Mucin-16 (MUC-16) also known as Ovarian cancer-related tumor marker CA125 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''MUC16''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. MUC-16 is a member of the

mucin Mucins () are a family of high molecular weight, heavily glycosylated proteins ( glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in ...

family

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

s. MUC-16 has found application as a

tumor marker A tumor marker is a biomarker that can be used to indicate the presence of cancer or the behavior of cancers (measure progression or response to therapy). They can be found in bodily fluids or tissue. Markers can help with assessing prognosis, s ...

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

that may be elevated in the blood of some patients with specific types of

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

s, most notably

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

, or other conditions that are benign.

Structure

Mucin 16 is a membrane associated mucin that possesses a single

transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...

domain. A unique property of MUC16 is its large size. MUC16 is more than twice as long as

MUC1 Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the ''MUC1'' gene in humans. Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its ...

and MUC4 and contains about 22,000

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

, making it the largest membrane-associated mucin. MUC16 is composed of three different domains: * An

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

domain * A

tandem repeat In genetics, tandem repeats occur in DNA when a pattern of one or more nucleotides is repeated and the repetitions are directly adjacent to each other, e.g. ATTCG ATTCG ATTCG, in which the sequence ATTCG is repeated three times. Several protein ...

domain * A

C-terminal domain The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

The N-terminal and tandem repeat domains are both entirely

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

and highly O-glycosylated. All mucins contain a tandem repeat domain that has repeating

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

sequences high in

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

and

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

. The C-terminal domain contains multiple extracellular SEA (sea urchin sperm protein, enterokinase, and agrin) modules, a transmembrane domain, and a

cytoplasmic The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...

tail. The extracellular region of MUC16 can be released from the cell surface by undergoing

proteolytic cleavage Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

. MUC16 is thought to be cleaved at a site in the SEA modules.

Function

MUC16 is a component of the ocular surface (including the

cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...

and

conjunctiva In the anatomy of the eye, the conjunctiva (: conjunctivae) is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with gobl ...

), the respiratory tract and the female reproductive tract

epithelia Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of many ...

. Since MUC16 is highly

glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

it creates a

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

environment that acts as a lubricating barrier against foreign particles and infectious agents on the

apical membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extra ...

of epithelial cells. Also, the cytoplasmic tail of MUC16 has been shown to interact with

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

by binding members of the

ERM protein family The ERM protein family consists of three closely related proteins, ezrin, radixin and moesin. The three paralogs, ezrin, radixin and moesin, are present in vertebrates, whereas other species have only one ERM gene. Therefore, in vertebrates these ...

. The expression of mucin 16 has been shown to be altered in

dry eye Dry eye syndrome, also known as keratoconjunctivitis sicca, is the condition of having dry eyes. Symptoms include dryness in the eye, irritation, redness, discharge, blurred vision, and easily fatigued eyes. Symptoms range from mild and occas ...

cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...

, and several types of cancers.

Role in cancer

MUC16 (CA-125) has been shown to play a role in advancing

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...

and tumor proliferation by several different mechanisms.

As a biomarker

Testing of CA-125 blood levels has been proposed as useful in treating

. While the test can give useful information for women already known to have ovarian cancer, CA-125 testing has not been found useful as a screening method because of the uncertain correlation between CA-125 levels and cancer. In addition to ovarian cancer, CA-125 can be elevated in patients who have conditions such as endometrial cancer, fallopian tube cancer, lung cancer, breast cancer, and gastrointestinal cancer. It can also be increased in pregnant women. Because of the wide variety of conditions that can increase serum levels, CA-125 is not used to detect cancer, but it is often used to monitor responses to chemotherapy, relapse, and disease progression in ovarian cancer patients.

Metastatic invasion

MUC16 is also thought to participate in cell-to-cell interactions that enable the

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

of tumor cells. This is supported by evidence showing that MUC16 binds selectively to

mesothelin Mesothelin, also known as MSLN, is a protein that in humans is encoded by the ''MSLN'' gene. Function Mesothelin is a 40 kDa protein that is expressed in mesothelial cells. The protein was first identified by its reactivity with monoclonal an ...

, a

normally expressed by the

mesothelial The mesothelium is a membrane composed of simple squamous epithelial cells of mesodermal origin, which forms the lining of several body cavities: the pleura (pleural cavity around the lungs), peritoneum (abdominopelvic cavity including the mesent ...

cells of the

peritoneum The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesotheli ...

(the lining of the abdominal cavity). MUC16 and mesothelin interactions are thought to provide the first step in tumor cell invasion of the peritoneum. The region (residues 296–359) consisting of 64 amino acids at the N-terminus of cell surface mesothelin has been experimentally established as the functional binding domain (named IAB) for MUC16/CA125. An immunoadhesin (HN125) that consists of the IAB domain of mesothelin and the human Fc portion has the ability to disrupt the heterotypic cancer cell adhesion mediated by the MUC16-mesothelin interaction. Mesothelin has also been found to be expressed in several types of cancers including

mesothelioma Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The area most commonly affected is the lining of the lungs and chest wall. Less commonly the lini ...

and

squamous cell carcinoma Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...

. Since mesothelin is also expressed by tumor cells, MUC16 and mesothelial interactions may aid in the gathering of other tumor cells to the location of a metastasis, thus increasing the size of the metastasis.

Induced motility

Evidence suggests that expression of the

tail of MUC16 enables tumor cells to grow, promotes cell motility and may facilitate invasion. This appears to be due to the ability of the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

domain of MUC16 to facilitate signaling that leads to a decrease in the expression of

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), is a protein that in humans is encoded by the ''CDH1'' gene (not to be confused with the APC/C activator protein CDH1). Mutations are correlated with Hereditary diffuse gastric cancer, gastric, Here ...

and increase the expression of

N-cadherin Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the ''CDH2'' gene. CDH2 has also been designated as CD325 (cluster of differentiation 325). Cadherin-2 is a transmembrane protein expressed in multi ...

and

vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods. Vimentin is a Intermediate filament#Type III, type III intermediate filamen ...

, which are expression patterns consistent with epithelial-mesenchymal transition.

Chemotherapy resistance

MUC16 may also play a role in reducing the sensitivity of cancer cells to drug therapy. For example, overexpression of MUC16 has been shown to protect cells from the effects of

genotoxic Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic s ...

drugs, such as

cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

Discovery

CA-125 was initially detected using the

murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

designated OC125. Robert Bast, Robert Knapp and their research team first isolated this monoclonal antibody in 1981. The protein was named "cancer antigen 125" because OC125 was the 125th antibody produced against the ovarian cancer cell line that was being studied.

References

External links

CA-125 blood test urban legend
at snopes.com * * CA-125 a
Lab Tests Online

CA-125 analyte monograph
from The Association for Clinical Biochemistry and Laboratory Medicine. * {{Tumor markers Tumor markers Proteins