title: Upregulation of endogenous ICAM-1 reduces ovarian cancer cell growth in the absence of immune cells.
abstract: Ovarian cancer is a difficult-to-treat cancer with a 5-year survival rate of only ∼45%, due to late diagnosis and therapy resistance. In need of new therapeutic approaches, induction of intercellular adhesion molecule (ICAM)-1 expression might be of interest, since the expression of ICAM-1 is lower in ovarian cancer cells compared with healthy ovarian cells and correlated with decreased tumorigenicity. Whereas ICAM-1 expression on tumor cells is of importance for attracting immune cells, ICAM-1 might also induce tumorigenicity and chemoresistance. In ovarian cancer, such a role of ICAM-1 is unclear. Here, we investigated whether ICAM-1 has a cell-biological role by bidirectional modulation of ICAM-1 expression using ICAM-targeting artificial transcription factors. For a panel of ovarian cancer cells, tumor growth and cisplatin sensitivity were evaluated. Induction of ICAM-1 expression (ranging from 3- to 228-fold on mRNA level and 1.7- to 108-fold on protein level) resulted in indications of decreased ovarian cancer cell growth and reduced cisplatin sensitivity. Repression ranged from 48 to 94% on mRNA level and 47 to 91% on protein level. This study shows that, next to its established immunogenic role, ICAM-1 affects cell biological behavior of ovarian cancer cells and, importantly, that reexpression by artificial transcription factors represents a powerful approach for functional validation of genes epigenetically silenced in cancer, such as ICAM-1.
authors.affiliation: Epigenetic Editing, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marloes L
authors.initials: ML
authors.lastname: de Groote
authors.forename: Hinke G
authors.initials: HG
authors.lastname: Kazemier
authors.forename: Christian
authors.initials: C
authors.lastname: Huisman
authors.forename: Bernardina T F
authors.initials: BT
authors.lastname: van der Gun
authors.forename: Marijke M
authors.initials: MM
authors.lastname: Faas
authors.forename: Marianne G
authors.initials: MG
authors.lastname: Rots
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C573420:ICAM1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1; D002945:Cisplatin
keywords: artificial transcription factor; cisplatin; epigenetics; tumor suppressor gene; zinc finger