MUC16

Fig1. Schematic representation of MUC16 structure. (Abhijit Aithal, 2018)

What is MUC16 protein?

MUC16 gene (mucin 16, cell surface associated) is a protein coding gene which situated on the short arm of chromosome 19 at locus 19p13. This gene encodes a protein that is a member of the mucin family. Mucins are high molecular weight, O-glycosylated proteins that play an important role in forming a protective mucous barrier, and are found on the apical surfaces of the epithelia. The encoded protein is a membrane-tethered mucin that contains an extracellular domain at its amino terminus, a large tandem repeat domain, and a transmembrane domain with a short cytoplasmic domain. The amino terminus is highly glycosylated, while the repeat region contains 156 amino acid repeats unit that are rich in serines, threonines, and prolines. Interspersed within the repeats are Sea urchin sperm protein Enterokinase and Agrin (SEA) modules, leucine-rich repeats and ankyrin (ANK) repeats. These regions together form the ectodomain, and there is a potential cleavage site found near an SEA module close to the transmembrane domain.

What is the function of MUC16 protein?

MUC16 is particularly notable for its role in the diagnosis and monitoring of epithelial ovarian cancer. It is a member of the mucin family, characterized by a large molecular weight and extensive glycosylation. MUC16 plays a crucial role in establishing protective mucosal barriers that serve as defenses against pathogenic assaults. MUC16 has a dual role in the tumor immune microenvironment. It can suppress tumor immunity by interacting with inhibitory receptors on immune cells, but also has the potential to enhance tumor immunity through the presentation of neoantigens derived from MUC16 mutations. Also, MUC16 is a multifunctional protein with implications in cell protection, cell signaling, tumorigenesis, and as a target for cancer therapy and diagnosis.

MUC16 Related Signaling Pathway

MUC16 is a high molecular weight glycoprotein that is involved in various biological processes and is associated with several signaling pathways, particularly in the context of tumor biology. MUC16 has been shown to activate the Janus kinase 2 (JAK2) / Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway, which is implicated in tumor growth and proliferation. MUC16 can interact with the epidermal growth factor receptor (EGFR) and subsequently activate the PI3K-Akt pathway, contributing to tumor cell survival and proliferation. MUC16 is suggested to activate the Wnt signaling pathway, promoting the translocation of β-catenin to the nucleus and the expression of downstream oncogenes.

MUC16 Related Diseases

It is not typically present in normal ovarian tissue but is often elevated in the serum of patients with epithelial ovarian carcinoma, making it a commonly used serologic biomarker for diagnosis and monitoring of this disease. MUC16 is also highly expressed in a variety of other tumors, including breast, cervical, pancreatic, and colorectal cancers, where its overexpression is associated with cancer progression, metastasis, and poor patient prognosis. Furthermore, MUC16 mutations have been linked to a higher tumor mutational burden and improved overall survival in non-small cell lung cancer (NSCLC) and melanoma patients treated with immune checkpoint inhibitors (ICIs). The role of MUC16 in the tumor immune microenvironment and its association with immunotherapy biomarkers suggest its potential as a target for cancer therapy and a predictor of treatment response.

Bioapplications of MUC16

It is primarily known for its role as a tumor marker, particularly for epithelial ovarian cancer, where its elevated levels in serum are indicative of the disease's presence. The protein's abnormal expression or mutation is associated with various cancers and plays a significant part in tumorigenesis, progression, and metastasis. Furthermore, MUC16's ability to modulate immune responses and its potential as a target for cancer therapy, including the development of monoclonal antibodies and other immunotherapies, highlights its importance in cancer treatment strategies.

Case Study 1: Alison Crawford, 2019

Bispecific antibodies that interact with tumor antigens on cancer cells and activating receptors on immune cells offer an innovative immunotherapy approach. Here, researchers describe a human bispecific antibody (REGN4018) that binds both Mucin 16 (MUC16) and CD3, thus bridging MUC16-expressing cells with CD3+ T cells. REGN4018 induced T cell activation and killing of MUC16-expressing tumor cells in vitro. Binding and cytotoxicity of REGN4018 in vitro were minimally affected by high concentrations of CA-125, the shed form of MUC16, which is present in patients. In preclinical studies with human ovarian cancer cells and human T cells in immunodeficient mice, REGN4018 potently inhibited growth of intraperitoneal ovarian tumors. Immuno-PET imaging demonstrated localization of REGN4018 in MUC16-expressing tumors and in T cell-rich organs such as the spleen and lymph nodes. Toxicology studies in cynomolgus monkeys showed minimal and transient increases in serum cytokines and C-reactive protein after REGN4018 administration, with no overt toxicity.

Fig1. Binding of REGN4018 to human and cynomolgus monkey MUC16 on a range of tumor cell lines shown by flow cytometry.

Fig2. T cells in the peritoneal cavity were examined for PD-1 expression.

Case Study 2: Ying Wang, 2008

The gene encoding human CA125 was identified as MUCIN16 (MUC16). A database search identified the orthologous mouse gene, Muc16. Reverse transcription-polymerase chain reaction and RNA in situ hybridization detected Muc16 transcripts in the surface epithelia of the upper respiratory tract, the mesothelia lining body cavities and the internal organs, as well as male and female reproductive organs, and the amnion. Antibodies raised against human MUC16 do not recognize mouse MUC16. Therefore, a rabbit anti-mouse polyclonal antibody against recombinant mouse MUC16 was generated. Immunohistochemistry using this anti-mouse MUC16 antibody revealed expression in the luminal epithelia of the trachea, the epithelia of the secretory glands in the oral cavity, the surface of the olfactory epithelia, as well as mesothelial cells lining body cavities (i.e., pleural, peritoneal, and pelvic cavities), and male and female reproductive organs. In addition, MUC16 protein was detected in other cell types, such as the surface epithelia of the cochlear duct and chief cells of the stomach, suggesting multiple roles for MUC16. In mouse serous epithelial ovarian cancer, MUC16 protein was detected at the apical surface of well-differentiated tumors, but not poorly differentiated tumors.

Fig3. Arrow indicates MUC16 expression in mast cells.

Fig4. Apical localization of mouse MUC16 protein.

MUC16 has several biochemical functions, for example, . Some of the functions are cooperated with other proteins, some of the functions could acted by MUC16 itself. We selected most functions MUC16 had, and list some proteins which have the same functions with MUC16. You can find most of the proteins on our site.

MUC16 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with MUC16 here. Most of them are supplied by our site. Hope this information will be useful for your research of MUC16.