DOCSLIB.ORG

Comparative Genomic Hybridization and Histological Variation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Comparative Genomic Hybridization and Histological Variation British Journal of Cancer (1999) 80(9), 1322–1331 © 1999 Cancer Research Campaign Article no. bjoc.1999.0525 Comparative genomic hybridization and histological variation in primitive neuroectodermal tumours JC Nicholson1,2, FM Ross1, JA Kohler2 and DW Ellison3 1Wessex Regional Genetics Laboratory, Salisbury, Wiltshire SP2 8BJ, UK; Departments of 2Child Health and 3Pathology, Southampton General Hospital, Southampton SO16 6YD, UK Summary The objective of this study was to test the hypothesis that chromosomal imbalances in central nervous system primitive neuroectodermal tumours (PNETs) reflect site and histology. We used comparative genomic hybridization to study 37 cases of PNET, of which four were cerebral and 31 were medulloblastomas classified histologically as classic (n = 17) or nodular/desmoplastic (n = 14). Tumour immunophenotype was characterized with antibodies to neuroglial, mesenchymal and epithelial markers. Chromosomal imbalances were detected in 28 medulloblastomas (90%), and significant associations between tumour variants and genetic abnormalities were demonstrated. Aberrations suggesting isochromosome 17q were present in eight (26%) medulloblastomas, of which seven were classic variants. None of these cases, or a further six with gain of 17q, showed immunoreactivity for glial fibrillary acidic protein. Loss on 9q was found in six cases (19%), five of them nodular/desmoplastic. Loss of 22 occurred in four (13%), all classic medulloblastomas in young patients with a poor outcome and immunoreactivity for more than one epithelial or mesenchymal marker. Different patterns of imbalance were found in the cerebral PNETs. There were no abnormalities of chromosome 17, but all three cases with imbalance showed losses of 3p12.3–p14. Keywords: medulloblastoma; cerebral PNET; comparative genomic hybridization; isochromosome 17q; monosomy 22; glial fibrillary acidic protein Tumours of the central nervous system (CNS) are the commonest most common, occurring in a third of cases overall (Mertens et al, solid neoplasms of childhood, and primitive neuroectodermal 1994). Other recognized patterns of abnormality have included tumours (PNETs) are the most numerous among these, accounting loss of the X or Y chromosome, trisomy 7, monosomy 22, double for approximately 25% of all childhood brain tumours (Packer, minutes and structural rearrangements, particularly of chromo- 1995). More than 90% of cases of CNS PNET occur in the somes 1, 7 and 11 (Heim and Mitelman, 1995; Bigner et al, 1997). posterior fossa as medulloblastomas. PNETs at other CNS sites Microsatellite analysis has corroborated the existence of chromo- resemble the classic medulloblastoma, which has a propensity for some 17 abnormalities by documenting loss of heterozygosity divergent differentiation along neuro-epithelial lines, manifesting (LOH) on 17p, as well as on chromosomes 9, 10, 11, 16 and 22 as expression of glial fibrillary acidic protein (GFAP) and/or (Blaeker et al, 1996). neuronal proteins or rarely as the presence of scattered ganglion All of these abnormalities result in genetic imbalance and there- cells (Tomlinson et al, 1992; Ellison and Love, 1998). In addition fore make these tumours particularly suitable for study by compar- to the classic medulloblastoma, several variants are recognized in ative genomic hybridization (CGH). Two previous studies (Schütz the World Health Organization classification of CNS tumours: et al, 1996; Reardon et al, 1997) found widely different numbers of desmoplastic medulloblastoma, melanotic medulloblastoma and abnormalities in medulloblastomas using CGH. The aims of this medullomyoblastoma (Kleihues et al, 1993). Desmoplastic medul- study were to screen a series of CNS PNETs, mostly medulloblas- loblastomas account for approximately 20% of medulloblastomas tomas, for chromosomal imbalance as revealed by CGH, to test the and frequently exhibit a nodular architecture in which cells often hypothesis that histological and immunophenotypical differences show a neuronal or glial immunophenotype; these nodular/desmo- among variants of PNET are associated with specific genetic plastic medulloblastomas are considered to form a histological abnormalities, and to assess the prognostic value of any commonly spectrum of tumours, distinct from classic medulloblastomas observed genetic abnormalities. (Giangaspero et al, 1991; Tomlinson et al, 1992). Cytogenetic studies of medulloblastoma and other PNETs have MATERIALS AND METHODS identified several non-random chromosomal aberrations in a high proportion of cases (Biegel et al, 1989; Bhattachajee et al, 1997; Patient group Bigner et al, 1997). Of these, isochromosome 17q [i(17q)] is the All biopsies (n = 39) came from patients (n = 37) attending the Wessex Neurological Centre in Southampton between 1985 and Received 16 November 1998 1997. Some tumour, surplus to diagnostic requirements, was Revised 21 January 1999 stored in each case at –170°C. All specimens used in the study Accepted 27 January 1999 were obtained prior to commencement of treatment, except in Correspondence to: JC Nicholson, Department of Child Health, Mail Point cases 8 and 13. 0021, G Level, Southampton General Hospital, Tremona Road, Southampton Most patients (n = 31) had a medulloblastoma. Of these, 17 SO16 6YD, UK showed classic histology, while the remaining 14 had a 1322 CGH analysis of PNETs 1323 Table 1 Clinical features of PNETs and CGH results Case Age at PNET Metastases Primary Chemotherapy Radiotherapy Survival CGH results diagnosis variant surgical (years) (years) resection 1 19.8 Classic MB No Subtotal No CS 4.8* rev ish enh(5,6,7,12q24,17,18),dim (X,2q14qter,3,8p12q24.1,9p,11,13q13q31, 14q23q31,16q) 2 14.3 Classic MB No Partial Yes CS 8.8* rev ish enh(7,17q),dim(2,8,11p, 12pterq22,13q,17p) 3 8.5 Classic MB No Subtotal Yes CS 3.3 rev ish enh(4p15.3pter,6q23qter, 9p,12q23qter,17q),dim(Y,5q34qter,8p12pter, 17p,18p,20) 4 0.7 Classic MB No Partial No No 0.3 rev ish dim(22) 5 1.6 Classic MB No Partial Yes No 0.3 rev ish enh(17,19q), dim(Yq,11q13.5q23) 6 6.3 Classic MB Spinal Complete Yes CS 1.4 rev ish enh(17q,18),dim(8,17p) 7 9.8 Classic MB Spinal Partial Yes CS 1.7 rev ish enh(17q),dim(Yq,17p) 8 6.5 Classic MB No Subtotal Yes CS 5.1 1st relapse: rev ish enh(1q,4p16,7q, 12q23qter,17q21qter),dim(4q22q28, 4q32qter, 5q33qter,8p21.3pter, 11p11.2p13,16q21qter) 2nd relapse: rev ish enh(1q,4p16,7q, 12q23qter, 17q21qter),dim(Y,4q22q25, 4q32qter, 5q33qter,8p21.3pter,11p, 16q21qter) 9 6.6 Classic MB No Complete Yes CS 2.8* No imbalances 10 3.3 Classic MB No Complete No CS 6.3* rev ish enh(1q,8,17q),dim(4q31qter,17p) 11 24.8 Classic MB Spinal Subtotal No CS 0.3* rev ish enh(10,17q),dim(17p) 12 4.8 Classic MB Spinal Complete No No 0.1 rev ish enh(2p13.3pter,12,17q,18), dim(4q24qter,16q21qter,17p) 13 30.3 Classic MB No Subtotal No CS 3.3 1st relapse: rev ish enh(Xq,3q,6q26q27,9p, 13,15q23qter,18p),dim(Xp,4q31q34, 9q22q34.1,10q21qter,11p14,11q14q22, 14,15q11q15,17p12pter),amp(2q14q21) 14 32.2 Classic MB Not known Biopsy No No 0 rev ish dim(10q,11,17p) 15 5.3 Classic MB No Subtotal Yes CS 1.5 rev ish dim(22) 16 0.3 Classic MB No Biopsy No No 0 rev ish dim(22) 17 0.7 Classic MB Spinal Subtotal Yes Local 1.3 rev ish enh(14),dim(22) 18 9.3 ndMB Spinal Subtotal Yes CS 0.8 no imbalances 19 5.1 ndMB No Subtotal Yes CS 6.4* rev ish enh(4,5,6,7,17q),dim(Y,8,17p) 20 11.2 ndMB No Subtotal No CS 1.3* rev ish enh(1,7,17q),dim(Xq12q25,Y,8,10,11, 13q13q21,14q11.2q13,14q24,15,20) 21 5.9 ndMB No Subtotal Yes CS 1.2* rev ish enh(2,7,15,17q),dim(3,8,10, 11p15pter,21) 22 5.3 ndMB No Subtotal No No 0.1 rev ish enh(7q,8q24,12q24,17q22qter,18, 19pterq12),dim(8p,10q21.3qter,19q13.2qter) 23 12.7 ndMB No Complete Yes CS 8.1* rev ish enh(1q31qter,2,4q21q25,9p,18), dim(4p15.2q13,4q26q32,8,9q22q34,10,16), amp(12p13,13q33) 24 3.6 ndMB No Complete No CS 7.4* rev ish dim(9q21q31) 25 19.6 ndMB No Subtotal No CS 4.5 Primary tumour: rev ish enh(3q),dim(Y) 1st relapse: rev ish enh(3q),dim(11q13q22) 26 22.8 ndMB No Complete No CS 7.2* rev ish dim(X,6q16q24) 27 7.3 ndMB No Complete No CS 1.3* rev ish enh(1q,2,3p14p21,7,9p,10p,13), dim(Xp,3q,4pterq26,5q,8q12qter,9q21.3q22, 10q,11q23qter,14,16,17p,18p),amp(4q28) 28 30.3 ndMB No Subtotal No CS 2.4 rev ish enh(20q),dim(9q22qter,17p) 29 25.6 ndMB Not known Complete No Local 6.4 rev ish enh(15q12q14) 30 27.9 ndMB Bone Partial No CS 5.6 No imbalances 31 4 ndMB No Subtotal No CS 0.9* rev ish enh(3,9p),dim(9q) 32 11.9 GNB No Complete No CS 10.3* rev ish enh(17q),dim(17p) 33 14.1 MmyoB Not known Complete No CS 10.3* rev ish enh(8) 34 8.3 cPNET No Biopsy Yes Palliative 0.6 rev ish enh(X,1,7p,9,13,16p,19,20,22),dim (3,4,5,6,8q13qter,10q11q22,10q24.3qter, 12p12q23,14,15q11q23,16q12q22.1,18q), amp(7p11.2p12,7q21.3q22) 35 2.6 cPNET No Subtotal Yes CS 5.7* rev ish enh(X,1p32pter,1q32qter,2p, 7q33qter),dim(3p12p14,3p21.3pter,5pterq33, 6,7p12p21.1,9p23q32,11,14q24qter) 36 6.4 cPNET Not known Partial No No 0.2 rev ish dim(3p13p21.1) 37 1.1 cPNET No Complete Yes No 0.8 No imbalances Survival: *denotes ongoing remission.
Load more

Recommended publications
  • Effects and Mechanisms of Eps8 on the Biological Behaviour of Malignant Tumours (Review)
    824 ONCOLOGY REPORTS 45: 824-834, 2021 Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review) KAILI LUO1, LEI ZHANG2, YUAN LIAO1, HONGYU ZHOU1, HONGYING YANG2, MIN LUO1 and CHEN QING1 1School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500; 2Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China Received August 29, 2020; Accepted December 9, 2020 DOI: 10.3892/or.2021.7927 Abstract. Epidermal growth factor receptor pathway substrate 8 1. Introduction (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which Malignant tumours are uncontrolled cell proliferation diseases is involved in cell mitosis, differentiation and other physiological caused by oncogenes and ultimately lead to organ and body functions. Numerous studies over the last decade have demon- dysfunction (1). In recent decades, great progress has been strated that Eps8 is overexpressed in most ubiquitous malignant made in the study of genes and signalling pathways in tumours and subsequently binds with its receptor to activate tumorigenesis. Eps8 was identified by Fazioli et al in NIH-3T3 multiple signalling pathways. Eps8 not only participates in the murine fibroblasts via an approach that allows direct cloning regulation of malignant phenotypes, such as tumour proliferation, of intracellular substrates for receptor tyrosine kinases (RTKs) invasion, metastasis and drug resistance, but is also related to that was designed to study the EGFR signalling pathway. Eps8 the clinicopathological characteristics and prognosis of patients.
    [Show full text]
  • Eps8l2 (F-8): Sc-514673
    SAN TA C RUZ BI OTEC HNOL OG Y, INC . Eps8L2 (F-8): sc-514673 BACKGROUND APPLICATIONS Eps8L2 (epidermal growth factor receptor kinase substrate 8-like protein 2), Eps8L2 (F-8) is recommended for detection of Eps8L2 of human origin by also known as EPS8R2 or PP13181, is a 715 amino acid protein that localizes Western Blotting (starting dilution 1:100, dilution range 1:100-1:1000), to the cytoplasm and belongs to the Eps8 (epidermal growth factor receptor immunoprecipitation [1-2 µg per 100-500 µg of total protein (1 ml of cell pathway substrate 8) family. Expressed in placenta and fibroblasts, Eps8L2 lysate)], immunofluorescence (starting dilution 1:50, dilution range 1:50- functions to stimulate the guanine exchange activity of Sos 1 (son of seven - 1:500) and solid phase ELISA (starting dilution 1:30, dilution range 1:30- less homolog 1), a protein that promotes the exchange of Ras-bound GDP 1:3000). for GTP. Additionally, Eps8L2 is thought to associate with Actin and, via this Suitable for use as control antibody for Eps8L2 siRNA (h): sc-96954, Eps8L2 association, may play a role in membrane ruffling and remodeling of the shRNA Plasmid (h): sc-96954-SH and Eps8L2 shRNA (h) Lentiviral Particles: Actin cytoskeleton. Through its ability to regulate protein activation and cyto- sc-96954-V. skeleton dynamics, Eps8L2 may participate in cell growth and differentiation events within the cell. Eps8L2, a protein that is expressed as two isoforms Molecular Weight of Eps8L2: 81 kDa. due to alternative splicing, contains one PID (phosphotyrosine interaction) Positive Controls: A-431 whole cell lysate: sc-2201, HeLa whole cell lysate: domain and one SH3 domain.
    [Show full text]
  • The Human Gene Connectome As a Map of Short Cuts for Morbid Allele Discovery
    The human gene connectome as a map of short cuts for morbid allele discovery Yuval Itana,1, Shen-Ying Zhanga,b, Guillaume Vogta,b, Avinash Abhyankara, Melina Hermana, Patrick Nitschkec, Dror Friedd, Lluis Quintana-Murcie, Laurent Abela,b, and Jean-Laurent Casanovaa,b,f aSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; bLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris Descartes University, Institut National de la Santé et de la Recherche Médicale U980, Necker Medical School, 75015 Paris, France; cPlateforme Bioinformatique, Université Paris Descartes, 75116 Paris, France; dDepartment of Computer Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; eUnit of Human Evolutionary Genetics, Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Institut Pasteur, F-75015 Paris, France; and fPediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, 75015 Paris, France Edited* by Bruce Beutler, University of Texas Southwestern Medical Center, Dallas, TX, and approved February 15, 2013 (received for review October 19, 2012) High-throughput genomic data reveal thousands of gene variants to detect a single mutated gene, with the other polymorphic genes per patient, and it is often difficult to determine which of these being of less interest. This goes some way to explaining why, variants underlies disease in a given individual. However, at the despite the abundance of NGS data, the discovery of disease- population level, there may be some degree of phenotypic homo- causing alleles from such data remains somewhat limited. geneity, with alterations of specific physiological pathways under- We developed the human gene connectome (HGC) to over- come this problem.
    [Show full text]
  • Essential Role for Abi1 in Embryonic Survival and WAVE2 Complex Integrity
    Essential role for Abi1 in embryonic survival and WAVE2 complex integrity Patrycja M. Dubieleckaa,1, Kathrin I. Ladweinb,1, Xiaoling Xionga, Isabelle Migeottec, Anna Chorzalskaa, Kathryn V. Andersonc, Janet A. Sawickid, Klemens Rottnerb,e, Theresia E. Stradalb,f, and Leszek Kotulaa,2 aLaboratory of Cell Signaling, New York Blood Center, New York, NY 10065; bHelmholtz Centre for Infection Research, D-38124 Braunschweig, Germany; cDevelopmental Biology Program, Sloan-Kettering Institute, New York, NY 10065; dLankenau Institute for Medical Research, Wynnewood, PA 19096; eInstitute of Genetics, University of Bonn, 53117 Bonn, Germany; and fInstitute for Molecular Cell Biology, University of Münster, D-48149 Münster, Germany Edited* by Hilary Koprowski, Thomas Jefferson University, Philadelphia, PA, and approved March 15, 2011 (received for review November 11, 2010) Abl interactor 1 (Abi1) plays a critical function in actin cytoskeleton activation to actin polymerization that drives lamellipodia pro- dynamics through participation in the WAVE2 complex. To gain trusion at the plasma membrane (13, 14). WAVE1 and WAVE3 a better understanding of the specific role of Abi1, we generated were proposed to have roles analogous to WAVE2 in the complex (8). Although the function of WAVE3 is less defined, the critical a conditional Abi1-KO mouse model and MEFs lacking Abi1 expres- fl sion. Abi1-KO cells displayed defective regulation of the actin cyto- role of the other two WAVEs in dorsal ruf e formation was demonstrated (15, 16). Mechanistically, it is proposed that native skeleton, and this dysregulation was ascribed to altered activity of WAVE2 complex is inactive (17–19) but is activated at the the WAVE2 complex.
    [Show full text]
  • Characterization of in Vivo Resistance to Osimertinib and JNJ-61186372
    Published OnlineFirst August 22, 2017; DOI: 10.1158/1535-7163.MCT-17-0413 Cancer Biology and Translational Studies Molecular Cancer Therapeutics Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance Kristina B. Emdal1, Antje Dittmann1, Raven J. Reddy1, Rebecca S. Lescarbeau1, Sheri L. Moores2, Sylvie Laquerre2, and Forest M. White1 Abstract Approximately 10% of non–small cell lung cancer (NSCLC) targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific patients in the United States and 40% of NSCLC patients in Asia increases in tyrosine-phosphorylated peptides from EGFR family have activating epidermal growth factor receptor (EGFR) muta- members, Shc1 and Gab1 or Src family kinase (SFK) substrates tions and are eligible to receive targeted anti-EGFR therapy. were observed, underscoring a differential ability of tumors to Despite an extension of life expectancy associated with this uniquely escape EGFR inhibition. Although most resistant tumors treatment, resistance to EGFR tyrosine kinase inhibitors and within each treatment group displayed a marked inhibition of anti-EGFR antibodies is almost inevitable. To identify additional EGFR as well as SFK signaling, the combination of EGFR inhibi- signaling routes that can be cotargeted to overcome resistance, we tion (osimertinib) and SFK inhibition (saracatinib or dasatinib) quantified tumor-specific molecular changes that govern resistant led to further decrease in cell growth in vitro. This result suggests cancer cell growth and survival. Mass spectrometry–based quan- that residual SFK signaling mediates therapeutic resistance and titative proteomics was used to profile in vivo signaling changes in that elimination of this signal through combination therapy may 41 therapy-resistant tumors from four xenograft NSCLC models.
    [Show full text]
  • Divergent Dysregulation of Gene Expression in Murine Models Of
    Kong et al. Molecular Autism 2014, 5:16 http://www.molecularautism.com/content/5/1/16 RESEARCH Open Access Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis Sek Won Kong1,5†, Mustafa Sahin2†, Christin D Collins3, Mary H Wertz2, Malcolm G Campbell5, Jarrett D Leech2, Dilja Krueger4, Mark F Bear4, Louis M Kunkel3 and Isaac S Kohane1,5* Abstract Background: Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. Methods: To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. Results: Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/−) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. Conclusions: Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/− mice mirror some, but not all, of the perturbed molecular pathways in the brain.
    [Show full text]
  • Understanding SOS (Son of Sevenless) Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul
    Understanding SOS (Son of Sevenless) Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul To cite this version: Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul. Understanding SOS (Son of Sevenless). Bio- chemical Pharmacology, Elsevier, 2011, 82 (9), pp.1049-1056. 10.1016/j.bcp.2011.07.072. hal- 02190799 HAL Id: hal-02190799 https://hal.archives-ouvertes.fr/hal-02190799 Submitted on 22 Jul 2019 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. *Manuscript Click here to view linked References Understanding SOS (Son of Sevenless). 1 1,2,‡ 1,2,3,‡ 1,2, † 2 Stéphane PIERRE , Anne-Sophie BATS , Xavier COUMOUL 3 4 5 1 6 INSERM UMR-S 747, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des 7 Saints Pères, 75006 Paris France 8 9 10 2 Université Paris Descartes, Centre universitaire des Saints-Pères, 45 rue des Saints Pères, 11 12 75006 Paris France 13 14 3 15 AP-HP, Hôpital Européen Georges Pompidou, Service de Chirurgie Gynécologique 16 17 Cancérologique, 75015 Paris France 18 19 ‡ These authors contributed equally to this work. 20 21 † 22 Address correspondence to: Xavier Coumoul, INSERM UMR-S 747, 45 rue des Saints-Pères 23 24 75006 Paris France; Phone: +33 1 42 86 33 59; Fax: +33 1 42 86 38 68; E-mail: 25 26 [email protected] 27 28 29 30 31 Key words: Son of Sevenless.
    [Show full text]
  • EPS8, an Adaptor Protein Acts As an Oncoprotein in Human Cancer
    Chapter 5 EPS8, an Adaptor Protein Acts as an Oncoprotein in Human Cancer Ming-Chei Maa and Tzeng-Horng Leu Additional information is available at the end of the chapter http://dx.doi.org/10.5772/54906 1. Introduction A spectrum of cellular activities including proliferation, differentiation and metabolism are controlled by growth factors and hormones. The effects of many growth factors are mediated and achieved via transmembrane receptor tyrosine kinases [1,2]. Following ligand binding, the intrinsic catalytic activity of the growth factor receptor tyrosine kinases (RTKs) is augmented. The autophosphorylated RTKs then transmit signals through their ability to recruit and/or phosphorylate intracellular substrates. Thus, identification and characterization of proteins that associate with and/or become tyrosyl phosphorylated by RTKs become critical to delineate RTKs-mediated signaling pathways. A variety of methodologies have been developed and applied to search for substrates of tyrosine kinases including RTKs [3-8]. Here, we focus on EGFR pathway substrate no. 8 (Eps8), a putative target of epidermal growth factor (EGF) receptor (EGFR), and discuss its biological function as well as its implication in human cancers. Given Eps8-elicited effects contribute to neoplasm, its potential as a therapeutic target for cancer treatment is anticipated. 1.1. The identification of Eps8 To dissect EGFR-mediated signaling, Di Fiore’s laboratory took advantage of immuno- affinity purification of an entire set of proteins phosphorylated in EGF-treated EGFR- overexpressing cells, followed by generation of antisera against the purified protein pool. With these antisera, bacterial expression libraries were immunologically screened. Several murine cDNAs (eps clones) representing genes encoding substrates for EGFR were obtained [7,8].
    [Show full text]
  • Overexpression of EPS8L3 Promotes Cell Proliferation by Inhibiting the Transactivity of FOXO1 in HCC
    Neoplasma, 65, 5, 2018 701 doi:10.4149/neo_2018_170725N503 Overexpression of EPS8L3 promotes cell proliferation by inhibiting the transactivity of FOXO1 in HCC C. X. ZENG1,*, L. Y. TANG2, C. Y. XIE2, F. X. LI1, J. Y. ZHAO1, N. JIANG3, Z. TONG3, S. B. FU3, F. J. WEN1, W. S. FENG1 1Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, China; 2Department of General Surgery, Zengcheng People’s Hospital, (BoJi-Affiliated Hospital of Sun Yat-Sen University), Zengcheng, China;3 Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China *Correspondence: [email protected] Received July 25, 2017 / Accepted February 1, 2018 The homology of epidermal growth factor receptor pathway substrate 8 (EPS8), EPS8L3, is elevated and significantly enhanced in hepatocellular carcinoma (HCC) tissues and cell lines compared to normal liver tissues and cell lines. MTT and colony formation assays demonstrated that EPS8L3 over-expression induces HCC cell proliferation and silencing reduces it. Further experiments illustrated that over-expressing EPS8L3 promotes p-AKT and Cyclin D1 expression, but inhibits the transcriptional activity of FOXO1. Colony formation assay also demonstrated that AKT inhibitor suppresses the effect of EPS8L3 on proliferation in EPS8L3-over-expressing cells, while AKT restores the proliferation of EPS8L3-silenced cells. This suggests that EPS8L3 promotes proliferation by hyper-activating the AKT signaling pathway and subsequently inhib- iting FOXO1 transcriptional activity. Our results provide a new view on EPS8L3 and human HCC progression and therefore EPS8L3 may prove a novel therapeutic target for HCC. Key words: hepatocellular carcinoma, EPS8L3, FOXO1, signaling pathway Liver cancer is the sixth most frequent incidence cancer [7]; (2) Gorsic et al.
    [Show full text]
  • Hyperactivation of HER2-SHCBP1-PLK1 Axis Promotes Tumor Cell Mitosis and Impairs Trastuzumab Sensitivity to Gastric Cancer
    ARTICLE https://doi.org/10.1038/s41467-021-23053-8 OPEN Hyperactivation of HER2-SHCBP1-PLK1 axis promotes tumor cell mitosis and impairs trastuzumab sensitivity to gastric cancer Wengui Shi 1,2,5, Gengyuan Zhang 3,5, Zhijian Ma4,5, Lianshun Li4,5, Miaomiao Liu4, Long Qin1,2, Zeyuan Yu3, ✉ Lei Zhao1,2, Yang Liu1,2, Xue Zhang4, Junjie Qin1,2, Huili Ye1,2, Xiangyan Jiang4, Huinian Zhou3, Hui Sun1,2 & ✉ Zuoyi Jiao 1,2,3,4 1234567890():,; Trastuzumab is the backbone of HER2-directed gastric cancer therapy, but poor patient response due to insufficient cell sensitivity and drug resistance remains a clinical challenge. Here, we report that HER2 is involved in cell mitotic promotion for tumorigenesis by hyperactivating a crucial HER2-SHCBP1-PLK1 axis that drives trastuzumab sensitivity and is targeted therapeutically. SHCBP1 is an Shc1-binding protein but is detached from scaffold protein Shc1 following HER2 activation. Released SHCBP1 responds to HER2 cascade by translocating into the nucleus following Ser273 phosphorylation, and then contributing to cell mitosis regulation through binding with PLK1 to promote the phosphorylation of the mitotic interactor MISP. Meanwhile, Shc1 is recruited to HER2 for MAPK or PI3K pathways activation. Also, clinical evidence shows that increased SHCBP1 prognosticates a poor response of patients to trastuzumab therapy. Theaflavine-3, 3’-digallate (TFBG) is identified as an inhi- bitor of the SHCBP1-PLK1 interaction, which is a potential trastuzumab sensitizing agent and, in combination with trastuzumab, is highly efficacious in suppressing HER2-positive gastric cancer growth. These findings suggest an aberrant mitotic HER2-SHCBP1-PLK1 axis underlies trastuzumab sensitivity and offer a new strategy to combat gastric cancer.
    [Show full text]
  • EPS8L2 Is a New Causal Gene for Childhood Onset Autosomal Recessive Progressive Hearing Loss Malika Dahmani1, Fatima Ammar-Khodja1, Crystel Bonnet2,3,4, Gaelle M
    Dahmani et al. Orphanet Journal of Rare Diseases (2015) 10:96 DOI 10.1186/s13023-015-0316-8 RESEARCH Open Access EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss Malika Dahmani1, Fatima Ammar-Khodja1, Crystel Bonnet2,3,4, Gaelle M. Lefèvre2,3,4, Jean-Pierre Hardelin3,4,5, Hassina Ibrahim6, Zahia Mallek7 and Christine Petit2,3,4,5,8* Abstract Background: More than 70 % of the cases of congenital deafness are of genetic origin, of which approximately 80 % are non-syndromic and show autosomal recessive transmission (DFNB forms). To date, 60 DFNB genes have been identified, most of which cause congenital, severe to profound deafness, whereas a few cause delayed progressive deafness in childhood. We report the study of two Algerian siblings born to consanguineous parents, and affected by progressive hearing loss. Method: After exclusion of GJB2 (the gene most frequently involved in non-syndromic deafness in Mediterranean countries), we performed whole-exome sequencing in one sibling. Results: A frame-shift variant (c.1014delC; p.Ser339Alafs*15) was identified in EPS8L2, encoding Epidermal growth factor receptor Pathway Substrate 8 L2, a protein of hair cells’ stereocilia previously implicated in progressive deafness in the mouse. This variant predicts a truncated, inactive protein, or no protein at all owing to nonsense-mediated mRNA decay. It was detected at the homozygous state in the two clinically affected siblings, and at the heterozygous state in the unaffected parents and one unaffected sibling, whereas it was never found in a control population of 150 Algerians with normal hearing or in the Exome Variant Server database.
    [Show full text]
  • Upregulation of EPS8L3 Is Associated with Tumorigenesis and Poor Prognosis in Patients with Liver Cancer
    MOLECULAR MEDICINE REPORTS 20: 2493-2499, 2019 Upregulation of EPS8L3 is associated with tumorigenesis and poor prognosis in patients with liver cancer PENG LI1*, TING HU2*, HONGSHENG WANG1, YING TANG3, YUE MA1, XIAODONG WANG4, YANSONG XU1 and GUANGYU CHEN1 1Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Beihua University, Jilin 132001; 2Department of Oncology, The First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021; 3Department of Nursing, Affiliated Hospital of Beihua University, Jilin 132001; 4Medical Department, Huailai County Hospital of Traditional Chinese Medicine, Zhangjiakou, Hebei 075400, P.R. China Received August 5, 2018; Accepted May 23, 2019 DOI: 10.3892/mmr.2019.10471 Abstract. Epidermal growth factor receptor kinase substrate 8 reduced the levels of phosphorylated PI3K and AKT in the (EPS8) plays critical roles in a variety of solid tumors. PI3K/AKT signaling pathway. Collectively, the results of the However, the biologic functions and clinical significance of present study, for the first time to the best of our knowledge, EPS8-like 3 (EPS8L3), an EPS8-related protein, in liver cancer demonstrated that EPS8L3 serves as an oncogene in liver remain unclear. To measure EPS8L3 expression in liver cancer cancer development; therefore, EPS8L3 may be a valuable cell lines, reverse transcription-quantitative PCR and western prognostic predictor for patients with liver cancer. blot analyses were performed. The correlation between 338 patients with liver cancer and various clinicopathological Introduction factors obtained from the Oncomine database were evaluated using the χ2 test. Survival of patients with different expres- Liver cancer, including hepatocellular carcinoma and intra- sion of EPS8L3 was determined using Kaplan-Meier survival hepatic cholangiocarcinoma, is one of the most common analysis with a log rank test, and Cox regression analysis was malignancies worldwide (1).
    [Show full text]