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.
Acknowledgments
The authors gratefully acknowledge financial support from National Institutes of Health/National Cancer Institute grants F31 CA159804 (L.B.), RO1 CA109545 (M.S.S.), and RO1 CA086984 (M.S.S.).
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©2014 by De Gruyter
Articles in the same Issue
- Frontmatter
- Guest Editorial
- Highlight: The protease web
- Angiotensin-I converting enzyme (ACE): structure, biological roles, and molecular basis for chloride ion dependence
- Non-B HIV-1 subtypes in sub-Saharan Africa: impact of subtype on protease inhibitor efficacy
- Inflammatory outcomes of apoptosis, necrosis and necroptosis
- Angiotensin-converting enzyme overexpression in myelocytes enhances the immune response
- The leader proteinase of foot-and-mouth disease virus: structure-function relationships in a proteolytic virulence factor
- Immune-modulating effects of alpha-1 antitrypsin
- Mammalian gamete fusion depends on the inhibition of ovastacin by fetuin-B
- The activity and localization patterns of cathepsins B and X in cells of the mouse gastrointestinal tract differ along its length
- Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium
- Homology model of human prothrombinase based on the crystal structure of Pseutarin C
- Specific targeting of human caspases using designed ankyrin repeat proteins
- Analysis of the evolution of granule associated serine proteases of immune defence (GASPIDs) suggests a revised nomenclature
Articles in the same Issue
- Frontmatter
- Guest Editorial
- Highlight: The protease web
- Angiotensin-I converting enzyme (ACE): structure, biological roles, and molecular basis for chloride ion dependence
- Non-B HIV-1 subtypes in sub-Saharan Africa: impact of subtype on protease inhibitor efficacy
- Inflammatory outcomes of apoptosis, necrosis and necroptosis
- Angiotensin-converting enzyme overexpression in myelocytes enhances the immune response
- The leader proteinase of foot-and-mouth disease virus: structure-function relationships in a proteolytic virulence factor
- Immune-modulating effects of alpha-1 antitrypsin
- Mammalian gamete fusion depends on the inhibition of ovastacin by fetuin-B
- The activity and localization patterns of cathepsins B and X in cells of the mouse gastrointestinal tract differ along its length
- Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium
- Homology model of human prothrombinase based on the crystal structure of Pseutarin C
- Specific targeting of human caspases using designed ankyrin repeat proteins
- Analysis of the evolution of granule associated serine proteases of immune defence (GASPIDs) suggests a revised nomenclature