DOCSLIB.ORG

Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: a View on Paradoxical Roles of KDM6B and EZH2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: a View on Paradoxical Roles of KDM6B and EZH2 epigenomes Review Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: A View on Paradoxical Roles of KDM6B and EZH2 Camille Lachat 1, Michaël Boyer-Guittaut 1,2, Paul Peixoto 1,3,† and Eric Hervouet 1,2,3,†,* 1 Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, INSERM, EFS BFC, UMR1098, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France; [email protected] (C.L.); [email protected] (M.B.-G.); [email protected] (P.P.) 2 DImaCell Platform, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France 3 EPIGENEXP Platform, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France * Correspondence: [email protected]; Tel.: +33-81666542 † These authors contributed equally to this work. Received: 3 December 2018; Accepted: 17 December 2018; Published: 20 December 2018 Abstract: EMT (epithelial to mesenchymal transition) is a plastic phenomenon involved in metastasis formation. Its plasticity is conferred in a great part by its epigenetic regulation. It has been reported that the trimethylation of lysine 27 histone H3 (H3K27me3) was a master regulator of EMT through two antagonist enzymes that regulate this mark, the methyltransferase EZH2 (enhancer of zeste homolog 2) and the lysine demethylase KDM6B (lysine femethylase 6B). Here we report that EZH2 and KDM6B are overexpressed in numerous cancers and involved in the aggressive phenotype and EMT in various cell lines by regulating a specific subset of genes. The first paradoxical role of these enzymes is that they are antagonistic, but both involved in cancer aggressiveness and EMT. The second paradoxical role of EZH2 and KDM6B during EMT and cancer aggressiveness is that they are also inactivated or under-expressed in some cancer types and linked to epithelial phenotypes in other cancer cell lines. We also report that new cancer therapeutic strategies are targeting KDM6B and EZH2, but the specificity of these treatments may be increased by learning more about the mechanisms of action of these enzymes and their specific partners or target genes in different cancer types. Keywords: cancer; EMT; metastasis; epigenetics; KDM6B; EZH2; H3K27 1. Introduction 1.1. Epithelial to Mesenchymal Transition (EMT) Epithelial to mesenchymal transition (EMT) is a phenomenon that leads epithelial cells to gradually acquire a mesenchymal phenotype. This process is associated with a loss of expression of specific epithelial proteins called “epithelial markers,” such as E-CADHERIN (coded by CDH1 gene), CLAUDIN, or OCCLUDIN, and a gain of expression of other proteins called “mesenchymal markers,” such as VIMENTIN or N-CADHERIN. At least three distinct types of EMT have been reported so far, even if they present highly similar mechanisms: (i) type I is implicated in embryo formation and organ development; (ii) type II is involved in wound healing, regeneration of tissues, and in organ fibrosis; and (iii) type III is implicated in cancer development and aggressiveness. The latter also plays a role in tumor escape, impairing the formation of the immune synapse or leading to the overexpression of the immune checkpoint inhibitor PD-L1 (programmed death ligand 1) [1–3], and in metastasis formation [4,5]. Indeed, in type III EMT, tumor cells have been shown to present a loss of expression of adhesion proteins [6], to secrete various metalloproteases, such as MMP9 or ADAM19 [7], leading to Epigenomes 2019, 3, 1; doi:10.3390/epigenomes3010001 www.mdpi.com/journal/epigenomes Epigenomes 2018, 4, x 2 of 22 the overexpression of the immune checkpoint inhibitor PD-L1 (programmed death ligand 1) [1–3], and in metastasis formation [4,5]. Indeed, in type III EMT, tumor cells have been shown to present a loss of expression of adhesion proteins [6], to secrete various metalloproteases, such as MMP9 or ADAM19 [7], leading to the digestion of the extracellular matrix and then to the escape of the primary Epigenomestumor2019 and, 3 ,the 1 migration through the blood or lymphatic circulation [4,5]. 2 of 21 All the changes occurring during EMT at the morphological, functional, or molecular levels can be reversed to return to the original epithelial phenotype. This phenomenon is called mesenchymal the digestionto epithelial of thetransition extracellular (MET) [8,9]. matrix Through and then this to process, the escape circulating of the primarycancer cells tumor can invade and the another migration throughorgan, the leading blood orto lymphaticthe formation circulation and growth [4,5]. of a secondary tumor called metastasis (Figure 1). However,All the changes the definition occurring of EMT during remains EMT complex at the morphological,since there is not functional,only one EMT or but molecular a multitude levels of can be reversedintermediate to return states to presenting the original different epithelial expressions phenotype. of epithelial This phenomenon and mesenchymal is called markers. mesenchymal This to epithelialplasticity transition has been described (MET) [8 to,9 ].be Through mainly linked this process, to the epigenetic circulating regulation cancer of cells EMT, can which invade is itself another organ,a highly leading plastic to the and formation reversible and process, growth as ofdescribed a secondary below. tumor called metastasis (Figure1). However, Type III EMT can be induced by various intra- or extra-cellular factors or stress. It has been the definition of EMT remains complex since there is not only one EMT but a multitude of intermediate described that EMT-activating transcription factors (EMT-ATFs), such as SNAIL, TWIST, and ZEB states presenting different expressions of epithelial and mesenchymal markers. This plasticity has been (zinc finger E-box-binding homeobox) families, are main regulators of EMT [10]. These EMT-ATFs are describedactivated to bevia mainly hypoxia, linked cytokines to the (TGF epigeneticβ, TNFα), regulationgrowth factors of EMT,(EGF), whichor by cellular is itself signaling a highly pathways plastic and reversible(WNT, process, HEDGEHOG, as described NF-κB, below.and NOTCH), and their activation leads to EMT induction [11]. FigureFigure 1. Roles 1. Roles of EMT of EMT in thein the formation formation of of metastases. metastases. Epithelial Epithelial cells, cells, expressing expressing epithelial epithelial markers, markers, can undergocan undergo EMT andEMT progressively and progressively acquire acquire a mesenchymal a mesenchymal phenotype phenotype characterized characterized by the by expression the of mesenchymalexpression of markers. mesenchymal EMT markers. is reversible EMTand is revers the oppositeible and the transition opposite is transition called MET is called (mesenchymal MET to epithelial(mesenchymal transition). to epithelial EMT and transi METtion). are EMT involved and MET in theare emergenceinvolved in ofthe metastases emergence byof metastases allowing cells to migrateby allowing to the cells blood to ormigrate lymphatic to the circulation blood or lymp andhatic then circulation invade another and then organ invade to generate another organ a secondary to generate a secondary tumor called metastasis. tumor called metastasis. 1.2. Epigenetic Regulation of EMT Type III EMT can be induced by various intra- or extra-cellular factors or stress. It has been describedThe that word EMT-activating “epigenetics” transcriptionwas used for the factors first time (EMT-ATFs), in 1942 by such Conrad as SNAIL,Hal Waddington, TWIST, andwho ZEB (zincused finger the E-box-binding term of “epigenotype” homeobox) to describe families, the are different main regulators phenomena of which EMT [are10]. involved These EMT-ATFs in the are activatedimplementation via hypoxia, of a phenotype cytokines from (TGF aβ genotype,, TNFα), growthand “epigenetics” factors (EGF), for studies or by cellularrelated to signaling the pathwaysunderstanding (WNT, HEDGEHOG, of this phenomenon NF-κB, [12]. and This NOTCH), definition and has their been activation widely modified leads to since EMT the induction 1940s to [11]. lead to the one currently used now: “Epigenetics is the study of the regulation of gene expression, 1.2. Epigeneticwithout DNA Regulation nucleotide of EMT sequence alteration, and linked to hereditary transmission.” This field includes the study of non-coding RNA (miRNA, lncRNA, etc.), which can bind DNA or mRNA and influenceThe word gene “epigenetics” transcription, was DNA used methylation for the first (methylation time in 1942of cytosines by Conrad in CpG Hal regions Waddington, leading to who usedthe the repression term of “epigenotype”of transcription) toand describe histone post-translational the different phenomena modifications which (Table are 1). involved Plasticity inof the implementationepigenetic regulation of a phenotype is conferred from by athe genotype, reversible andcharacter “epigenetics” of the corresponding for studies biochemical related to the understandingreactions. Indeed, of this DNA phenomenon methylatio [n,12 histone]. This definitionpost-translational has been mo widelydifications, modified and non-coding since the RNA 1940s to leadexpression to the one can currently be reversed used according now: “Epigenetics to the cell pathophysiological is the study of the context. regulation Moreover, of gene epigenetic expression, without DNA nucleotide sequence alteration, and linked to hereditary transmission.” This field includes the study of non-coding RNA (miRNA, lncRNA, etc.), which can bind DNA or mRNA and influence gene transcription, DNA methylation
Load more

Recommended publications
  • (Kiss-1): Essential Players in Suppressing Tumor Metastasis
    DOI:http://dx.doi.org/10.7314/APJCP.2013.14.11.6215 Kisspeptins (KiSS-1) as Supressors of Cancer Metastasis MINI-REVIEW Kisspeptins (KiSS-1): Essential Players in Suppressing Tumor Metastasis Venugopal Vinod Prabhu, Kunnathur Murugesan Sakthivel, Chandrasekharan Guruvayoorappan* Abstract Kisspeptins (KPs) encoded by the KiSS-1 gene are C-terminally amidated peptide products, including KP- 10, KP-13, KP-14 and KP-54, which are endogenous agonists for the G-protein coupled receptor-54 (GPR54). Functional analyses have demonstrated fundamental roles of KiSS-1 in whole body homeostasis including sexual differentiation of brain, action on sex steroids and metabolic regulation of fertility essential for human puberty and maintenance of adult reproduction. In addition, intensive recent investigations have provided substantial evidence suggesting roles of Kisspeptin signalling via its receptor GPR54 in the suppression of metastasis with a variety of cancers. The present review highlights the latest studies regarding the role of Kisspeptins and the KiSS-1 gene in tumor progression and also suggests targeting the KiSS-1/GPR54 system may represent a novel therapeutic approach for cancers. Further investigations are essential to elucidate the complex pathways regulated by the Kisspeptins and how these pathways might be involved in the suppression of metastasis across a range of cancers. Keywords: Kisspeptins - GPR54 receptor - KiSS-1 gene - metastasis - cancer Asian Pac J Cancer Prev, 14 (11), 6215-6220 Introduction deaths (Stafford et al., 2008). There are around 20 different metastasis suppressor genes which brings a valuable Cancer is a class of disease characterized by out-of- mechanistic insight for guiding specific therapeutic control cell growth.
    [Show full text]
  • Malignant Pleural Mesothelioma: State- Of-The-Art on Current Therapies and Promises for the Future
    Prime Archives in Cancer Research Book Chapter Malignant Pleural Mesothelioma: State- of-the-Art on Current Therapies and Promises for the Future Fabio Nicolini1, Martine Bocchini1, Giuseppe Bronte2, Angelo Delmonte2, Massimo Guidoboni3, Lucio Crinò2 and Massimiliano Mazza1* 1Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Italy 2Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Italy 3Immunotherapy and Cell Therapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Italy *Corresponding Author: Massimiliano Mazza, Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Published January 11, 2021 This Book Chapter is a republication of an article published by Massimiliano Mazza, et al. at Frontiers in Oncology in January 2020. (Nicolini F, Bocchini M, Bronte G, Delmonte A, Guidoboni M, Crinò L and Mazza M (2020) Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future. Front. Oncol. 9:1519. doi: 10.3389/fonc.2019.01519) How to cite this book chapter: Fabio Nicolini, Martine Bocchini, Giuseppe Bronte, Angelo Delmonte, Massimo Guidoboni, Lucio Crinò, Massimiliano Mazza. Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future. In: Heidari A, editor. Prime Archives in Cancer Research. Hyderabad, India: Vide Leaf. 2021. 1 www.videleaf.com Prime Archives in Cancer Research © The Author(s) 2021. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    [Show full text]
  • Regulators at Every Step—How Micrornas Drive Tumor Cell Invasiveness and Metastasis
    cancers Review Regulators at Every Step—How microRNAs Drive Tumor Cell Invasiveness and Metastasis 1,2,3, 1,2, 1, Tomasz M. Grzywa y , Klaudia Klicka y and Paweł K. Włodarski * 1 Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; [email protected] (T.M.G.); [email protected] (K.K.) 2 Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland 3 Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland * Correspondence: [email protected] These authors contributed equally to this work. y Received: 19 November 2020; Accepted: 7 December 2020; Published: 10 December 2020 Simple Summary: Tumor cell invasiveness and metastasis are key processes in cancer progression and are composed of many steps. All of them are regulated by multiple microRNAs that either promote or suppress tumor progression. Multiple studies demonstrated that microRNAs target the mRNAs of multiple genes involved in the regulation of cell motility, local invasion, and metastatic niche formation. Thus, microRNAs are promising biomarkers and therapeutic targets in oncology. Abstract: Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial–mesenchymal transition (EMT), hence modulating cell migration and invasiveness.
    [Show full text]
  • Targeting EZH2 for the Treatment of Soft Tissue Sarcomas
    Karolak et al. J Cancer Metastasis Treat 2021;7:15 Journal of Cancer DOI: 10.20517/2394-4722.2021.05 Metastasis and Treatment Review Open Access Targeting EZH2 for the treatment of soft tissue sarcomas Magdalena Karolak1, Ian Tracy1, Janet Shipley2, Zoë S Walters1 1Translational Epigenomics Team, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK. 2Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK. Correspondence to: Zoë S Walters, Translational Epigenomics Team, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK. E-mail: [email protected] How to cite this article: Karolak M, Tracy I, Shipley J, Walters ZS. Targeting EZH2 for the treatment of soft tissue sarcomas. J Cancer Metastasis Treat 2021;7:15. https://dx.doi.org/10.20517/2394-4722.2021.05 Received: 7 Jan 2021 First Decision: 2 Feb 2021 Revised: 8 Feb 2021 Accepted: 25 Feb 2021 Available online: 26 Mar 2021 Academic Editor: Ian Judson Copy Editor: Yue-Yue Zhang Production Editor: Yue-Yue Zhang Abstract Soft tissue sarcomas (STS) are a heterogenous group of rare malignancies of mesenchymal origin, affecting both children and adults. The majority of STS have a poor prognosis and advanced stage at the time of diagnosis. Standard treatments for STS largely constitute tumour resection with chemotherapy and/or radiotherapy, and there has been little significant advancement in the application of novel therapies for treatment of these tumours. The current multimodal approach to therapy often leads to long-term side effects, and for some patients, resistance to cytotoxic agents is associated with local recurrence and/or metastasis.
    [Show full text]
  • Epithelioid Sarcoma—From Genetics to Clinical Practice
    cancers Review Epithelioid Sarcoma—From Genetics to Clinical Practice Anna M. Czarnecka 1,2,* , Pawel Sobczuk 1,3,* , Michal Kostrzanowski 1,4 , Mateusz Spalek 1 , Marzanna Chojnacka 5, Anna Szumera-Cieckiewicz 6,7 and Piotr Rutkowski 1 1 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] (M.K.); [email protected] (M.S.); [email protected] (P.R.) 2 Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland 3 Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland 4 Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland 5 Department of Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] 6 Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] 7 Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland * Correspondence: [email protected] (A.M.C.); [email protected] (P.S.) Received: 29 June 2020; Accepted: 24 July 2020; Published: 29 July 2020 Abstract: Epithelioid sarcoma is a mesenchymal soft tissue sarcoma often arising in the extremities, usually in young adults with a pick of incidence at 35 years of age. Epithelioid sarcoma (ES) is characterized by the loss of SMARCB1/INI1 (integrase interactor 1) or other proteins of the SWI/SNF complex.
    [Show full text]
  • Use of the Tree-Based Scan Statistic for Surveillance of Infant Outcomes Following Maternal Perinatal Medication Use Appendices: Code Lists
    Use of the Tree-Based Scan Statistic for Surveillance of Infant Outcomes Following Maternal Perinatal Medication Use Appendices: Code Lists Elizabeth A Suarez1, Michael Nguyen2, Di Zhang3, Yueqin Zhao3, Danijela Stojanovic2, Monica Munoz4, Jane Liedtka5, Abby Anderson6, Wei Liu7, Steven Bird7, Inna Dashevsky1, David Cole1, Sandra DeLuccia1, Talia Menzin1, Jennifer Noble1, Judith C Maro1 1. Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA; 2. Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD; 3. Office of Biostatistics, Center for Drug Evaluation and Research, FDA, Silver Spring, MD; 4. Division of Pharmacovigilance, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD; 5. Division of Pediatric and Maternal Health, Center for Drug and Evaluation Research, US Food and Drug Administration, Silver Spring, MD; 6. Division of Bone, Reproductive, and Urologic Products, Center for Drug and Evaluation Research, US Food and Drug Administration, Silver Spring, MD; 7. Division of Epidemiology, Center for Drug and Evaluation Research, US Food and Drug Administration, Silver Spring, MD February 9, 2021 The Sentinel System is sponsored by the U.S. Food and Drug Administration (FDA) to proactively monitor the safety of FDA-regulated medical products and complements other existing FDA safety surveillance capabilities. The Sentinel System is one piece of FDA’s Sentinel Initiative, a long-term, multi-faceted effort to develop a national electronic system. Sentinel Collaborators include Data and Academic Partners that provide access to healthcare data and ongoing scientific, technical, methodological, and organizational expertise.
    [Show full text]
  • Diet, Nutrients, Phytochemicals, and Cancer Metastasis Suppressor Genes
    Cancer Metastasis Rev DOI 10.1007/s10555-012-9369-5 Diet, nutrients, phytochemicals, and cancer metastasis suppressor genes Gary G. Meadows # Springer Science+Business Media, LLC (outside the USA) 2012 Abstract The major factor in the morbidity and mortality of EGF Epidermal growth factor cancer patients is metastasis. There exists a relative lack of EGFR Epidermal growth factor receptor specific therapeutic approaches to control metastasis, and EPA Eicosapentaenoic acid this is a fruitful area for investigation. A healthy diet and IFN Interferon lifestyle not only can inhibit tumorigenesis but also can have KAI1 Kangai 1 a major impact on cancer progression and survival. Many MALL Mal-like chemicals found in edible plants are known to inhibit meta- MAPK Mitogen activated protein kinase static progression of cancer. While the mechanisms under- MKK Mitogen-activated protein kinase kinase lying antimetastatic activity of some phytochemicals are miR Micro RNA being delineated, the impact of diet, dietary components, NDRG N-myc downstream-regulated gene and various phytochemicals on metastasis suppressor genes NM23 Nonmetastatic gene 23 is underexplored. Epigenetic regulation of metastasis sup- PDCD Programmed cell death pressor genes promises to be a potentially important mech- PEBP Phosphatidylethanolamine binding protein anism by which dietary components can impact cancer PTEN Phosphatase and tensin homolog metastasis since many dietary constituents are known to RASSF Ras-associated domain family modulate gene expression. The review addresses this area RECK Reversion-inducing-cysteine-rich protein with of research as well as the current state of knowledge regard- kazal motifs ing the impact of diet, dietary components, and phytochem- RhoGDI2 Rho GDP-dissociation inhibitor 2 icals on metastasis suppressor genes.
    [Show full text]
  • Tazemetostat (Tazverik™) EOCCO POLICY
    tazemetostat (Tazverik™) EOCCO POLICY Policy Type: PA/SP Pharmacy Coverage Policy: EOCCO184 Description Tazemetostat (Tazverik) is an orally administered inhibitor of methyltransferase, EZH2. Length of Authorization N/A Quantity Limits Product Name Dosage Form Indication Quantity Limit Epithelioid sarcoma, advanced or metastatic, not eligible for resection; Follicular lymphoma, relapsed or refractory, tazemetostat EZH2 mutation-positive, in 200 mg tablets 240 tablets/30 days (Tazverik) that that have received at least two therapies; Follicular lymphoma, relapsed or refractory, in those with no satisfactory alternative therapy Initial Evaluation I. Tazemetostat (Tazverik) is considered investigational when used for all conditions, including but not limited to: A. Epithelioid sarcoma B. Non-Hodgkin lymphoma, including follicular lymphoma Renewal Evaluation I. N/A 1 tazemetostat (Tazverik™) EOCCO POLICY Supporting Evidence I. Background: Epithelioid sarcoma is a very rare cancer of the soft tissue, generally seen in younger populations (average age of 27). This aggressive condition is known for recurrence, spread to locoregional lymph nodes, and eventually distant metastases. Common sites of origin include fingers, hands, forearms, feet, and other limbs. First-line management is typically surgery, with local recurrence necessitating amputation in many cases. Although, not specifically FDA-approved for epithelioid sarcoma, there are several systemic therapies used in the metastatic setting. Often, anthracycline based regimens (e.g., doxorubicin with or without ifosfamide), gemcitabine, pazopanib (Votrient), doxetaxel, sunitinib (Sutent), dacarbazine, epirubicin, and temozolomide. II. Efficacy: Tazemetostat (Tazverik) was approved on data from a Phase 2 trial. Pooled data from two cohorts, five and six (n=62, n=44), were used to support the approval. Seventy-seven percent of patients had prior surgery and 61% had prior chemotherapy.
    [Show full text]
  • MRTFB Suppresses Colorectal Cancer Development Through Regulating SPDL1 and MCAM
    MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM Takahiro Kodamaa,b,c, Teresa A. Mariana,b, Hubert Leea, Michiko Kodamaa, Jian Lid, Michael S. Parmacekd, Nancy A. Jenkinsa,e, Neal G. Copelanda,e,1, and Zhubo Weia,b,1 aHouston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030; bHouston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX 77030; cDepartment of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, 5650871 Suita, Osaka, Japan; dDepartment of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104; and eGenetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 Contributed by Neal G. Copeland, October 7, 2019 (sent for review June 18, 2019; reviewed by Masaki Mori and Hiroshi Seno) Myocardin-related transcription factor B (MRTFB) is a candidate tumor- shown to regulate cell cycle progression (9) and HCC xenograft suppressor gene identified in transposon mutagenesis screens of the tumor growth (10). Functional validation using cell culture sys- intestine, liver, and pancreas. Using a combination of cell-based assays, tems have also shown that reduced expression of MRTFB by in vivo tumor xenograft assays, and Mrtfb knockout mice, we demon- RNA interference leads to increased CRC cell invasion (4), strate here that MRTFB is a human and mouse colorectal cancer suggesting its important role in tumor progression. (CRC) tumor suppressor that functions in part by inhibiting cell Based on these results, we decided to conditionally delete invasion and migration. To identify possible MRTFB transcriptional Mrtfb in the mouse intestine to further explore its role in CRC.
    [Show full text]
  • Exploring Mechanisms of Metastasis Suppression in Metastatic Melanoma by Kelsey R
    Exploring mechanisms of metastasis suppression in metastatic melanoma By Kelsey R. Hampton B.Sc., University of Northern Iowa, 2012 Submitted to the graduate degree program in Molecular and Integrative Physiology and the Graduate Faculty of the University of Kansas Medical Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Co-Chair: Danny Welch, Ph.D. Co-Chair: Michael Wolfe, Ph. D. Chad Slawson, Ph.D. Nikki Cheng, Ph.D. Shrikant Anant, Ph.D. Adam Krieg, Ph.D. Date Defended: 12 April 2017 The dissertation committee for Kelsey Hampton certifies that this is the approved version of the following dissertation: Exploring mechanisms of metastasis suppression in metastatic melanoma Co-Chair: Danny Welch Co-Chair: Michael Wolfe Date Approved: 05/11/2017 ii Abstract Melanoma is responsible for 76% of deaths from skin cancer, making it the deadliest form of commonly diagnosed skin cancer. The deadly nature of melanoma is due to its tendency towards rapid metastasis early in tumor progression. Metastasis is the process of cells exiting the primary tumor and forming secondary tumors in other parts of the body. Metastasis accounts for as much as 90% of morbidity and mortality associated with cancer. Therapeutically targeting and treating melanoma metastases is a challenging clinical goal, as metastatic cells are heterogeneous and can be morphologically and genetically distinct from the primary tumor. This dissertation examines two distinct approaches towards preventing or treating disseminated melanoma metastases: 1) Re-introduction of metastasis suppressor protein fragments to prevent metastatic colonization, and 2) Treating disseminated metastases with a targeted small molecule treatment.
    [Show full text]
  • Soft Tissue Sarcoma: an Insight on Biomarkers at Molecular, Metabolic and Cellular Level
    cancers Review Soft Tissue Sarcoma: An Insight on Biomarkers at Molecular, Metabolic and Cellular Level Serena Pillozzi 1,* , Andrea Bernini 2, Ilaria Palchetti 3 , Olivia Crociani 4, Lorenzo Antonuzzo 1,4, Domenico Campanacci 5 and Guido Scoccianti 6 1 Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; lorenzo.antonuzzo@unifi.it 2 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; [email protected] 3 Department of Chemistry Ugo Schiff, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy; ilaria.palchetti@unifi.it 4 Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; olivia.crociani@unifi.it 5 Department of Health Science, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; domenicoandrea.campanacci@unifi.it 6 Department of Orthopaedic Oncology and Reconstructive Surgery, University of Florence, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; [email protected] * Correspondence: serena.pillozzi@unifi.it Simple Summary: Soft tissue sarcoma is a rare mesenchymal malignancy. Despite the advancements in the fields of radiology, pathology and surgery, these tumors often recur locally and/or with metastatic disease. STS is considered to be a diagnostic challenge due to the large variety of histologi- Citation: Pillozzi, S.; Bernini, A.; cal subtypes with clinical and histopathological characteristics which are not always distinct. One of Palchetti, I.; Crociani, O.; Antonuzzo, the important clinical problems is a lack of useful biomarkers. Therefore, the discovery of biomarkers L.; Campanacci, D.; Scoccianti, G. Soft that can be used to detect tumors or predict tumor response to chemotherapy or radiotherapy could Tissue Sarcoma: An Insight on help clinicians provide more effective clinical management.
    [Show full text]
  • Association of Polymorphisms in Metastasis Suppressor Genes
    Antar et al. Journal of the Egyptian National Cancer Institute (2020) 32:24 Journal of the Egyptian https://doi.org/10.1186/s43046-020-00037-1 National Cancer Institute RESEARCH Open Access Association of polymorphisms in metastasis suppressor genes NME1 and KISS1 with breast cancer development and metastasis Sarah Antar1* , Naglaa Mokhtar1, Mahmoud Adel Abd elghaffar2 and Amal K. Seleem1 Abstract Background: NME1 and KISS1 genes are two tumor metastasis suppressor genes, mapped to chromosomes 17q21.3 and 1q32 respectively. Here, we analyzed the association of EcoR1 (rs34214448—G/T) polymorphism in NME1 gene and 9 del T (rs5780218—A/-) polymorphism in KISS1 gene with breast cancer development and metastasis. Results: The study included 75 women newly diagnosed with breast cancer recruited from Oncology Center at Mansoura University Hospitals and 37 age-matched healthy female volunteers as a control group. DNA was extracted from peripheral blood samples and genotyping of rs34214448 and rs5780218 SNPs was carried out by PCR-RFLP technique. NME1 EcoR1 (rs34214448) polymorphism has a statistically significant association with breast cancer risk (P < 0.001). Most of breast cancer group (55%) had heterozygous (G/T) genotype while most of control group (95%) had homozygous wild (G/G) genotype (P < 0.0005). Also, KISS1 rs5780218 polymorphism has a statistically significant association with breast cancer risk. The wild (A/A) genotype was associated with lower risk of breast cancer (A/- + -/- vs. A/A: OR = 3.1, 95% CI = 1.15–8.36, P = 0.025). EcoR1 (rs34214448) polymorphism revealed a significant association with tumor stage and distant metastasis as patients.
    [Show full text]