Mucin-16

Did You Know?

• CA-125 was initially detected using the murine monoclonal antibody designated OC125.
• Robert Bast, Robert Knapp and their research team first isolated the OC125 antibody in 1981.
• The protein was named 'cancer antigen 125' because OC125 was the 125th antibody produced against the ovarian cancer cell line being studied.

Structure

Mucin 16 is a membrane-associated mucin with a single transmembrane domain and is the largest such mucin, containing about 22,000 amino acids. It comprises three domains: an N-terminal domain, a tandem repeat domain, and a C-terminal domain. The N-terminal and tandem repeat domains are extracellular and highly O-glycosylated. The C-terminal domain includes multiple SEA modules, a transmembrane domain, and a cytoplasmic tail. The extracellular region can be released via proteolytic cleavage at a site within the SEA modules.

Function

MUC16 is a component of the ocular surface, respiratory tract, and female reproductive tract epithelia. Its high glycosylation creates a hydrophilic environment that lubricates and protects epithelial cells from foreign particles and infectious agents. The cytoplasmic tail interacts with the cytoskeleton through ERM protein family members. Its expression is altered in dry eye, cystic fibrosis, and several cancers.

Role in cancer

MUC16 (CA-125) contributes to tumorigenesis and proliferation through multiple mechanisms. Testing of CA-125 blood levels is used to monitor chemotherapy response, relapse, and disease progression in ovarian cancer patients, but it is not useful for screening due to uncertain correlation with cancer and elevation in many conditions, including endometrial, fallopian tube, lung, breast, and gastrointestinal cancers, as well as pregnancy. MUC16 participates in cell-to-cell interactions that facilitate metastasis; it binds selectively to mesothelin, a glycoprotein on peritoneal mesothelial cells, via the IAB domain (residues 296–359) of mesothelin. This interaction is thought to be the first step in peritoneal tumor cell invasion. An immunoadhesin (HN125) containing the IAB domain can disrupt MUC16-mesothelin-mediated cancer cell adhesion. Mesothelin is also expressed in mesothelioma, ovarian cancer, and squamous cell carcinoma, and MUC16-mesothelin interactions may help aggregate tumor cells at metastasis sites. The cytoplasmic tail of MUC16 promotes tumor cell growth, motility, and invasion by signaling that decreases E-cadherin and increases N-cadherin and vimentin, consistent with epithelial-mesenchymal transition.