Mucin-4 (MUC-4) is a

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 most ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''MUC4''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. Like other mucins, MUC-4 is a high-molecular weight glycoprotein. The major constituents of

mucus Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It ...

, the viscous secretion that covers epithelial surfaces such as those in the trachea, colon, and cervix, are highly glycosylated proteins called mucins. These glycoproteins play important roles in the protection of the epithelial cells and have been implicated in epithelial renewal and differentiation. This gene encodes an integral membrane glycoprotein found on the cell surface, although secreted isoforms may exist. At least two dozen transcript variants of this gene have been found, although for many of them the full-length transcript has not been determined or they are found only in tumor tissues. MUC-4 has been found to play various roles in the progression of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

, particularly due to its signaling and anti-adhesive properties which contribute to tumor development and metastasis. It is also found to play roles in other diseases such as endometriosis and inflammatory bowel disease. MUC-4 belongs to the human mucin family that is membrane-anchored and can range in molecular weight from 550 to 930

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

for the actual protein, and up to 4,650 kDa with glycosylation.

Structure

MUC4 is an O-glycoprotein that can reach up to 2

micrometers The micrometre ( international spelling as used by the International Bureau of Weights and Measures; SI symbol: μm) or micrometer (American spelling), also commonly known as a micron, is a unit of length in the International System of Unit ...

outside the cell. MUC4 mucin consists of a large extracellular alpha subunit that is heavily glycosylated and a beta subunit that is anchored in the cell membrane and extends into the cytosol. This beta subunit is considered an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

, whose role in cancer is increasingly being recognized particularly due to its involvement in signalling pathways, particularly with

ErbB2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...

(Her2). This subunit serves as a ligand for

, which is suggested to cause the repression of apoptosis found in many cancer cells. The large alpha subunit that is glycosylated likely confers the anti-adhesive properties to the cell, allowing for cell–cell and cell–matrix detachment in normal as well as cancerous cells. The heavy glycosylation may also serve as a reservoir for growth factors, which may become released upon degradation. The two subunits of MUC4 are transcribed from a single gene made of 25 exons and with its exon/intron structure identical to that of the mouse gene. Over 24 splice variants have been found for MUC4 using commercial mRNAs or total RNAs extracted from cancer cell lines. Some predicted forms are soluble, while others are membrane bound. However, most of these splice variants are likely artefactual. Many polymorphisms are observed in the tandem repeat region of the alpha subunit, which has a variable number of repeats.

Function

Normal

In normal functioning, MUC-4 is known to play anti-adhesive roles in the body, such as in lubricating the reproductive lining. It is also found in the respiratory tract - particularly in the

trachea The trachea, also known as the windpipe, is a cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air- breathing animals with lungs. The trachea extends from the ...

and lung - and the

digestive tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

- in the

esophagus The esophagus ( American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to ...

and colon - as well as in the visual and auditory systems. In these roles, MUC-4 serves to protect and lubricate the epithelium, which facilitates transport and traps foreign particles. One example of its function in the reproductive lining relates to blastocyst implantation resulting from MUC4 downregulation. It is found to be overexpressed during the luteal phase of menstruation. MUC-4 may also have a role in fetal morphogenic development. MUC-4 is not found in the

gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...

, or liver except in abnormal conditions such as cancer. MUC-4, however, may normally be found in bodily fluids like saliva, tears, and milk. In the soluble form, MUC-4 appears to lubricate the epithelial mucosa.

Disease

MUC-4 is thought to play a role in cancer progression by repressing apoptosis and consequently increasing tumor cell proliferation. The molecular mechanism is thought to be through a MUC-4 complex with

ERBB2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...

receptors, which alters downstream signaling and down regulates

CDKN1B Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the ''Cip/Kip'' family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded pro ...

. The beta subunit of MUC-4 appears to serve as a ligand that causes the phosphorylation of

, but does not activate the

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...

pathways. MUC-4 may also affect

HER2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...

signaling, and result in its stabilization. As a mucin, MUC-4 also alters adhesive properties of the cell. When overexpressed, the disorganization of mucins may reduce adhesion to other cells as well as the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...

, promoting cancer cell migration and metastasis.

Role in cancer

Pancreatic

MUC4 is often overexpressed in pancreatic adenocarcinomas and has been shown to promote tumor growth and metastasis, though the mechanism by which it does so is not known. MUC4 detection is emerging as a method to diagnose pancreatic cancer, especially since MUC4 is not detectably expressed in normal pancreas and increased expression of MUC-4 suggests a greater progression of the disease. Scientists have recently experimented with MUC4 inhibition in pancreatic cancer using drug delivery methods such as microRNAs. Such efforts have been successful at reducing

EGF receptor EGF may refer to: * E.G.F., a Gabonese company * East Grand Forks, Minnesota, a city * East Garforth railway station in England * Epidermal growth factor * Equity Group Foundation, a Kenyan charity * European Gendarmerie Force, a military unit o ...

expression, its downstream signaling, and consequently malignant behavior of the cancer cell such as migration, invasion, and cell detachment. Bile acids have been found to stimulate

carcinogenesis 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 abno ...

in pancreatic ductal adenocarcinoma cells through increased expression of MUC4.Gál E, Veréb Z, Kemény L, et al. Bile accelerates carcinogenic processes in pancreatic ductal adenocarcinoma cells through the overexpression of MUC4. Sci Rep. 2020;10(1):22088. Published 2020 Dec 16. doi:10.1038/s41598-020-79181-6

Esophageal

MUC4 expression in esophageal cancer often leads to increased tumor proliferation and migration. Like with prostate cancer, increased expression of MUC4 suggests greater development of esophageal cancer.

Bile acids Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Prima ...

present in

gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is one of the upper gastrointestinal chronic diseases where stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/ ...

are thought to contribute to this over-expression of MUC4. By inhibiting MUC-4, scientists have been able to reduce cancer cell proliferation, migration, and tumor size as well as reduce protein S100A4 expression, presenting MUC-4 as a good therapeutic target for the treatment of esophageal cancer.

Breast

Unlike pancreatic and esophageal cancers, MUC4 expression is suppressed in the

primary tumor A primary tumor is a tumor growing at the anatomical site where tumor progression began and proceeded to yield a cancerous mass. Most cancers develop at their primary site but then go on to metastasize or spread to other parts of the body. These fur ...

when compared to normal cells. It, however, is found to be overexpressed in lymph node metastases. The initial reduction in MUC-4 appears to promote the transition to the primary tumor, but its subsequent increase in expression facilitate metastasis and ultimately increased malignancy

Other

MUC4 is found to be overexpressed in papillary thyroid carcinoma, and could serve as a potential marker of malignancy and prognosis. MUC-4 is also found to be a very sensitive and specific marker in low-grade fibromyxoid sarcoma.

Role in other diseases

MUC-4 is also relevant to several other disease conditions. Polymorphisms in the MUC4 gene have been found to play a role in the progression of endometriosis and related infertility, as well as dysplastic cervical disorders. MUC-4 also has important roles in inflammatory bowel disease such as Crohn's disease and is found to be overexpressed in

ulcerative colitis Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...

References

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