Chromosome Instability, Chromosome Transcriptome, and Clonal Evolution of Tumor Cell Populations
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Single Nucleotide Polymorphisms in DKK3 Gene Are Associated with Prostate Cancer Risk and Progression ______
ORIGINAL ARTICLE Vol. 41 (5): 869-897, September - October, 2015 doi: 10.1590/S1677-5538.IBJU.2014.0041 Single nucleotide polymorphisms in DKK3 gene are associated with prostate cancer risk and progression _______________________________________________ Min Su Kim 1, Ha Na Lee 2, Hae Jong Kim 3,4, Soon Chul Myung 5 1Department of Urology, Seoul Medical Center, Seoul, Korea; 2Department of Urology, Seoul Seonam Hospital, EwhaWomans University, Seoul, Korea; 3Research Institue for Biomedical and Pharmaceutical Sciences, Chung-Ang University, Seoul, Korea; 4Advanced Urogenital Diseas Research Center, Chung-Ang University, College of Medicine, Seoul, Korea; 5Department of Urology, Chung-Ang University, College of Medicine, Seoul, Korea ABSTRACT ARTICLE INFO ______________________________________________________________ ______________________ We had investigated whether sequence variants within DKK3 gene are associated with Key words: the development of prostate cancer in a Korean study cohort. We evaluated the asso- Biological Markers; Genetic ciation between 53 single nucleotide polymorphisms (SNPs) in the DKK3 gene and Variation; Prostatic Neoplasms; prostate cancer risk as well as clinical characteristics (PSA, clinical stage, pathological Polymorphism, Single Nucleotide stage and Gleason score) in Korean men (272 prostate cancer subjects and 173 benign prostate hyperplasia subjects) using unconditional logistic regression analysis. Of the Int Braz J Urol. 2015; 41: 869-97 53 SNPs and 25 common haplotypes, 5 SNPs and 4 haplotypes were -
Short Bowel Syndrome Results in Increased Gene Expression
Schall et al. BMC Genomics (2017) 18:23 DOI 10.1186/s12864-016-3433-4 RESEARCH ARTICLE Open Access Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model Kathy A. Schall1, Matthew E. Thornton2, Mubina Isani1, Kathleen A. Holoyda1, Xiaogang Hou1, Ching-Ling Lien3, Brendan H. Grubbs2 and Tracy C. Grikscheit1,4* Abstract Background: Much of the morbidity associated with short bowel syndrome (SBS) is attributed to effects of decreased enteral nutrition and administration of total parenteral nutrition (TPN). We hypothesized that acute SBS alone has significant effects on gene expression beyond epithelial proliferation, and tested this in a zebrafish SBS model. Methods: In a model of SBS in zebrafish (laparotomy, proximal stoma, distal ligation, n = 29) or sham (laparotomy alone, n = 28) surgery, RNA-Seq was performed after 2 weeks. The proximal intestine was harvested and RNA isolated. The three samples from each group with the highest amount of RNA were spiked with external RNA controls consortium (ERCC) controls, sequenced and aligned to reference genome with gene ontology (GO) enrichment analysis performed. Gene expression of ctnnb1, ccnb1, ccnd1, cyp7a1a, dkk3, ifng1-2, igf2a, il1b, lef1, nos2b, saa1, stat3, tnfa and wnt5a were confirmed to be elevated in SBS by RT-qPCR. Results: RNA-seq analysis identified 1346 significantly upregulated genes and 678 significantly downregulated genes in SBS zebrafish intestine compared to sham with Ingenuity analysis. The upregulated genes were involved in cell proliferation, acute phase response signaling, innate and adaptive immunity, bile acid regulation, production of nitric oxide and reactive oxygen species, cellular barrier and coagulation. -
RSU1) in Cancer Cell Metastasis: a Tale of a Tumor Suppressor
International Journal of Molecular Sciences Review Ras Suppressor-1 (RSU1) in Cancer Cell Metastasis: A Tale of a Tumor Suppressor Maria Louca 1, Triantafyllos Stylianopoulos 1 and Vasiliki Gkretsi 2,* 1 Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678 Nicosia, Cyprus; [email protected] (M.L.); [email protected] (T.S.) 2 Biomedical Sciences Program, Department of Life Sciences, School of Sciences, European University Cyprus, 1516 Nicosia, Cyprus * Correspondence: [email protected]; Tel.: +357-22-559-630 Received: 18 May 2020; Accepted: 5 June 2020; Published: 7 June 2020 Abstract: Cancer is a multifactorial disease responsible for millions of deaths worldwide. It has a strong genetic background, as mutations in oncogenes or tumor suppressor genes contribute to the initiation of cancer development. Integrin signaling as well as the signaling pathway of Ras oncogene, have been long implicated both in carcinogenesis and disease progression. Moreover, they have been involved in the promotion of metastasis, which accounts for the majority of cancer-related deaths. Ras Suppressor-1 (RSU1) was identified as a suppressor of Ras-induced transformation and was shown to localize to cell-extracellular matrix adhesions. Recent findings indicate that its expression is elevated in various cancer types, while its role in regulating metastasis-related cellular processes remains largely unknown. Interestingly, there is no in vivo work in the field to date, and thus, all relevant knowledge stems from in vitro studies. In this review, we summarize recent studies using breast, liver and brain cancer cell lines and highlight the role of RSU1 in regulating cancer cell invasion. -
Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies
ANTICANCER RESEARCH 37 : 301-308 (2017) doi:10.21873/anticanres.11321 Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies KEN SUZAWA 1* , KAZUHIKO SHIEN 1,2* , HUANG PENG 3, MASAKIYO SAKAGUCHI 4, MASAMI WATANABE 5,6,7 , SHINSUKE HASHIDA 1,2 , YUHO MAKI 1, HIROMASA YAMAMOTO 1, SHUTA TOMIDA 8, JUNICHI SOH 1, HIROAKI ASANO 1, KAZUNORI TSUKUDA 1, YASUTOMO NASU 5,6,7 , HIROMI KUMON 3,5,7 , SHINICHIRO MIYOSHI 1 and SHINICHI TOYOOKA 1,2 Departments of 1Thoracic Surgery, 2Clinical Genomic Medicine and 4Cell Biology, 5Urology, 3Collaborative Research Center for Okayama Medical Innovation Center, and 8Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 6Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan; 7Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University, Okayama, Japan Abstract. Background: Reduced expression in immortalized Both advanced-stage non-small cell lung cancer (NSCLC) cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and malignant mesothelioma (MM) are aggressive tumors and and its overexpression by adenovirus vector (Ad-REIC) present a dismal prognosis. Despite advances in treatment exhibits a remarkable therapeutic effect on various human regimens for both diseases, such as surgical resection, cancer types through a mechanism triggered by endoplasmic chemotherapy, molecular-targeted therapy and radiotherapy, reticulum stress. Materials and Methods: We examined the treatment outcome is still unsatisfactory. Gene therapy for direct anti-tumor effect of Ad-REIC gene therapy on lung thoracic malignancies represents a novel therapeutic approach cancer and malignant mesothelioma cell lines in vitro, and and has been evaluated in a number of clinical trials over the the distant bystander effect using immunocompetent mouse last two decades (1). -
NIH Public Access Author Manuscript Pharmacogenet Genomics
NIH Public Access Author Manuscript Pharmacogenet Genomics. Author manuscript; available in PMC 2012 September 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Pharmacogenet Genomics. 2011 September ; 21(9): 607–613. doi:10.1097/FPC.0b013e3283415515. PharmGKB summary: very important pharmacogene information for PTGS2 Caroline F. Thorna, Tilo Grosserc, Teri E. Kleina, and Russ B. Altmana,b aDepartment of Genetics, Stanford University Medical Center, Stanford, California bDepartment of Bioengineering, Stanford University Medical Center, Stanford, California cInstitute for Translational Medicine and Therapeutics, University of Pennsylvania, Pennsylvania, USA Keywords cyclooxygenase-2; coxibs; non-steroidal anti-inflammatory drugs; pharmacogenomics; PTGS2; rs20417; rs5275; rs689466 Very important pharmacogene: PTGS2 This PharmGKB summary briefly discusses the PTGS2 gene and current understanding of its function, structure, regulation, and pharmacogenomic relevance. We also present three variants with pharmacogenomic significance and highlight the gaps in our knowledge of PTGS2-drug interactions. Overview The PTGS2 gene codes for prostaglandin G/H synthase-2, which catalyses the first two steps in the metabolism of arachadonic acid. Prostaglandin G/H synthase-2 has two active sites, a hydroperoxidase and a cyclooxygenase (COX) site, and is colloquially termed COX-2. The bifunctional enzyme performs the bis-dioxygenation and reduction of arachadonic acid to form prostaglandin (PG)G2 and H2. PGH2 is then converted to other PGs that modulate inflammation, including PGD2, PGE2, PGF2α, PGI2, and thromboxane A2 (This pathway is shown in the Lipid maps database at http://www.lipidmaps.org/data/IntegratedPathways Data/SetupIntegratedPathways.pl? imgsize=730&Mode=RAW2647&DataType=FAEicosanoidsMedia). COX-2 is the target for nonsteroidal anti-inflammatory drugs (NSAIDS) including those that were purposefully designed (pd) to be selective for COX-2 (pdNSAIDs or coxibs). -
Multi-Targeted Mechanisms Underlying the Endothelial Protective Effects of the Diabetic-Safe Sweetener Erythritol
Multi-Targeted Mechanisms Underlying the Endothelial Protective Effects of the Diabetic-Safe Sweetener Erythritol Danie¨lle M. P. H. J. Boesten1*., Alvin Berger2.¤, Peter de Cock3, Hua Dong4, Bruce D. Hammock4, Gertjan J. M. den Hartog1, Aalt Bast1 1 Department of Toxicology, Maastricht University, Maastricht, The Netherlands, 2 Global Food Research, Cargill, Wayzata, Minnesota, United States of America, 3 Cargill RandD Center Europe, Vilvoorde, Belgium, 4 Department of Entomology and UCD Comprehensive Cancer Center, University of California Davis, Davis, California, United States of America Abstract Diabetes is characterized by hyperglycemia and development of vascular pathology. Endothelial cell dysfunction is a starting point for pathogenesis of vascular complications in diabetes. We previously showed the polyol erythritol to be a hydroxyl radical scavenger preventing endothelial cell dysfunction onset in diabetic rats. To unravel mechanisms, other than scavenging of radicals, by which erythritol mediates this protective effect, we evaluated effects of erythritol in endothelial cells exposed to normal (7 mM) and high glucose (30 mM) or diabetic stressors (e.g. SIN-1) using targeted and transcriptomic approaches. This study demonstrates that erythritol (i.e. under non-diabetic conditions) has minimal effects on endothelial cells. However, under hyperglycemic conditions erythritol protected endothelial cells against cell death induced by diabetic stressors (i.e. high glucose and peroxynitrite). Also a number of harmful effects caused by high glucose, e.g. increased nitric oxide release, are reversed. Additionally, total transcriptome analysis indicated that biological processes which are differentially regulated due to high glucose are corrected by erythritol. We conclude that erythritol protects endothelial cells during high glucose conditions via effects on multiple targets. -
Molecular Genetic Analysis of Rbm45/Drbp1: Genomic Structure, Expression, and Evolution Lauren E
Journal of Student Research (2018) Volume 7, Issue 2, pp 49-61 Research Article Molecular Genetic Analysis of Rbm45/Drbp1: Genomic Structure, Expression, and Evolution Lauren E. Pricea,f, Abigail B. Loewen Faulb,f, Aleksandra Vuchkovskaa, Kevin J. Lopeza, Katie M. Fastb, Andrew G. Ecka, David W. Hoferera,e, and Jeffrey O. Hendersona,b,c,d,g RNA recognition motif-type RNA-binding domain containing proteins (RBDPs) participate in RNA metabolism including regulating mRNA stability, nuclear-cytoplasmic shuttling, and splicing. Rbm45 is an RBDP first cloned from rat brain and expressed spatiotemporally during rat neural development. More recently, RBM45 has been associated with pathological aggregates in the human neurological disorders amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer’s. Rbm45 and the neural developmental protein musashi-1 are in the same family of RDBPs and have similar expression patterns. In contrast to Musashi-1, which is upregulated during colorectal carcinogenesis, we found no association of RBM45 overexpression in human colon cancer tissue. In order to begin characterizing RNA-binding partners of Rbm45, we have successfully cloned and expressed human RBM45 in an Intein fusion-protein expression system. Furthermore, to gain a better understanding of the molecular genetics and evolution of Rbm45, we used an in silico approach to analyze the gene structure of the human and mouse Rbm45 homologues and explored the evolutionary conservation of Rbm45 in metazoans. Human RBM45 and mouse Rbm45 span ~17 kb and 13 kb, respectively, and contain 10 exons, one of which is non-coding. Both genes have TATA-less promoters with an initiator and a GC-rich element. -
Role of PINCH and Its Partner Tumor Suppressor Rsu-1 in Regulating Liver Size and Tumorigenesis
Role of PINCH and Its Partner Tumor Suppressor Rsu-1 in Regulating Liver Size and Tumorigenesis Shashikiran Donthamsetty1, Vishakha S. Bhave2, Wendy M. Mars1, William C. Bowen1, Anne Orr1, Meagan M. Haynes1, Chuanyue Wu1, George K. Michalopoulos1* 1 University of Pittsburgh School of Medicine, Department of Pathology, Pittsburgh, Pennsylvania, United States of America, 2 Philadelphia College of Osteopathic Medicine, School of Pharmacy, Department of Pharmaceutical Sciences, Suwannee, Georgia, United States of America Abstract Particularly interesting new cysteine-histidine-rich protein (PINCH) protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK)-PINCH-Parvin-α) complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1). We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice). PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. -
Transcriptomic and Epigenomic Characterization of the Developing Bat Wing
ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight. -
Transcriptome Profiling and Differential Gene Expression In
G C A T T A C G G C A T genes Article Transcriptome Profiling and Differential Gene Expression in Canine Microdissected Anagen and Telogen Hair Follicles and Interfollicular Epidermis Dominique J. Wiener 1,* ,Kátia R. Groch 1 , Magdalena A.T. Brunner 2,3, Tosso Leeb 2,3 , Vidhya Jagannathan 2 and Monika M. Welle 3,4 1 Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Science, Texas A&M University, College Station, TX 77843, USA; [email protected] 2 Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; [email protected] (M.A.T.B.); [email protected] (T.L.); [email protected] (V.J.) 3 Dermfocus, Vetsuisse Faculty, University Hospital of Bern, 3010 Bern, Switzerland; [email protected] 4 Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland * Correspondence: [email protected]; Tel.: +1-979-862-1568 Received: 30 June 2020; Accepted: 3 August 2020; Published: 4 August 2020 Abstract: The transcriptome profile and differential gene expression in telogen and late anagen microdissected hair follicles and the interfollicular epidermis of healthy dogs was investigated by using RNAseq. The genes with the highest expression levels in each group were identified and genes known from studies in other species to be associated with structure and function of hair follicles and epidermis were evaluated. Transcriptome profiling revealed that late anagen follicles expressed mainly keratins and telogen follicles expressed GSN and KRT15. The interfollicular epidermis expressed predominately genes encoding for proteins associated with differentiation. All sample groups express genes encoding for proteins involved in cellular growth and signal transduction. -
Dickkopf-3 Links HSF1 and YAP/TAZ Signalling to Control Aggressive Behaviours in Cancer-Associated fibroblasts
ARTICLE https://doi.org/10.1038/s41467-018-07987-0 OPEN Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts Nicola Ferrari 1,8, Romana Ranftl1, Ievgeniia Chicherova1, Neil D. Slaven2, Emad Moeendarbary3,4, Aaron J. Farrugia1, Maxine Lam1, Maria Semiannikova1, Marie C. W. Westergaard5, Julia Tchou6, Luca Magnani 2 & Fernando Calvo1,7 1234567890():,; Aggressive behaviours of solid tumours are highly influenced by the tumour microenviron- ment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer- associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour- promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs. 1 Tumour Microenvironment Team, Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK. 2 Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK. 3 Department of Mechanical Engineering, University College London, London WC1E 7JE, UK. -
CELF RNA Binding Proteins Promote Axon Regeneration in C. Elegans and Mammals 1 Through Alternative Splicing of Syntaxins 2 Lizh
1 CELF RNA binding proteins promote axon regeneration in C. elegans and mammals 2 through alternative splicing of Syntaxins 3 Lizhen Chen1,2,§, Zhijie Liu3, Bing Zhou4, Chaoliang Wei4, Yu Zhou4, Michael G. Rosenfeld2,3, 4 Xiangdong Fu4, Andrew D. Chisholm1,*, Yishi Jin1,2,4,* 5 6 1 Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, 7 La Jolla, CA92093 8 2 Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 9 92093 10 3 Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 11 92093 12 4 Department of Cellular and Molecular Medicine, School of Medicine, University of California, 13 San Diego, La Jolla, CA 92093 14 15 * to whom correspondence should be addressed 16 § Current address: Barshop Institute for Longevity and Aging Studies, Department of Cellular 17 and Structural Biology, University of Texas Health Science Center San Antonio, San Antonio, 18 Texas 78245 19 With 7 Figures, 3 Videos, 9 figure supplements, 7 Supplementary Files 20 Key words: UNC-75, CLIP-seq, alternative splicing, SNARE, DRG, CUGBP, ETR3 21 1 22 Abstract 23 Axon injury triggers dramatic changes in gene expression. While transcriptional regulation 24 of injury-induced gene expression is widely studied, less is known about the roles of RNA 25 binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. 26 elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon 27 regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) 28 we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75.