title: Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium.
abstract: Mucin16 [MUC16/cancer antigen 125 (CA-125)], a high-molecular-weight glycoprotein expressed on the ovarian tumor cell surface, potentiates metastasis via selective binding to mesothelin on peritoneal mesothelial cells. Shed MUC16/CA-125 is detectable in sera from ovarian cancer patients. We investigated the potential role of membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane collagenase highly expressed in ovarian cancer cells, in MUC16/CA-125 ectodomain shedding. An inverse correlation between MT1-MMP and MUC16 immunoreactivity was observed in human ovarian tumors and cells. Further, when MUC16-expressing OVCA433 cells were engineered to overexpress MT1-MMP, surface expression of MUC16/CA-125 was lost, whereas cells expressing the inactive E240A mutant retained surface MUC16/CA-125. As a functional consequence, decreased adhesion of cells expressing catalytically active MT1-MMP to three-dimensional meso-mimetic cultures and intact ex vivo peritoneal tissue explants was observed. Nevertheless, meso-mimetic invasion is enhanced in MT1-MMP-expressing cells. Together, these data support a model wherein acquisition of catalytically active MT1-MMP expression in ovarian cancer cells induces MUC16/CA-125 ectodomain shedding, reducing adhesion to meso-mimetic cultures and to intact peritoneal explants. However, proteolytic clearing of MUC16/CA-125, catalyzed by MT1-MMP, may then expose integrins for high-affinity cell binding to peritoneal tissues, thereby anchoring metastatic lesions for subsequent proliferation within the collagen-rich sub-mesothelial matrix.
authors.forename: Lana
authors.initials: L
authors.lastname: Bruney
authors.forename: Kaitlynn C
authors.initials: KC
authors.lastname: Conley
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Moss
authors.forename: Yueying
authors.initials: Y
authors.lastname: Liu
authors.forename: M Sharon
authors.initials: MS
authors.lastname: Stack
mesh_terms: D000818:Animals; D018394:CA-125 Antigen / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D018301:Neoplasms, Mesothelial / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010529:Peritoneal Cavity / Q000473:pathology*
chemical_list: D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins; C000715528:Msln protein, mouse; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D000090204:Mesothelin