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Formin Proteins in Normal Tissues and Cancer

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Formin Proteins in Normal Tissues and Cancer FORMIN PROTEINS IN NORMAL TISSUES AND CANCER Maria Gardberg TURUN YLIOPISTON JULKAISUJA – ANNALES UNIVERSITATIS TURKUENSIS Sarja - ser. D osa - tom. 1163 | Medica - Odontologica | Turku 2015 University of Turku Faculty of Medicine Institute of Biomedicine Department of Pathology National Graduate School of Clinical Investigation (CLIGS) Doctoral Programme of Clinical Investigation (CLIDP) University of Turku and Turku University Hospital Supervised by Professor Olli Carpén Department of Pathology Turku University Hospital and University of Turku, Turku, Finland Reviewed by Docent Maria Vartiainen Professor Veli-Pekka Lehto Institute of Biotechnology Department of Pathology University of Helsinki, Helsinki, Finland University of Helsinki, Helsinki, Finland Opponent Professor Robert Grosse Institute of Pharmacology University of Marburg, Marburg, Germany The originality of this thesis has been checked in accordance with the University of Turku quality assurance system using the Turnitin OriginalityCheck service. ISBN 978-951-29-6044-6 (PRINT) ISBN 978-951-29-6045-3 (PDF) ISSN 0355-9483 Painosalama Oy – Turku, Finland 2015 To my family 4 Abstract ABSTRACT Maria Gardberg Formin proteins in normal tissues and cancer Department of Pathology, University of Turku, Turku, Finland (2015) The actin cytoskeleton is a dynamic structure that determines cell shape. Actin turnover is mandatory for migration in normal and malignant cells. In epithelial cancers invasion is frequently accompanied by epithelial to mesenchymal transition (EMT). In EMT, cancer cells acquire a migratory phenotype through transcriptional reprogramming. EMT requires substantial re-organization of actin. During the past decade, new actin regulating proteins have been discovered. Among these are members of the formin family. To study formin expression in tissues and cells, antibodies for detection of formin proteins FMNL1 (Formin-like protein 1), FMNL2 (Formin-like protein 2) and FHOD1 (Formin homology 2 domain containing protein 1) were used. The expression of formins was characterized in normal tissues and selected cancers using immunohistochemistry. The functional roles of formins were studied in cancer cell lines. We found that FMNL2 is widely expressed. It is a filopodial component in cultured melanoma cells. In clinical melanoma, FMNL2 expression has prognostic significance. FHOD1 is a formin expressed in mesenchymal cell types. FHOD1 expression is increased in oral squamous cell carcinoma (SCC) EMT. Importantly, FHOD1 participates in invasion of cultured oral SCC cells. FMNL1 expression is low in normal epithelia, but high in leukocytes and smooth muscle cells. Expression of FMNL1 can be found in carcinoma; we detected FMNL1 expressing cells in basal type of breast cancer. Our results indicate that formins are differentially expressed in normal tissues and that their expression may shift in cancer. Functionally FMNL2 and FHOD1 participate in processes related to cancer progression. Studying formins is increasingly important since they are potential drug targets. Key words: formin, actin cytoskeleton, immunohistochemistry, EMT, melanoma, breast cancer, squamous cell carcinoma Tiivistelmä 5 TIIVISTELMÄ Maria Gardberg Formiinit terveissä kudoksissa ja syövässä Patologian oppiaine, Biolääketieteen laitos, Turun Yliopisto, Turku (2015) Solujen aktiinitukiranka on dynaaminen rakenne, joka määrää solujen muodon. Solujen liikkuminen ja syöpäsolujen invaasio edellyttää huomattavaa aktiinitukirangan muokkaus- ta. Epiteeliperäisten syöpäsolujen invaasiokykyyn liittyy monesti epiteeli-mesenkymaalinen transitio (EMT). EMT on käsitteenä tunnettu yksilön kehitysbiologiasta, jossa se on välttä- mätön kehon osien ja kudosten muovautumisessa. Kehityksellistä prosessia muistuttavalla tavalla syöpäsolujen EMT:ssa transkriptio muuttuu, minkä seurauksena syöpäsolut irtoavat ympäristöstään, muuttuvat pitkänomaisiksi ja tehokkaasti liikkuviksi. Muutokset edellyttä- vät tehokasta aktiinisäikeiden muokkausta. Yksi aktiinitukirankaa muokkaavien proteiinien perheitä ovat formiinit. Ne ovat viimeisen vuosikymmenen aikana olleet aktiivisen tutkimuksen kohteena. Formiinien keskeinen toi- minto on aktiinisäikeiden muodostaminen. Tutkiaksemme formiinien ilmentymistä kudoksissa, varmistimme kolmen formiinin vasta-ai- neen luotettavan toimivuuden. Vasta-aineet oli valmistettu formiinien FMNL1 (Formin-like protein 1), FMNL2 (Formin-like protein 2) ja FHOD1 (Formin homology 2 domain containing protein 1) immunohistokemialliseen tunnistamiseen. Näiden vasta-aineiden avulla kartoi- timme formiinien ilmentymisprofiilit normaaleissa kudoksissa, ja jatkoimme tutkimalla nii- den ilmentymistä syöpäkudoksissa ja funktiota viljellyissä syöpäsoluissa. Osoitimme että FMNL2 ilmentyminen on laajaa normaalikudoksissa. FMNL2 paikantuu solu- kalvon ulokkeisiin viljellyissä melanoomasoluissa, ja sillä on ennusteellinen merkitys kliinisessä melanoomassa. FHOD1 puolestaan ilmentyy mesenkymaalisissa kudoskomponenteissa. FHOD1 ilmentyminen nousee suun levyepiteelikarsinooman EMT:ssa. Saatoimme solukokein osoittaa, että FHOD1 osallistuu EMT:hen liitettyihin toimintoihin. Lopuksi tutkimme FMNL1 ilmentymis- tä, ja totesimme sen lähes rajoittuvan valkosoluihin ja sileälihassoluihin. Terveissä epiteeleissä FMNL1 ilmentyminen on vähäinen, mutta saattaa lisääntyä basaalisessa rintasyövässä. Tuloksemme osoittavat että formiinit ilmentyvät toisistaan poikkeavalla profiililla normaa- leissa kudoksissa. Lisäksi niiden ilmentyminen voi muuttua syövässä. Viljellyissä syöpäso- luissa formiinit osallistuvat syövän progressioon eli invaasiokykyä ja metastasointia edistä- viin toimintoihin. Formiinien tutkiminen syövässä on entistäkin tärkeämpää, koska niille on jo löytynyt pienimolekyläärinen inhibiittori. Formiinien toiminnan inhibointi saattaa tulevai- suudessa kehittyä osaksi syövän lääkkeellistä hoitoa. Avainsanat: formiini, aktiinitukiranka, immunohistokemia, EMT, melanooma, rintasyöpä, levyepiteelisyöpä 6 Table of Contents TABLE OF CONTENTS ABSTRACT...................................................................................................................... 4 TIIVISTELMÄ.................................................................................................................. 5 ABBREVIATIONS............................................................................................................ 8 LIST OF ORIGINAL PUBLICATIONS............................................................................... 10 1. INTRODUCTION...................................................................................................... 11 2. REVIEW OF THE LITERATURE.................................................................................. 12 2.1. Cancer invasion and metastasis............................................................................. 12 2.2. Epithelial to mesenchymal transition (EMT).........................................................13 2.3. The actin cytoskeleton........................................................................................... 14 2.4. Formins..................................................................................................................17 2.4.1. The formin protein family...........................................................................17 2.4.2. Formins in human disease..........................................................................20 2.4.3. FMNL1........................................................................................................ 22 2.4.4. FMNL2........................................................................................................ 23 2.4.5. FMNL3........................................................................................................ 24 2.4.6. FHOD1........................................................................................................ 24 2.5. Prognostic clinicopathological parameters in cutaneous melanoma....................26 3. AIMS OF THE STUDY............................................................................................... 29 4. MATERIALS AND METHODS................................................................................... 30 4.1. Cell lines and cell culture (I-IV).............................................................................. 30 4.2. Melanoma patients and tissue samples (IV).........................................................31 4.3. Other tissues (I-III)................................................................................................. 32 4.4. Immunohistochemistry, immunocytochemistry and microscopy (I-IV).................32 4.5. Transfections.........................................................................................................34 4.5.1. Small interfering RNAs (I-IV).......................................................................34 4.5.2. Transfection of FMNL1 constructs (III)........................................................34 4.6. Western blot analysis............................................................................................ 35 4.7. Northern blot analysis (I, II)................................................................................... 35 4.8. Bioinformatics (I-III)............................................................................................... 36 4.9. mRNA microarray (II)............................................................................................. 36 4.10. Quantitative reverse transcription polymerase chain
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