title: Metadherin exon 11 skipping variant enhances metastatic spread of ovarian cancer.
abstract: Metastatic ovarian cancer has a dismal prognosis and current chemotherapeutic approaches have very limited success. Metadherin (MTDH) is expressed in human ovarian cancer tissue and its expression inversely correlates with patients overall survival. Consistent with these studies, we observed MTDH expression in tissue specimens of FIGO Stage III ovarian carcinomas (72/83 cases). However, we also observed this in normal human ovarian epithelial (OE) cells, which raised the question of whether MTDH-variants with functional differences exist. We identified a novel MTDH exon 11 skipping variant (MTDHdel) which was seen at higher levels in ovarian cancer compared to benign OE cells. We analyzed MTDH-binding partner interactions and found that 12 members of the small ribosomal subunit and several mRNA binding proteins bound stronger to MTDHdel than to wildtype MTDH which indicates differential effects on gene translation. Knockdown of MTDH in ovarian cancer cells reduced the amount of distant metastases and improved the survival of ovarian cancer-bearing mice. Selective overexpression of the MTDHdel enhanced murine and human ovarian cancer progression and caused a malignant phenotype in originally benign human OE cells. MTDHdel was detectable in microdissected ovarian cancer cells of some human tissue specimens of ovarian carcinomas. In summary, we have identified a novel MTDH exon 11 skipping variant that shows enhanced binding to small ribosomal subunit members and that caused reduced overall survival of ovarian cancer bearing mice. Based on the findings in the murine system and in human tissues, MTDHdel must be considered a major promalignant factor for ovarian cancer.
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, University of Freiburg, Germany; Department of Psychiatry and Psychotherapy, Freiburg University Medical Center, University of Freiburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Haug
authors.forename: Dominik
authors.initials: D
authors.lastname: Schnerch
authors.forename: Sebastian
authors.initials: S
authors.lastname: Halbach
authors.forename: Justin
authors.initials: J
authors.lastname: Mastroianni
authors.forename: Verónica I
authors.initials: VI
authors.lastname: Dumit
authors.forename: Marie
authors.initials: M
authors.lastname: Follo
authors.forename: Annette
authors.initials: A
authors.lastname: Hasenburg
authors.forename: Martin
authors.initials: M
authors.lastname: Köhler
authors.forename: Heide
authors.initials: H
authors.lastname: Dierbach
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herzog
authors.forename: Amelie
authors.initials: A
authors.lastname: Proske
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.forename: Joern
authors.initials: J
authors.lastname: Dengjel
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.forename: Silke
authors.initials: S
authors.lastname: Laßmann
authors.forename: Ralph
authors.initials: R
authors.lastname: Wäsch
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005091:Exons; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D016601:RNA-Binding Proteins; D017384:Sequence Deletion
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; C483038:Mtdh protein, mouse; D016601:RNA-Binding Proteins
keywords: astrocyte elevated gene-1; exon skipping variant; metadherin; ovarian cancer; small ribosomal subunit members