 cell adhesion. Although there are few mutations in Wnt signalling components in CCA there 81 are high levels of nuclear -catenin in the majority of CCA (7, 9). Importantly, 82 pharmacological inhibition of Wnt signalling decreases CCA formation in mouse models (7). 83 NOTCH signalling is also of central importance to the development of CCA (10). Notch 84 signalling involves four transmembrane NOTCH receptors and two families of ligands, 85 Serrate/Jagged (JAG-1, -2) and Delta-like (DLL-1, -3, -4), along with other proteins that 86 transduce and regulate the signal. Upon ligand binding, Notch receptors are sequentially 87 cleaved by an ADAM family protease and the γ-secretase protease complex. Cleavage 88 releases the NOTCH intracellular domain (ICD) which interacts with the DNA binding 89 protein RBP-J/CSL and MAML1 co-activator resulting in transcriptional activation of 90 NOTCH target genes, including the HES and HEY family of genes encoding bHLH 91 transcriptional repressors (reviewed in (11)). In hepatic regeneration models, Wnt and Notch 92 signalling promote different cell fates; Notch signalling promotes biliary fate in Hepatic 93 Progenitor Cells and Wnt signalling promotes hepatic specification (12). Dysregulation of 94 Notch signalling in mouse hepatocytes through constitutive Notch1 ICD or Notch2 ICD 95 expression can result in either hepatocellular carcinoma (HCC) or CCA depending on the co- 96 operating oncogene. NOTCH3 is not expressed in adult liver but Notch3 expression is 97 elevated in CCA patient samples and knockout of Notch3 in a mouse model of CCA 5 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 16, 2019; DOI: 10.1158/0008-5472.CAN-19-0942 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 98 abrogates tumour growth (10). Notch3 ICD is known to be a key driver of CCA in part 99 through activation of PI3K/Akt signalling (10). However, it is not known which genes the 100 Notch3 ICD regulates nor is the interplay between Notch3 ICD signalling and Wnt signalling 101 understood. 102 The Proline-Rich Homeodomain protein/Haematopoietically Expressed Homeobox 103 (PRH/HHEX) protein is a transcription factor encoded by the HHEX gene that is required in 104 the development of many tissue types including the liver and bile duct (reviewed (13)), where 105 PRH regulates hepatic (HNF4a) and biliary (Onecut1)
Load more

Recommended publications
  • Activated Peripheral-Blood-Derived Mononuclear Cells
    Transcription factor expression in lipopolysaccharide- activated peripheral-blood-derived mononuclear cells Jared C. Roach*†, Kelly D. Smith*‡, Katie L. Strobe*, Stephanie M. Nissen*, Christian D. Haudenschild§, Daixing Zhou§, Thomas J. Vasicek¶, G. A. Heldʈ, Gustavo A. Stolovitzkyʈ, Leroy E. Hood*†, and Alan Aderem* *Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103; ‡Department of Pathology, University of Washington, Seattle, WA 98195; §Illumina, 25861 Industrial Boulevard, Hayward, CA 94545; ¶Medtronic, 710 Medtronic Parkway, Minneapolis, MN 55432; and ʈIBM Computational Biology Center, P.O. Box 218, Yorktown Heights, NY 10598 Contributed by Leroy E. Hood, August 21, 2007 (sent for review January 7, 2007) Transcription factors play a key role in integrating and modulating system. In this model system, we activated peripheral-blood-derived biological information. In this study, we comprehensively measured mononuclear cells, which can be loosely termed ‘‘macrophages,’’ the changing abundances of mRNAs over a time course of activation with lipopolysaccharide (LPS). We focused on the precise mea- of human peripheral-blood-derived mononuclear cells (‘‘macro- surement of mRNA concentrations. There is currently no high- phages’’) with lipopolysaccharide. Global and dynamic analysis of throughput technology that can precisely and sensitively measure all transcription factors in response to a physiological stimulus has yet to mRNAs in a system, although such technologies are likely to be be achieved in a human system, and our efforts significantly available in the near future. To demonstrate the potential utility of advanced this goal. We used multiple global high-throughput tech- such technologies, and to motivate their development and encour- nologies for measuring mRNA levels, including massively parallel age their use, we produced data from a combination of two distinct signature sequencing and GeneChip microarrays.
    [Show full text]
  • Prospective Isolation of NKX2-1–Expressing Human Lung Progenitors Derived from Pluripotent Stem Cells
    The Journal of Clinical Investigation RESEARCH ARTICLE Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 2 1Center for Regenerative Medicine, and The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 3Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 4Department of Anatomy, UCSF, San Francisco, California, USA. 5Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. 6Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, Massachusetts, USA. 7Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA. 8Columbia Center for Translational Immunology & Columbia Center for Human Development, Columbia University Medical Center, New York, New York, USA. 9Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee, USA. 10Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA. It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1–expressing (NKX2-1+) precursor cells.
    [Show full text]
  • Thyroid Gland Development and Function in the Zebrafish Model P
    THYROID GLAND DEVELOPMENT AND FUNCTION IN THE ZEBRAFISH MODEL P. Porazzi, D. Calebiro, F. Benato, N. Tiso, L. Persani To cite this version: P. Porazzi, D. Calebiro, F. Benato, N. Tiso, L. Persani. THYROID GLAND DEVELOPMENT AND FUNCTION IN THE ZEBRAFISH MODEL. Molecular and Cellular Endocrinology, Elsevier, 2009, 312 (1-2), pp.14. 10.1016/j.mce.2009.05.011. hal-00521550 HAL Id: hal-00521550 https://hal.archives-ouvertes.fr/hal-00521550 Submitted on 28 Sep 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: THYROID GLAND DEVELOPMENT AND FUNCTION IN THE ZEBRAFISH MODEL Authors: P. Porazzi, D. Calebiro, F. Benato, N. Tiso, L. Persani PII: S0303-7207(09)00277-9 DOI: doi:10.1016/j.mce.2009.05.011 Reference: MCE 7224 To appear in: Molecular and Cellular Endocrinology Received date: 6-3-2009 Revised date: 20-5-2009 Accepted date: 20-5-2009 Please cite this article as: Porazzi, P., Calebiro, D., Benato, F., Tiso, N., Persani, L., THYROID GLAND DEVELOPMENT AND FUNCTION IN THE ZEBRAFISH MODEL, Molecular and Cellular Endocrinology (2008), doi:10.1016/j.mce.2009.05.011 This is a PDF file of an unedited manuscript that has been accepted for publication.
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • The Genetic Factors of Bilaterian Evolution Peter Heger1*, Wen Zheng1†, Anna Rottmann1, Kristen a Panfilio2,3, Thomas Wiehe1
    RESEARCH ARTICLE The genetic factors of bilaterian evolution Peter Heger1*, Wen Zheng1†, Anna Rottmann1, Kristen A Panfilio2,3, Thomas Wiehe1 1Institute for Genetics, Cologne Biocenter, University of Cologne, Cologne, Germany; 2Institute for Zoology: Developmental Biology, Cologne Biocenter, University of Cologne, Cologne, Germany; 3School of Life Sciences, University of Warwick, Gibbet Hill Campus, Coventry, United Kingdom Abstract The Cambrian explosion was a unique animal radiation ~540 million years ago that produced the full range of body plans across bilaterians. The genetic mechanisms underlying these events are unknown, leaving a fundamental question in evolutionary biology unanswered. Using large-scale comparative genomics and advanced orthology evaluation techniques, we identified 157 bilaterian-specific genes. They include the entire Nodal pathway, a key regulator of mesoderm development and left-right axis specification; components for nervous system development, including a suite of G-protein-coupled receptors that control physiology and behaviour, the Robo- Slit midline repulsion system, and the neurotrophin signalling system; a high number of zinc finger transcription factors; and novel factors that previously escaped attention. Contradicting the current view, our study reveals that genes with bilaterian origin are robustly associated with key features in extant bilaterians, suggesting a causal relationship. *For correspondence: [email protected] Introduction The taxon Bilateria consists of multicellular animals
    [Show full text]
  • The Tumor Suppressor HHEX Inhibits Axon Growth When Prematurely Expressed in Developing Central Nervous System Neurons
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by epublications@Marquette Marquette University e-Publications@Marquette Biological Sciences Faculty Research and Biological Sciences, Department of Publications 9-1-2015 The umorT Suppressor HHEX Inhibits Axon Growth when Prematurely Expressed in Developing Central Nervous System Neurons Matthew .T Simpson Marquette University Ishwariya Venkatesh Marquette University Ben L. Callif Marquette University Laura K. Thiel Marquette University Denise M. Coley Marquette University See next page for additional authors Accepted version. Molecular and Cellular Neuroscience, Vol 68 )September 2015): 272-283. DOI. © 2015 Elsevier Inc. Used with permission. NOTICE: this is the author’s version of a work that was accepted for publication in Molecular and Cellular Neuroscience. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Molecular and Cellular Neuroscience, Vol 68 )September 2015): 272-283. DOI. Authors Matthew T. Simpson, Ishwariya Venkatesh, Ben L. Callif, Laura K. Thiel, Denise M. Coley, Kristen N. Winsor, Zimei Wang, Audra A. Kramer, Jessica K. Lerch, and Murray G. Blackmore This article is available at e-Publications@Marquette: https://epublications.marquette.edu/bio_fac/515 NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. The Tumor Suppressor HHEX Inhibits Axon Growth When Prematurely Expressed in Developing Central Nervous System Neurons Matthew T.
    [Show full text]
  • Rapid Evolution of Mammalian X-Linked Testis-Expressed Homeobox Genes
    Copyright 2004 by the Genetics Society of America DOI: 10.1534/genetics.103.025072 Rapid Evolution of Mammalian X-Linked Testis-Expressed Homeobox Genes Xiaoxia Wang and Jianzhi Zhang1 Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109 Manuscript received November 26, 2003 Accepted for publication February 11, 2004 ABSTRACT Homeobox genes encode transcription factors that function in various developmental processes and are usually evolutionarily conserved in their sequences. However, two X-chromosome-linked testis-expressed homeobox genes, one from rodents and the other from fruit flies, are known to evolve rapidly under positive Darwinian selection. Here we report yet another case, from primates. TGIFLX is an X-linked homeobox gene that originated by retroposition of the autosomal gene TGIF2, most likely in a common ancestor of rodents and primates. While TGIF2 is ubiquitously expressed, TGIFLX is exclusively expressed in adult testis. A comparison of the TGIFLX sequences among 16 anthropoid primates revealed a signifi- cantly higher rate of nonsynonymous nucleotide substitution (dN) than synonymous substitution (dS), strongly suggesting the action of positive selection. Although the high dN/dS ratio is most evident outside ف the homeobox, the homeobox has a dN/dS of 0.89 and includes two codons that are likely under selection. Furthermore, the rate of radical amino acid substitutions that alter amino acid charge is significantly greater than that of conservative substitutions, suggesting that the selection promotes diversity of the protein charge profile. More interestingly, an analysis of 64 orthologous homeobox genes from humans and mice shows substantially higher rates of amino acid substitution in X-linked testis-expressed genes than in other genes.
    [Show full text]
  • Figure S1. Reverse Transcription‑Quantitative PCR Analysis of ETV5 Mrna Expression Levels in Parental and ETV5 Stable Transfectants
    Figure S1. Reverse transcription‑quantitative PCR analysis of ETV5 mRNA expression levels in parental and ETV5 stable transfectants. (A) Hec1a and Hec1a‑ETV5 EC cell lines; (B) Ishikawa and Ishikawa‑ETV5 EC cell lines. **P<0.005, unpaired Student's t‑test. EC, endometrial cancer; ETV5, ETS variant transcription factor 5. Figure S2. Survival analysis of sample clusters 1‑4. Kaplan Meier graphs for (A) recurrence‑free and (B) overall survival. Survival curves were constructed using the Kaplan‑Meier method, and differences between sample cluster curves were analyzed by log‑rank test. Figure S3. ROC analysis of hub genes. For each gene, ROC curve (left) and mRNA expression levels (right) in control (n=35) and tumor (n=545) samples from The Cancer Genome Atlas Uterine Corpus Endometrioid Cancer cohort are shown. mRNA levels are expressed as Log2(x+1), where ‘x’ is the RSEM normalized expression value. ROC, receiver operating characteristic. Table SI. Clinicopathological characteristics of the GSE17025 dataset. Characteristic n % Atrophic endometrium 12 (postmenopausal) (Control group) Tumor stage I 91 100 Histology Endometrioid adenocarcinoma 79 86.81 Papillary serous 12 13.19 Histological grade Grade 1 30 32.97 Grade 2 36 39.56 Grade 3 25 27.47 Myometrial invasiona Superficial (<50%) 67 74.44 Deep (>50%) 23 25.56 aMyometrial invasion information was available for 90 of 91 tumor samples. Table SII. Clinicopathological characteristics of The Cancer Genome Atlas Uterine Corpus Endometrioid Cancer dataset. Characteristic n % Solid tissue normal 16 Tumor samples Stagea I 226 68.278 II 19 5.740 III 70 21.148 IV 16 4.834 Histology Endometrioid 271 81.381 Mixed 10 3.003 Serous 52 15.616 Histological grade Grade 1 78 23.423 Grade 2 91 27.327 Grade 3 164 49.249 Molecular subtypeb POLE 17 7.328 MSI 65 28.017 CN Low 90 38.793 CN High 60 25.862 CN, copy number; MSI, microsatellite instability; POLE, DNA polymerase ε.
    [Show full text]
  • In Vitro Targeting of Transcription Factors to Control the Cytokine Release Syndrome in 2 COVID-19 3
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.29.424728; this version posted December 30, 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-NC 4.0 International license. 1 In vitro Targeting of Transcription Factors to Control the Cytokine Release Syndrome in 2 COVID-19 3 4 Clarissa S. Santoso1, Zhaorong Li2, Jaice T. Rottenberg1, Xing Liu1, Vivian X. Shen1, Juan I. 5 Fuxman Bass1,2 6 7 1Department of Biology, Boston University, Boston, MA 02215, USA; 2Bioinformatics Program, 8 Boston University, Boston, MA 02215, USA 9 10 Corresponding author: 11 Juan I. Fuxman Bass 12 Boston University 13 5 Cummington Mall 14 Boston, MA 02215 15 Email: [email protected] 16 Phone: 617-353-2448 17 18 Classification: Biological Sciences 19 20 Keywords: COVID-19, cytokine release syndrome, cytokine storm, drug repurposing, 21 transcriptional regulators 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.29.424728; this version posted December 30, 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-NC 4.0 International license. 22 Abstract 23 Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing 24 hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators 25 of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription 26 factors (TFs) for therapeutic targeting using approved drugs.
    [Show full text]
  • Genome-Wide Analyses Identify Transcription Factors Required for Proper Morphogenesis of Drosophila Sensory Neuron Dendrites
    Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Genome-wide analyses identify transcription factors required for proper morphogenesis of Drosophila sensory neuron dendrites Jay Z. Parrish,1 Michael D. Kim,1 Lily Yeh Jan, and Yuh Nung Jan2 Departments of Physiology and Biochemistry, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA Dendrite arborization patterns are critical determinants of neuronal function. To explore the basis of transcriptional regulation in dendrite pattern formation, we used RNA interference (RNAi) to screen 730 transcriptional regulators and identified 78 genes involved in patterning the stereotyped dendritic arbors of class I da neurons in Drosophila. Most of these transcriptional regulators affect dendrite morphology without altering the number of class I dendrite arborization (da) neurons and fall primarily into three groups. Group A genes control both primary dendrite extension and lateral branching, hence the overall dendritic field. Nineteen genes within group A act to increase arborization, whereas 20 other genes restrict dendritic coverage. Group B genes appear to balance dendritic outgrowth and branching. Nineteen group B genes function to promote branching rather than outgrowth, and two others have the opposite effects. Finally, 10 group C genes are critical for the routing of the dendritic arbors of individual class I da neurons. Thus, multiple genetic programs operate to calibrate dendritic coverage, to coordinate the elaboration of primary versus secondary branches, and to lay out these dendritic branches in the proper orientation. [Keywords: Transcription; RNAi; Drosophila; neuron; dendrite] Supplemental material is available at http://www.genesdev.org.
    [Show full text]
  • The Tumor Suppressor HHEX Inhibits Axon Growth When Prematurely Expressed in Developing Central Nervous System Neurons
    Marquette University e-Publications@Marquette Biological Sciences Faculty Research and Biological Sciences, Department of Publications 9-1-2015 The umorT Suppressor HHEX Inhibits Axon Growth when Prematurely Expressed in Developing Central Nervous System Neurons Matthew .T Simpson Marquette University Ishwariya Venkatesh Marquette University Ben L. Callif Marquette University Laura K. Thiel Marquette University Denise M. Coley Marquette University See next page for additional authors Accepted version. Molecular and Cellular Neuroscience, Vol 68 )September 2015): 272-283. DOI. © 2015 Elsevier Inc. Used with permission. NOTICE: this is the author’s version of a work that was accepted for publication in Molecular and Cellular Neuroscience. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Molecular and Cellular Neuroscience, Vol 68 )September 2015): 272-283. DOI. Authors Matthew T. Simpson, Ishwariya Venkatesh, Ben L. Callif, Laura K. Thiel, Denise M. Coley, Kristen N. Winsor, Zimei Wang, Audra A. Kramer, Jessica K. Lerch, and Murray G. Blackmore This article is available at e-Publications@Marquette: https://epublications.marquette.edu/bio_fac/515 NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. The Tumor Suppressor HHEX Inhibits Axon Growth When Prematurely Expressed in Developing Central Nervous System Neurons Matthew T. Simpson Department of Biomedical Sciences, Marquette University Milwaukee, WI Ishwariya Venkatesh Department of Biomedical Sciences, Marquette University Milwaukee, WI Ben L.
    [Show full text]
  • Integrative Analysis of DNA Methylation and Gene Expression in Skin Cutaneous Melanoma by Bioinformatic Approaches
    Integrative Analysis of DNA Methylation and Gene Expression in Skin Cutaneous Melanoma by Bioinformatic Approaches Yan Sun Huazhong University of Science and Technology Zhilin Wu Huazhong University of Science and Technology Rui Chen Huazhong University of Science and Technology Yan Wu Huazhong University of Science and Technology Yun Lin ( [email protected] ) Huazhong University of Science and Technology Research Article Keywords: Driven genes, Expression, Immune, Methylation, Prognosis, Skin cutaneous melanoma Posted Date: September 2nd, 2021 DOI: https://doi.org/10.21203/rs.3.rs-858303/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/16 Abstract Skin cutaneous melanoma is the most life-threatening skin cancer. Finding key methylation genes of prognostic value is an under-explored but intriguing eld in the research of skin cutaneous melanoma. This work is aimed to identify survival related methylated genes and their specic methylation sites in skin cutaneous melanoma via an integrative analysis with bioinformatic approaches. The original data, including gene methylation and expression les, were downloaded from the Cancer Genome Atlas database. Statistical analysis revealed that skin cutaneous melanoma patients with highly expressed and hypomethylated HHEX had a better outcome than patients with lowly-expressed and hypermethylated HHEX. In addition, fteen methylation sites of HHEX were identied to be signicantly correlated with HHEX expression changes. In various pathological stages, the expression levels of HHEX were different, and exhibited a downward trend from stage to stage . Therefore, we speculate that the driven gene HHEX may play an important role in the survival of skin cutaneous melanoma.
    [Show full text]