title: MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis.
abstract: OBJECTIVE
  MUC16 (CA125) protein is a high molecular weight mucin overexpressed in the majority of epithelial ovarian cancers (EOC) but not in the epithelium of normal ovaries suggesting that it might play a role in EOC pathogenesis. Here, we explored the phenotypic consequences of MUC16 knockdown and expression of its C-terminal domain with the aim of establishing a role for MUC16 in tumorigenesis.
  
  
  METHODS
  MUC16 was down-regulated by stably expressing an anti-MUC16 endoplasmic reticulum-targeted single-chain antibody which prevented MUC16 cell surface localization in NIH:OVCAR3 cells. In addition, we generated epitope tagged, N-terminal region-deleted MUC16 constructs with (MUC16TMU) and without (MUC16CTD) cytoplasmic tail deletions and stably expressed them in SKOV3 cells.
  
  
  RESULTS
  Although MUC16 knockdown did not affect the cell growth rate, knockdown cells reached a stationary growth phase after 4 days whereas control cells continued to grow for up to 7 days. Colony formation assays in soft agar demonstrated that MUC16 knockdown cells had >8-fold reduction in their ability to form colonies. Importantly, MUC16 knockdown completely prevents the formation of subcutaneous tumors in nude mice. Conversely, we show that ectopic expression of the MUC16CTD enhances SKOV3 tumor cell growth, colony formation in soft agar and enhances tumor growth and metastases in SCID mice. In addition, MUC16CTD expression increases cell motility, invasiveness, and metastatic property. Deletion of the cytoplasmic tail from the MUC16CTD completely abolished its ability to enhance tumor cell growth, cell motility and invasiveness. Furthermore, the increased invasive properties of MUC16CTD-expressing cells correlated with decreased expression of E-cadherin and increased expression of N-cadherin and vimentin.
  
  
  CONCLUSIONS
  These findings provide the first evidence for a critical role of MUC16 in tumor cell growth, tumorigenesis and metastases.
authors.affiliation: Département de Microbiologie et Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12ième Avenue Nord, Sherbrooke, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Thériault
authors.forename: Maxime
authors.initials: M
authors.lastname: Pinard
authors.forename: Marina
authors.initials: M
authors.lastname: Comamala
authors.forename: Martine
authors.initials: M
authors.lastname: Migneault
authors.forename: Julie
authors.initials: J
authors.lastname: Beaudin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Matte
authors.forename: Marianne
authors.initials: M
authors.lastname: Boivin
authors.forename: Alain
authors.initials: A
authors.lastname: Piché
authors.forename: Claudine
authors.initials: C
authors.lastname: Rancourt
mesh_terms: D000818:Animals; D018394:CA-125 Antigen / Q000096:biosynthesis* / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D014183:Transplantation, Heterologous; D014746:Vimentin / Q000096:biosynthesis
chemical_list: D018394:CA-125 Antigen; D015820:Cadherins; C451759:MUC16 protein, human; D008565:Membrane Proteins; D014746:Vimentin