CA-125

Last updated
MUC16
The Structure of MUC16 EN.png
Identifiers
Aliases MUC16 , CA125, mucin 16, cell surface associated
External IDs OMIM: 606154 HomoloGene: 133291 GeneCards: MUC16
Orthologs
SpeciesHumanMouse
Entrez

94025

n/a

Ensembl

ENSG00000181143

n/a

UniProt

Q8WXI7

n/a

RefSeq (mRNA)

NM_024690

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RefSeq (protein)

NP_078966

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Location (UCSC) Chr 19: 8.85 – 8.98 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

CA-125 (cancer antigen 125, carcinoma antigen 125, or carbohydrate antigen 125) also known as mucin 16 or MUC16 is a protein that in humans is encoded by the MUC16 gene. [3] [4] MUC16 is a member of the mucin family glycoproteins. [5] CA-125 has found application as a tumor marker or biomarker that may be elevated in the blood of some patients with specific types of cancers, most notably ovarian cancer, or other conditions that are benign. [6] [7]

Contents

Structure

Mucin 16 is a membrane associated mucin that possesses a single transmembrane domain. [8] A unique property of MUC16 is its large size. MUC16 is more than twice as long as MUC1 and MUC4 and contains about 22,000 amino acids, making it the largest membrane-associated mucin. [9]

MUC16 is composed of three different domains: [10]

The N-terminal and tandem repeat domains are both entirely extracellular and highly O-glycosylated. All mucins contain a tandem repeat domain that has repeating amino acid sequences high in serine, threonine and proline. [11] The C-terminal domain contains multiple extracellular SEA (sea urchin sperm protein, enterokinase, and agrin) modules, [12] a transmembrane domain, and a cytoplasmic tail. [10] The extracellular region of MUC16 can be released from the cell surface by undergoing proteolytic cleavage. [13] MUC16 is thought to be cleaved at a site in the SEA modules. [14]

Function

MUC16 is a component of the ocular surface (including the cornea and conjunctiva), the respiratory tract and the female reproductive tract epithelia. Since MUC16 is highly glycosylated it creates a hydrophilic environment that acts as a lubricating barrier against foreign particles and infectious agents on the apical membrane of epithelial cells. [15] Also, the cytoplasmic tail of MUC16 has been shown to interact with cytoskeleton by binding members of the ERM protein family. [16] The expression of mucin 16 has been shown to be altered in dry eye, cystic fibrosis, and several types of cancers. [17]

Role in cancer

Tumor metastasis initiated by interactions between MUC16 and mesothelin. Peritoneal metastasis of Ovarian Cancer.tiff
Tumor metastasis initiated by interactions between MUC16 and mesothelin.

MUC16 (CA-125) has been shown to play a role in advancing tumorigenesis and tumor proliferation by several different mechanisms.

As a biomarker

Testing of CA-125 blood levels has been proposed as useful in treating ovarian cancer. 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. [18] 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. [19]

Metastatic invasion

Interaction of MUC16 (CA125) and mesothelin Interaction of MUC16-CA125 and mesothelin..tif
Interaction of MUC16 (CA125) and mesothelin

MUC16 is also thought to participate in cell-to-cell interactions that enable the metastasis of tumor cells. This is supported by evidence showing that MUC16 binds selectively to mesothelin, a glycoprotein normally expressed by the mesothelial cells of the peritoneum (the lining of the abdominal cavity). [21] MUC16 and mesothelin interactions are thought to provide the first step in tumor cell invasion of the peritoneum. [22] 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. [23] 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. [24]

Mesothelin has also been found to be expressed in several types of cancers including mesothelioma, ovarian cancer and squamous cell carcinoma. [25] 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. [22]

Induced motility

Evidence suggests that expression of the cytoplasmic 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 domain of MUC16 to facilitate signaling that leads to a decrease in the expression of E-cadherin and increase the expression of N-cadherin and vimentin, which are expression patterns consistent with epithelial-mesenchymal transition. [26]

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 drugs, such as cisplatin. [27]

Discovery

CA-125 was initially detected using the murine monoclonal antibody designated OC125. Robert Bast, Robert Knapp and their research team first isolated this monoclonal antibody in 1981. [28] The protein was named “cancer antigen 125” because OC125 was the 125th antibody produced against the ovarian cancer cell line that was being studied. [29]

Related Research Articles

Monoclonal antibody Monospecific antibody that is made by identical immune cells that are all clones of a unique parent cell

A monoclonal antibody is an antibody made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.

Chimeric antigen receptor T cells are T cells that have been genetically engineered to produce an artificial T cell receptor for use in immunotherapy.

Single-chain variable fragment Fragment

A single-chain variable fragment (scFv) is not actually a fragment of an antibody, but instead is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of ten to about 25 amino acids. The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original immunoglobulin, despite removal of the constant regions and the introduction of the linker. The image to the right shows how this modification usually leaves the specificity unaltered.

Cancer immunotherapy Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspeciality of oncology.

Goblet cell

Goblet cells are simple columnar epithelial cells that secrete gel-forming mucins, like mucin MUC5AC. The goblet cells mainly use the merocrine method of secretion, secreting vesicles into a duct, but may use apocrine methods, budding off their secretions, when under stress. The term goblet refers to the cell's goblet-like shape. The apical portion is shaped like a cup, as it is distended by abundant mucus laden granules; its basal portion lacks these granules and is shaped like a stem.

Single-domain antibody Antibody fragment

A single-domain antibody (sdAb), also known as a nanobody, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight of only 12–15 kDa, single-domain antibodies are much smaller than common antibodies which are composed of two heavy protein chains and two light chains, and even smaller than Fab fragments and single-chain variable fragments.

Selectin Transmembrane proteins with a lectin-like domain, an epidermal growth factor-like domain, and a variable number of domains homologous to complement regulatory proteins

The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.

CD44 Cell–cell interactions, cell adhesion and migration.

The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on chromosome 11. CD44 has been referred to as HCAM, Pgp-1, Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.

P-selectin Type-1 transmembrane protein

P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.

Mesothelin

Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.

MUC1

Mucin 1, cell surface associated (MUC1), also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen or EMA, is a mucin encoded by the MUC1 gene in humans. MUC1 is a glycoprotein with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and several other organs. Mucins protect the body from infection by pathogen binding to oligosaccharides in the extracellular domain, preventing the pathogen from reaching the cell surface. Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers. Joyce Taylor-Papadimitriou identified and characterised the antigen during her work with breast and ovarian tumors.

A bispecific monoclonal antibody is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen. Naturally occurring antibodies typically only target one antigen. Upon development, BsAbs can be manufactured in several structural formats. Through different mechanism of action, BsAbs can be designed to recruit and activate immune cells, to interfere with receptor signaling and inactivate signaling ligands, and to force association of protein complexes. BsAbs have advantages compared to ordinary monoclonal antibodies, while BsAbs have problems and disadvantages. The major current applications of BsAbs have been explored for cancer immunotherapy and drug delivery, while BsAbs can also be applied to treat other diseases, including Alzeimer's disease and so on.

CD47 Protein-coding gene in humans

CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.

Epithelial cell adhesion molecule

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.

HAVCR2

Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.

Tumor-associated glycoprotein 72 (TAG-72) is a glycoprotein found on the surface of many cancer cells, including ovary, breast, colon, lung, and pancreatic cancers. It is a mucin-like molecule with a molar mass of over 1000 kDa.

A431 cells are a model human cell line used in biomedical research.

A rabbit hybridoma is a hybrid cell line formed by the fusion of an antibody producing rabbit B cell with a cancerous B-cell (myeloma).

Joyce Taylor-Papadimitriou FMedSci is a British molecular biologist and geneticist. She is Senior Fellow and Visiting Professor at King's College London specialising in the area of cellular, genetic and proteomic studies on patient breast tumour samples, and works within the Breast Cancer Biology Group. She was the first to identify that the action of interferon type 1 requires the synthesis of effector proteins.

SK-OV-3 is an ovarian cancer cell line derived from the ascites of a 64-year-old Caucasian female with an ovarian serous cystadenocarcinoma. The SK-OV-3 cell line is also hypodiploid, with a modal number of chromosomes of 43, occurring in 63.3% of cells. SK-OV-3 are positive for many of the antigens used to identify cancers of epithelial origin in clinical practice, including vimentin (VIM), high molecular weight cytokeratin (HMWK), low molecular weight cytokeratin (LMWK), epithelial membrane antigen (EMA) and leucocyte common antigen (LCA).

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000181143 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ Yin BW, Lloyd KO (Jul 2001). "Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16". The Journal of Biological Chemistry. 276 (29): 27371–5. doi: 10.1074/jbc.M103554200 . PMID   11369781.
  4. ↑ Yin BW, Dnistrian A, Lloyd KO (Apr 2002). "Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene". International Journal of Cancer. 98 (5): 737–40. doi: 10.1002/ijc.10250 . PMID   11920644. S2CID   39365316.
  5. ↑ Duraisamy S, Ramasamy S, Kharbanda S, Kufe D (May 2006). "Distinct evolution of the human carcinoma-associated transmembrane mucins, MUC1, MUC4 AND MUC16". Gene. 373: 28–34. doi:10.1016/j.gene.2005.12.021. PMID   16500040.
  6. ↑ "CA 125 test". Mayo Clinic . Retrieved 3 January 2022.
  7. ↑ Bast RC, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB (1998). "CA 125: the past and the future". The International Journal of Biological Markers. 13 (4): 179–87. doi:10.1177/172460089801300402. PMID   10228898. S2CID   46589946.
  8. ↑ Gipson IK (Oct 2007). "The ocular surface: the challenge to enable and protect vision: the Friedenwald lecture". Investigative Ophthalmology & Visual Science. 48 (10): 4390, 4391–8. doi:10.1167/iovs.07-0770. PMC   2886589 . PMID   17898256.
  9. ↑ Gniewek P, Kolinski A (Jan 2012). "Coarse-grained modeling of mucus barrier properties". Biophysical Journal. 102 (2): 195–200. Bibcode:2012BpJ...102..195G. doi:10.1016/j.bpj.2011.11.4010. PMC   3260744 . PMID   22339855.
  10. 1 2 O'Brien TJ, Beard JB, Underwood LJ, Dennis RA, Santin AD, York L (Nov–Dec 2001). "The CA 125 gene: an extracellular superstructure dominated by repeat sequences". Tumour Biology. 22 (6): 348–66. doi:10.1159/000050638. PMID   11786729. S2CID   20219942.
  11. ↑ Hollingsworth MA, Swanson BJ (Jan 2004). "Mucins in cancer: protection and control of the cell surface". Nature Reviews. Cancer. 4 (1): 45–60. doi:10.1038/nrc1251. PMID   14681689. S2CID   23171728.
  12. ↑ Kufe DW (Dec 2009). "Mucins in cancer: function, prognosis and therapy". Nature Reviews. Cancer. 9 (12): 874–85. doi:10.1038/nrc2761. PMC   2951677 . PMID   19935676.
  13. ↑ Goodell CA, Belisle JA, Gubbels JA, Migneault M, Rancourt C, Connor J, Kunnimalaiyaan M, Kravitz R, Tucker W, Zwick M, Patankar MS (2009). "Characterization of the tumor marker muc16 (ca125) expressed by murine ovarian tumor cell lines and identification of a panel of cross-reactive monoclonal antibodies". Journal of Ovarian Research. 2 (1): 8. doi:10.1186/1757-2215-2-8. PMC   2708168 . PMID   19538730.
  14. ↑ Palmai-Pallag T, Khodabukus N, Kinarsky L, Leir SH, Sherman S, Hollingsworth MA, Harris A (Jun 2005). "The role of the SEA (sea urchin sperm protein, enterokinase and agrin) module in cleavage of membrane-tethered mucins". The FEBS Journal. 272 (11): 2901–11. doi: 10.1111/j.1742-4658.2005.04711.x . PMID   15943821. S2CID   25637234.
  15. ↑ Perez BH, Gipson IK (Nov 2008). "Focus on Molecules: human mucin MUC16". Experimental Eye Research. 87 (5): 400–1. doi:10.1016/j.exer.2007.12.008. PMC   2586928 . PMID   18289532.
  16. ↑ Blalock TD, Spurr-Michaud SJ, Tisdale AS, Heimer SR, Gilmore MS, Ramesh V, Gipson IK (Oct 2007). "Functions of MUC16 in corneal epithelial cells". Investigative Ophthalmology & Visual Science. 48 (10): 4509–18. doi: 10.1167/iovs.07-0430 . PMID   17898272.
  17. ↑ Bafna S, Kaur S, Batra SK (May 2010). "Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells". Oncogene. 29 (20): 2893–904. doi:10.1038/onc.2010.87. PMC   2879972 . PMID   20348949.
  18. ↑ "Can Ovarian Cancer Be Found Early?". American Cancer Society. 11 April 2018.
  19. ↑ Hu M, Lan Y, Lu A, Ma X, Zhang L (2019). "Glycan-based biomarkers for diagnosis of cancers and other diseases: Past, present, and future". Progress in Molecular Biology and Translational Science. 162: 241–252. doi:10.1016/bs.pmbts.2018.12.002. ISBN   9780128177389. PMID   30905444.
  20. ↑ Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M (February 2009). "A binding domain on mesothelin for CA125/MUC16". The Journal of Biological Chemistry. 284 (6): 3739–49. doi: 10.1074/jbc.M806776200 . PMC   2635045 . PMID   19075018.
  21. ↑ Rump A, Morikawa Y, Tanaka M, Minami S, Umesaki N, Takeuchi M, Miyajima A (March 2004). "Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion". The Journal of Biological Chemistry. 279 (10): 9190–8. doi: 10.1074/jbc.M312372200 . PMID   14676194.
  22. 1 2 Gubbels JA, Belisle J, Onda M, Rancourt C, Migneault M, Ho M, Bera TK, Connor J, Sathyanarayana BK, Lee B, Pastan I, Patankar MS (October 2006). "Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors". Molecular Cancer. 5 (1): 50. doi:10.1186/1476-4598-5-50. PMC   1635730 . PMID   17067392.
  23. ↑ Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M (February 2009). "A binding domain on mesothelin for CA125/MUC16". The Journal of Biological Chemistry. 284 (6): 3739–49. doi: 10.1074/jbc.M806776200 . PMC   2635045 . PMID   19075018.
  24. ↑ Xiang X, Feng M, Felder M, Connor JP, Man YG, Patankar MS, Ho M (2011). "HN125: A Novel Immunoadhesin Targeting MUC16 with Potential for Cancer Therapy". Journal of Cancer. 2: 280–91. doi:10.7150/jca.2.280. PMC   3100680 . PMID   21611109.
  25. ↑ Chang K, Pastan I (January 1996). "Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers". Proceedings of the National Academy of Sciences of the United States of America. 93 (1): 136–40. Bibcode:1996PNAS...93..136C. doi: 10.1073/pnas.93.1.136 . PMC   40193 . PMID   8552591.
  26. ↑ Thériault C, Pinard M, Comamala M, Migneault M, Beaudin J, Matte I, Boivin M, Piché A, Rancourt C (Jun 2011). "MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis". Gynecologic Oncology. 121 (3): 434–43. doi:10.1016/j.ygyno.2011.02.020. PMID   21421261.
  27. ↑ Boivin M, Lane D, Piché A, Rancourt C (Dec 2009). "CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis". Gynecologic Oncology. 115 (3): 407–13. doi:10.1016/j.ygyno.2009.08.007. PMID   19747716.
  28. ↑ Bast RC, Feeney M, Lazarus H, Nadler LM, Colvin RB, Knapp RC (Nov 1981). "Reactivity of a monoclonal antibody with human ovarian carcinoma". The Journal of Clinical Investigation. 68 (5): 1331–7. doi:10.1172/JCI110380. PMC   370929 . PMID   7028788.
  29. ↑ Schmidt C (Sep 2011). "CA-125: a biomarker put to the test". Journal of the National Cancer Institute. 103 (17): 1290–1. doi:10.1093/jnci/djr344. PMID   21852262.
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