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The Role of Integrins in Enterovirus Infections and in Metastasis of Cancer

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The Role of Integrins in Enterovirus Infections and in Metastasis of Cancer TURUN YLIOPISTON JULKAISUJA ANNALES UNIVERSITATIS TURKUENSIS _____________________________________________________________________ SARJA – SER. D OSA– TOM. 908 MEDICA - ODONTOLOGICA THE ROLE OF INTEGRINS IN ENTEROVIRUS INFECTIONS AND IN METASTASIS OF CANCER by Åse Karttunen TURUN YLIOPISTO UNIVERSITY OF TURKU Turku 2010 TURUN YLIOPISTON JULKAISUJA ANNALES UNIVERSITATIS TURKUENSIS _____________________________________________________________________ SARJA – SER. D OSA– TOM. 908 MEDICA - ODONTOLOGICA THE ROLE OF INTEGRINS IN ENTEROVIRUS INFECTIONS AND IN METASTASIS OF CANCER by Åse Karttunen TURUN YLIOPISTO UNIVERSITY OF TURKU Turku 2010 From the Department of Virology, University of Turku, Turku, the Department of Virology, Haartman Institute, the Helsinki Biomedical Graduate School, University of Helsinki, Helsinki, and the Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland. Supervised by Professor Timo Hyypiä Department of Virology University of Turku Turku, Finland Reviewed by Professor Klaus Hedman Haartman Institute Department of Virology University of Helsinki Helsinki, Finland and Docent Arno Hänninen Department of Medical Microbiology and Immunology University of Turku Turku, Finland Opponent Professori Ari Hinkkanen A. I. Virtanen-instituutti Bioteknologia ja molekulaarinen lääketiede Itä-Suomen yliopisto Kuopio, Finland ISBN 978-951-29-4313-5 (PRINT) ISBN 978-951-29-4314-2 (PDF) ISSN 03559483 Helsinki University Printing House Helsinki 2010 To my Family ABSTRACT Åse Karttunen THE ROLE OF INTEGRINS IN ENTEROVIRUS INFECTIONS AND IN METASTASIS OF CANCER The Department of Virology, University of Turku, Turku, the Department of Virology, Haartman Institute, and the Helsinki Biomedical Graduate School, University of Helsinki, Helsinki, and the Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland. Annales Universitatis Turkuensis, Medica-Odontologica, Yliopistopaino, Helsinki, 2010. Integrins are a family of transmembrane glycoproteins, composed of two different subunits (α and β). Altered expression of integrins in tumor cells contributes to metastasis tendency by influencing on the cells‟ attachment to adjacent cells and their migration. Viral pathogens, including certain enteroviruses, use integrins as receptors. Enteroviruses have also been suggested to be involved in the etiopathogenesis of type 1 diabetes. The study focuses on the role of integrins in the pathogenesis of metastasis to cortical bone and on type 1 diabetes (T1D) and echovirus 1 infection. In the first part of the thesis, the role of different integrins in the initial attachment of MDA-MD-231 breast cancer cells to bovine cortical bone disks was studied. A close correlation between α2β1 and α3β1 integrin receptor expression and the capability of the tumor to attach to bone were observed. In the second part, a possible correlation between susceptibility to enterovirus infections in diabetic children and differences in enterovirus receptor genes, including certain integrins, was investigated. In parallel, virus-specific neutralizing antibodies and diabetic risk alleles were studied. In the diabetic group, an amino acid change was detected in the polio virus receptor and the neutralizing antibody titers against echovirus 30 were lower. However, to obtain statistically sustainable results, a larger number of individuals should be analyzed. Echovirus 1 (EV1) enters cells by attaching to the α2I domain of the α2β1 integrin. In the third part EV1 was shown to attach to a chimeric receptor construct of the transferrin receptor and the α2I domain and to enter cells through clathrin-mediated endocytosis that is normally not used by the virus. The chimeric receptor was recycled to the plasma membrane, whereas the virus remained in intracellular vesicles. The virus replication cycle was initiated in these cells, suggesting that evolution pressure could possibly cause the virus to evolve to use a different entry mechanism. Moreover, a cDNA microarray analysis of host gene expression during EV1 replication showed that 0.53% of the total genes, including several immediate early genes, were differently expressed. Keywords: Integrin, breast cancer, metastasis, human enterovirus, echovirus 1, type 1 diabetes, clathrin mediated endocytosis TIIVISTELMÄ Åse Karttunen INTEGRIINIEN MERKITYS ENTEROVIRUSINFEKTIOSSA JA SYÖVÄN ETÄPESÄKKEIDEN MUODOSTUMISESSA Virusoppi, Turun Yliopisto, Haartman-instituutti, Virologian osasto ja Biolääketieteellinen tutkijakoulu, Helsingin Yliopisto, Helsinki, ja Biokemian ja farmasian laitos, Åbo Akademi, Turku. Annales Universitatis Turkuensis, Yliopistopaino, Helsinki, 2010. Integriinit ovat solukalvon läpäiseviä glykoproteiineja, jotka koostuvat kahdesta alayksiköstä (alfa ja beta). Ne ovat vuorovaikutuksessa solukalvon kanssa soluadheesiossa ja migraatiossa. Muuttunut integriinien ilmentyminen syöpäsoluissa vaikuttaa soluadheesioon ja soluliikkuvuuteen ja voi täten vaikuttaa solun taipumukseen muodostaa etäpesäkkeitä. Tiettyjen integriinien tuotto rintasyövässä korreloituu sairauden ennusteeseen ja metastasointiherkkyyteen. Eräät enterovirukset hyödyntävät solun integriinejä päästääkseen solun sisälle. Enterovirusten aiheuttamat taudinkuvat ihmisissä vaihtelevat nuhakuumeista sydänlihastulehduksiin ja keskushermostoinfektioihin. Enterovirusinfektioilla voi olla merkitystä myös tyypin I diabeteksen puhkeamisessa. Tässä väitöskirjatyössä on tutkittu integriinien osuutta syövän etäpesäkkeiden leviämisessä luukudokseen sekä niiden toimintaa enterovirusten, kuten echovirus 1:n reseptoreina ja reseptorien ilmentymistä suhteessa tyypin I diabetekseen. Väitöskirjan ensimmäisessä osatyössä tutkittiin integriinien merkitystä rintasyöpäsolujen varhaisessa kiinnittymisessä kortikaalisille luukiekoille. Vahva yhteys nähtiin α2β1 ja α3β1 integriinien ilmentymisessä ja kyvyssä sitoutua kortikaaliseen luukudokseen. Toisessa osatyössä tutkittiin, voisivatko muutokset enterovirusten reseptorimolekyyleissä korreloida tyypin 1 diabeteksen puhkeamiseen. Sekvenssianalyysi tehtiin kuuden tunnetuimman enterovirusreseptorin (PVR, ICAM-1, DAF, CAR, v3 ja 21 integriini) geenialueilta, ja virusspesifiset vasta-aineet määritettiin seerumista. Diabetesryhmästä geenivaihtelua löytyi PVR:sta ja vasta-aineet echovirus 30:tä vastaan olivat matalammat kuin kontrolliryhmässä. Tulokset pitää kuitenkin vielä varmistaa suuremmassa ryhmässä tilastollisen luotettavuuden selvittämiseksi. Echovirus I (EV1) sitoutuu 21 integriinin 2 alayksikön I-domeeniin (2I), ja kolmannessa osatyössä osoitettiin että virus pystyi infektoimaan solut, jotka ilmensivät pinnallaan reseptorikimeeraa, missä 2I-jakso oli liitetty transferriinireseptoriin. Virus kuljetettiin soluun klatriinivälitteisesti, mikä eroaa EV1:n normaalisti käyttämistä soluuntukeutumisreiteistä. Lisäksi cDNA-mikrosiruanalyysi isäntäsolun geeniekspressiosta EV1-replikaation aikana osoitti, että 0.53% geeniekspressiosta oli muuttunut, sisältäen monia solun toiminnalle keskeisiä geenejä. CONTENTS ABSTRACT TIIVISTELMÄ CONTENTS………………………………………………………………………..... 7 ABBREVIATIONS………………………………………………………………....... 9 LIST OF ORGINAL PUBLICATIONS…………………………………………..... 12 1 INTRODUCTION………………………………………………………………...... 13 2 REWIEW OF THE LITERATURE……………………………………………… 14 2.1 INTEGRINS……………………………………………………………………. 14 2.2 THE ROLE OF INTEGRINS IN BREAST CANCER METASTASIS TO THE SKELETON…………………………………………………………….......... 17 2.3 PICORNAVIRUSES……………………………………………………............ 20 2.3.1 Structure of picornaviruses.………………….………………................. 23 2.3.2 Picornavirus infection cycle……………………………………….......... 23 2.4 CELLULAR RECEPTORS FOR PICORNAVIRUSES….…………………… 25 2.5 INTERNALIZATION OF PICORNAVIRUSES INTO HOST CELLS………. 30 2.5.1 Clathrin-dependent endocytosis………………………………………… 31 2.5.2 Lipid raft/caveolae-mediated endocytosis.……………………………… 33 2.5.3 Macropinocytosis……………………………………………………….. 37 2.6 HOST GENE EXPRESSION INDUCED BY ENTEROVIRUS INFECTION………………………………………………………………………... 38 2.7 TYPE 1 DIABETES …………………………………………………………... 40 3 AIMS OF THE STUDY…………………………………………………………..... 45 4 MATERIALS AND METHODS………………………………………………….. 46 4.1 Viruses (II, III)……………………………..…………………………………... 46 4.2 Antibodies and other reagents (I, III)…………………………………………... 46 4.3 Cell cultures (I-III) and transfections (III)……………………………………... 47 4.4 RNA and DNA purification (II)……………………………………………….. 47 4.5 Design of primers, construction of the chimeric receptor and sequencing (II, III)………………………………………………………………………………….. 48 4.6 RT-PCR (III)…………………………………………………………………… 49 4.7 HLA Typing (II)……………………………………………………………….. 49 4.8 Cell adhesion assay measuring attachment to cortical bone (I)………………. 49 4.9 FACS analysis (I, III)…………………………………………………………... 50 4.10 Immunofluorescence and confocal microscopy (III)………………………… 50 4.11 Infectivity assays with drugs (III)……………………………………………. 51 4.12 Determination of neutralizing antibody levels (II)..…………………………. 51 4.13 Infectivity titration (III)………………………………………………………. 52 4.14 Human cDNA U133A arrays and clustering…………………………………. 52 5 RESULTS AND DISCUSSION…………………………………………………… 53 5.1 THE ROLE OF INTEGRINS IN BREAST CANCER METASTASIS TO THE SKELETON (I)……………......................................................................................... 53 5.1.1 High surface expression of α2β1 and α3β1 integrins on human breast cancer MDA-MB-231 facilitates attachment to cortical bone matrix…………... 53 5.1.2 Correlation between surface expression of α2β1 and α3β1 integrins on tumor cells and their tendency to anchor to cortical
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