title: The OPCML tumor suppressor functions as a cell surface repressor-adaptor, negatively regulating receptor tyrosine kinases in epithelial ovarian cancer.
abstract: Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy, and its molecular basis is poorly understood. We previously demonstrated that opioid binding protein cell adhesion molecule (OPCML) was frequently epigenetically inactivated in epithelial ovarian cancers, with tumor suppressor function in vitro and in vivo. Here, we further show the clinical relevance of OPCML and demonstrate that OPCML functions by a novel mechanism in epithelial ovarian cancer cell lines and normal ovarian surface epithelial cells by regulating a specific repertoire of receptor tyrosine kinases: EPHA2, FGFR1, FGFR3, HER2, and HER4. OPCML negatively regulates receptor tyrosine kinases by binding their extracellular domains, altering trafficking via nonclathrin-dependent endocytosis, and promoting their degradation via a polyubiquitination-associated proteasomal mechanism leading to signaling and growth inhibition. Exogenous recombinant OPCML domain 1-3 protein inhibited the cell growth of epithelial ovarian cancers cell in vitro and in vivo in 2 murine ovarian cancer intraperitoneal models that used an identical mechanism. These findings demonstrate a novel mechanism of OPCML-mediated tumor suppression and provide a proof-of-concept for recombinant OPCML protein therapy in epithelial ovarian cancers.
  
  
  CONCLUSIONS
  The OPCML tumor suppressor negatively regulates a specific spectrum of receptor tyrosine kinases in ovarian cancer cells by binding to their extracellular domain and altering trafficking to a nonclathrin, caveolin-1–associated endosomal pathway that results in receptor tyrosine kinase polyubiquitination and proteasomal degradation. Recombinant OPCML domain 1-3 recapitulates this mechanism and may allow for the implementation of an extracellular tumor-suppressor replacement strategy.
authors.affiliation: Ovarian Cancer Action Research Centre, Division of Cancer, Imperial College London Hammersmith Campus, London, United Kingdom. a.mckie@imperial.ac.uk
authors.forename: Arthur B
authors.initials: AB
authors.lastname: McKie
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vaughan
authors.forename: Elisa
authors.initials: E
authors.lastname: Zanini
authors.forename: Imoh S
authors.initials: IS
authors.lastname: Okon
authors.forename: Louay
authors.initials: L
authors.lastname: Louis
authors.forename: Camila
authors.initials: C
authors.lastname: de Sousa
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shaposhnikov
authors.forename: Joshua L C
authors.initials: JL
authors.lastname: Wong
authors.forename: Hatice
authors.initials: H
authors.lastname: Gungor
authors.forename: Szymon
authors.initials: S
authors.lastname: Janczar
authors.forename: Mona
authors.initials: M
authors.lastname: El-Bahrawy
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Chayen
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C059785:OPCML protein, human; D020794:Receptor Protein-Tyrosine Kinases