Epithelial cell adhesion molecule

Last updated

EPCAM
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases EPCAM , DIAR5, EGP-2, EGP314, EGP40, ESA, HNPCC8, KS1/4, KSA, M4S1, MIC18, MK-1, TACSTD1, TROP1, epithelial cell adhesion molecule, BerEp4, MOC-31, Ber-Ep4
External IDs OMIM: 185535; MGI: 106653; HomoloGene: 1764; GeneCards: EPCAM; OMA:EPCAM - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4072

17075

Ensembl

ENSG00000119888

ENSMUSG00000045394

UniProt

P16422

Q99JW5

RefSeq (mRNA)

NM_002354

NM_008532

RefSeq (protein)

NP_002345

NP_032558

Location (UCSC) Chr 2: 47.35 – 47.39 Mb Chr 17: 87.94 – 87.96 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. [5] EpCAM is also involved in cell signaling, [6] migration, [7] proliferation, and differentiation. [8] Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. [9] 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. [10]

Contents

Expression pattern

First discovered in 1979, EpCAM was initially described as a dominant surface antigen on human colon carcinoma. [11] Because of its prevalence on many carcinomas, it has been "discovered" many different times. [12] EpCAM therefore has many aliases the most notable of which include TACSTD1 (tumor-associated calcium signal transducer 1), CD326 (cluster of differentiation 326), and the 17-1A antigen. [13]

EpCAM expression is not limited to human colon carcinomas; in fact, EpCAM is expressed in a variety of human epithelial tissues, carcinomas, and progenitor and stem cells. However, EpCAM is not found in non-epithelial cells or cancers of non-epithelial origin. EpCAM is expressed on the basolateral membrane of all simple (especially glandular), pseudo-stratified, and transitional epithelia. In contrast, normal squamous stratified epithelia are negative for EpCAM. The level of expression may differ significantly between the individual tissue types. In the gastrointestinal tract, the gastric epithelium expresses very low levels of EpCAM. Expression levels are substantially higher in small intestine, and in colon EpCAM is probably expressed at the highest levels among all epithelial cell types. [13]

EpCAM is frequently upregulated in carcinomas but is not expressed in cancers of non-epithelial origin. In cancer cells, EpCAM is expressed in a dispersed pattern across the cell membrane. [14] However, EpCAM expression in carcinomas is often heterogeneous; some cells in a tumor have more EpCAM than other cells in the same tumor.

Squamous carcinomas often express EpCAM whereas normal squamous cells do not express EpCAM. EpCAM expression differs between different types of renal cell carcinomas, and EpCAM expression increases during development of androgen resistance in prostate cancer. [15] All of this points towards the utility of EpCAM as a diagnostic tool for various cancers.

Structure

Although it is identified as a cell adhesion molecule, EpCAM does not structurally resemble any of the four major families of cell adhesion molecules, namely cadherins, integrins, selectins, and members of the immunoglobulin super-family. [13]

EpCAM is a glycosylated, 30- to 40-kDa type I membrane protein. The sequence of the EpCAM molecule predicts the presence of three potential N-linked glycosylation sites. It is composed of 314 amino acids. EpCAM consists of an extracellular domain (242 amino acids) with epidermal growth factor (EGF)- and thyroglobulin repeat-like domains, a single transmembrane domain (23 amino acids), and a short intracellular domain (26 amino acids). [10] The extracellular domain is sometimes referred to as EpEX, and the intracellular domain is sometimes referred to as EpICD. [14]

Function

The exact function of EpCAM is currently being elucidated, but EpCAM appears to play many different roles.

Cell adhesion

EpCAM was first found to play a role in homotypic cell adhesion. [5] This means that EpCAM on the surface of one cell binds to the EpCAM on a neighboring cell thereby holding the cells together. The adhesions mediated by EpCAM are relatively weak, as compared to some other adhesion molecules, such as classic cadherins.

EpICD is required for EpCAM to mediate intercellular adhesion; EpCAM mediates intercellular adhesion and associates with the actin cytoskeleton via EpICD. [16]

EpCAM has a negative impact on cadherin-mediated adhesions. Overexpression of EpCAM does not alter overall total cellular level of cadherins but rather decreases the association of the cadherin/catenin complex in the cytoskeleton. As EpCAM expression increases, the total amount of α-catenin decreases, whereas cellular β-catenin levels remain constant. [17]

The homotypic adhesive activity has been questioned, as a variety of in vivo and in vitro biochemical experiments have failed to detect trans-interactions. [18] EpCAM pro-adhesive activity could be explained by alternative models, [19] based on its ability to regulate PKC signalling and myosin activity. [20]

Recently, it has been discovered that EpCAM contributes to the maintenance of tight junctions. [21]

Active proliferation in a number of epithelial tissues is associated with increased or de novo EpCAM expression. This is especially evident in tissues that normally reveal no or low levels of EpCAM expression, such as squamous epithelium. The level of EpCAM expression correlates with the proliferative activity of intestinal cells, and inversely correlates with their differentiation. [8]

Role in cancer

EpCAM can be cleaved which lends the molecule oncogenic potential. Upon cleavage, the extracellular domain (EpEX) is released into the area surrounding the cell, and the intracellular domain (EpICD) is released into the cytoplasm of the cell. EpICD forms a complex with the proteins FHL2, β-catenin, and Lef inside the nucleus. This complex then binds to DNA and promotes the transcription of various genes. Targets of upregulation include c-myc, e-fabp, and cyclins A & E. [6] This has the effect of promoting tumor growth. Additionally, EpEX that has been cleaved can stimulate the cleavage of additional EpCAM molecules resulting in a positive feedback loop. [14] The amount of β-catenin in the nucleus can modulate the expression level of EpCAM. [22]

EpCAM may also play a role in epithelial mesenchymal transition (EMT) in tumors, although its exact effects are poorly understood. Its ability to suppress E-cadherin suggests that EpCAM would promote EMT and tumor metastasis, but its homotypic cell adhesion properties can counteract its ability to suppress E-cadherin. [23] Results from different studies are often conflicting. In one study, for example, silencing of EpCAM with short interfering RNA (siRNA) led to a reduction of proliferation, migration, and invasion of breast cancer cells in vitro [7] supporting the role of EpCAM in promoting EMT. In another study, cells undergoing EMT were found to downregulate EpCAM. [24] In one study, epithelial tumors were often strongly positive for EpCAM, but mesenchymal tumors showed only occasional and weak positivity. [15] It has been suggested that EpCAM expression is downregulated during EMT but then upregulated once the metastasis reaches its future tumor site. [25]

Clinical significance

Target for immunotherapy

It has been speculated that since EpCAM in normal epithelia is expressed mostly on the basolateral membrane, it would be much less accessible to antibodies than EpCAM in cancer tissue, where it is homogeneously distributed on the cancer cell surface. In addition to being overexpressed in many carcinomas, EpCAM is expressed in cancer stem cells, making EpCAM an attractive target for immunotherapy. However, the heterogeneous expression of EpCAM in carcinomas and the fact that EpCAM is not tumor-specific (i.e., it is found in normal epithelium) raise concerns that immunotherapy directed towards EpCAM could have severe side effects. [13] As the role of EpCAM in cancer cell signaling is better understood, EpCAM signaling rather than EpCAM itself may be a target for therapeutic intervention. [14]

Edrecolomab, catumaxomab, nofetumomab and other monoclonal antibodies are designed to bind to it. [10] [26]

Histopathology

Comparison H&E stain (left) with BerEP4 immunohistochemistry staining (right) on a pathological section having basal cell carcinoma (BCC) with squamous cell metaplasia. Only BCC cells are stained with BerEP4 in this image. BCC with squamous cell metaplasia with HE and BerEP4 staining.jpg
Comparison H&E stain (left) with BerEP4 immunohistochemistry staining (right) on a pathological section having basal cell carcinoma (BCC) with squamous cell metaplasia. Only BCC cells are stained with BerEP4 in this image.

EpCAM is often overexpressed in certain carcinomas, including in breast cancer, colon cancer and basal cell carcinoma of the skin. [28] The diagnosis of such conditions can therefore be assisted by immunohistochemistry using BerEp4, which is an antibody to EpCAM. [28]

Genetic disorders

A problem in EpCAM can indirectly cause Lynch syndrome, [29] a genetic disorder that leads to increased risk of cancer. Deletion of a portion of the 3' end of the EpCAM gene causes epigenetic inactivation of the MSH2 gene by hypermethylating the promoter region of the MSH2 gene.

Mutations in EpCAM have also been associated with congenital tufting enteropathy [30] which causes intractable diarrhea in newborn children.

Related Research Articles

<span class="mw-page-title-main">Cell adhesion</span> Process of cell attachment

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

<span class="mw-page-title-main">Mucin-16</span> Mammalian protein found in Homo sapiens

Mucin-16(MUC-16) also known as Ovarian cancer-related tumor marker CA125 is a protein that in humans is encoded by the MUC16 gene. MUC-16 is a member of the mucin family glycoproteins. MUC-16 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.

<span class="mw-page-title-main">Cadherin</span> Calcium-dependent cell adhesion molecule

Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with numerous adaptors and signaling proteins, collectively referred to as the cadherin adhesome.

<span class="mw-page-title-main">Cell junction</span> Multiprotein complex that forms a point of contact or adhesion in animal cells

Cell junctions or junctional complexes are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also maintain the paracellular barrier of epithelia and control paracellular transport. Cell junctions are especially abundant in epithelial tissues. Combined with cell adhesion molecules and extracellular matrix, cell junctions help hold animal cells together.

<span class="mw-page-title-main">Catenin</span> Type of protein

Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind filamentous actin (F-actin). β-Catenin binds directly to the cytoplasmic tail of classical cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.

The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.

<span class="mw-page-title-main">CD44</span> Cell-surface glycoprotein

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.

<span class="mw-page-title-main">Catenin beta-1</span> Mammalian protein found in humans

Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.

α-Catenin Primary protein link between cadherins and the actin cytoskeleton

α-Catenin (alpha-catenin) functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and α-actinin can bind to alpha-catenin. It has been suggested that alpha-catenin does not bind with high affinity to both actin filaments and the E-cadherin-beta-catenin complex at the same time. It has been observed that when α-catenin is not in a molecular complex with β-catenin, it dimerizes and functions to regulate actin filament assembly, possibly by competing with Arp2/3 protein. α-Catenin exhibits significant protein dynamics. However, a protein complex including a cadherin, actin, β-catenin and α-catenin has not been isolated.

<span class="mw-page-title-main">T-cadherin</span> GPI-anchored signaling protein

T-cadherin, also known as cadherin 13, H-cadherin (heart), and CDH13, is a unique member of the cadherin protein family. Unlike typical cadherins that span across the cell membrane with distinct transmembrane and cytoplasmic domains, T-cadherin lacks these features and is instead anchored to the cell's plasma membrane through a GPI anchor.

<span class="mw-page-title-main">Mucin short variant S1</span> Human protein

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 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.

<span class="mw-page-title-main">CD97</span> Mammalian protein found in humans

Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene. CD97 is a member of the adhesion G protein-coupled receptor (GPCR) family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

p120 catenin Protein found in humans

p120 catenin, or simply p120, also called catenin delta-1, is a protein that in humans is encoded by the CTNND1 gene.

<span class="mw-page-title-main">CDH3 (gene)</span> Protein-coding gene in humans

Cadherin-3, also known as P-Cadherin, is a protein that in humans is encoded by the CDH3 gene.

<span class="mw-page-title-main">SNAI1</span> Protein

Zinc finger protein SNAI1 is a protein that in humans is encoded by the SNAI1 gene. Snail is a family of transcription factors that promote the repression of the adhesion molecule E-cadherin to regulate epithelial to mesenchymal transition (EMT) during embryonic development.

<span class="mw-page-title-main">ALCAM</span> Protein-coding gene in the species Homo sapiens

CD166 antigen is a 100-105 kD typeI transmembrane glycoprotein that is a member of the immunoglobulin superfamily of proteins. In humans it is encoded by the ALCAM gene. It is also called CD166, MEMD, SC-1/DM-GRASP/BEN in the chicken, and KG-CAM in the rat.

<span class="mw-page-title-main">Cadherin-1</span> Human protein-coding gene

Cadherin-1 or Epithelial cadherin(E-cadherin), is a protein that in humans is encoded by the CDH1 gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. CDH1 has also been designated as CD324. It is a tumor suppressor gene.

<span class="mw-page-title-main">Catenin alpha-1</span> Protein found in humans

αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene. αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.

A mesenchymal–epithelial transition (MET) is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. MET is the reverse process of epithelial–mesenchymal transition (EMT) and it has been shown to occur in normal development, induced pluripotent stem cell reprogramming, cancer metastasis and wound healing.

mir-205 Micro RNA involved in the regulation of multiple genes

In molecular biology miR-205 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. They are involved in numerous cellular processes, including development, proliferation, and apoptosis. Currently, it is believed that miRNAs elicit their effect by silencing the expression of target genes.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000119888 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000045394 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO (April 1994). "Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule". The Journal of Cell Biology. 125 (2): 437–46. doi:10.1083/jcb.125.2.437. PMC   2120036 . PMID   8163559.
  6. 1 2 Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M, et al. (February 2009). "Nuclear signalling by tumour-associated antigen EpCAM". Nature Cell Biology. 11 (2): 162–71. doi:10.1038/ncb1824. PMID   19136966. S2CID   8616872.
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  8. 1 2 Litvinov SV, van Driel W, van Rhijn CM, Bakker HA, van Krieken H, Fleuren GJ, Warnaar SO (March 1996). "Expression of Ep-CAM in cervical squamous epithelia correlates with an increased proliferation and the disappearance of markers for terminal differentiation". The American Journal of Pathology. 148 (3): 865–75. PMC   1861708 . PMID   8774141.
  9. ↑ Münz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O (July 2004). "The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation". Oncogene. 23 (34): 5748–58. doi: 10.1038/sj.onc.1207610 . PMID   15195135. S2CID   32348616.
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  12. ↑ Baeuerle PA, Gires O (February 2007). "EpCAM (CD326) finding its role in cancer". British Journal of Cancer. 96 (3): 417–23. doi:10.1038/sj.bjc.6603494. PMC   2360029 . PMID   17211480.
  13. 1 2 3 4 Balzar M, Winter MJ, de Boer CJ, Litvinov SV (October 1999). "The biology of the 17-1A antigen (Ep-CAM)". Journal of Molecular Medicine. 77 (10): 699–712. doi:10.1007/s001099900038. PMID   10606205. S2CID   13253137.
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  15. 1 2 Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, Dirnhofer S (January 2004). "Frequent EpCam protein expression in human carcinomas". Human Pathology. 35 (1): 122–8. doi:10.1016/j.humpath.2003.08.026. PMID   14745734.
  16. ↑ Balzar M, Bakker HA, Briaire-de-Bruijn IH, Fleuren GJ, Warnaar SO, Litvinov SV (August 1998). "Cytoplasmic tail regulates the intercellular adhesion function of the epithelial cell adhesion molecule". Molecular and Cellular Biology. 18 (8): 4833–43. doi:10.1128/MCB.18.8.4833. PMC   109068 . PMID   9671492.
  17. ↑ Litvinov SV, Balzar M, Winter MJ, Bakker HA, Briaire-de Bruijn IH, Prins F, et al. (December 1997). "Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins". The Journal of Cell Biology. 139 (5): 1337–48. doi:10.1083/jcb.139.5.1337. PMC   2140211 . PMID   9382878.
  18. ↑ Gaber A, Kim SJ, Kaake RM, Benčina M, Krogan N, Šali A, et al. (September 2018). "EpCAM homo-oligomerization is not the basis for its role in cell-cell adhesion". Scientific Reports. 8 (1): 13269. Bibcode:2018NatSR...813269G. doi:10.1038/s41598-018-31482-7. PMC   6125409 . PMID   30185875.
  19. ↑ Fagotto F, Aslemarz A (September 2020). "EpCAM cellular functions in adhesion and migration, and potential impact on invasion: A critical review". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1874 (2): 188436. doi: 10.1016/j.bbcan.2020.188436 . PMID   32976980. S2CID   221939186.
  20. ↑ Maghzal N, Kayali HA, Rohani N, Kajava AV, Fagotto F (November 2013). "EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC". Developmental Cell. 27 (3): 263–77. doi: 10.1016/j.devcel.2013.10.003 . PMID   24183651.
  21. ↑ Varadarajan S, Raya-Sandino A, Nusrat A (December 2022). "Clipping EpCAM to release Claudin-7 for the greater good of the epithelial barrier". The Journal of Cell Biology. 222 (1): e202211127. doi: 10.1083/jcb.202211127 . PMC   9754701 . PMID   36516449.
  22. ↑ Yamashita T, Budhu A, Forgues M, Wang XW (November 2007). "Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma". Cancer Research. 67 (22): 10831–9. doi: 10.1158/0008-5472.CAN-07-0908 . PMID   18006828.
  23. ↑ Patriarca C, Macchi RM, Marschner AK, Mellstedt H (February 2012). "Epithelial cell adhesion molecule expression (CD326) in cancer: a short review". Cancer Treatment Reviews. 38 (1): 68–75. doi:10.1016/j.ctrv.2011.04.002. PMID   21576002.
  24. ↑ Santisteban M, Reiman JM, Asiedu MK, Behrens MD, Nassar A, Kalli KR, et al. (April 2009). "Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells". Cancer Research. 69 (7): 2887–95. doi:10.1158/0008-5472.CAN-08-3343. PMC   2664865 . PMID   19276366.
  25. ↑ van der Gun BT, Melchers LJ, Ruiters MH, de Leij LF, McLaughlin PM, Rots MG (November 2010). "EpCAM in carcinogenesis: the good, the bad or the ugly". Carcinogenesis. 31 (11): 1913–21. doi: 10.1093/carcin/bgq187 . PMID   20837599.
  26. ↑ Punt CJ, Nagy A, Douillard JY, Figer A, Skovsgaard T, Monson J, et al. (August 2002). "Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study". Lancet. 360 (9334): 671–7. doi:10.1016/S0140-6736(02)09836-7. PMID   12241873. S2CID   42391189.
  27. ↑ Sunjaya AP, Sunjaya AF, Tan ST (2017). "The Use of BEREP4 Immunohistochemistry Staining for Detection of Basal Cell Carcinoma". Journal of Skin Cancer. 2017: 2692604. doi: 10.1155/2017/2692604 . PMC   5804366 . PMID   29464122.
  28. 1 2 Dasgeb B, Mohammadi TM, Mehregan DR (2013). "Use of Ber-EP4 and Epithelial Specific Antigen to Differentiate Clinical Simulators of Basal Cell Carcinoma". Biomarkers in Cancer. 5: 7–11. doi: 10.4137/BIC.S11856 . PMC   3791948 . PMID   24179394.
  29. ↑ Tomita N, Yamano T, Matsubara N, Tamura K (February 2013). "[A novel genetic disorder of Lynch syndrome - EPCAM gene deletion]". Gan to Kagaku Ryoho. Cancer & Chemotherapy. 40 (2): 143–7. PMID   23411950.
  30. ↑ Sivagnanam M, Mueller JL, Lee H, Chen Z, Nelson SF, Turner D, et al. (August 2008). "Identification of EpCAM as the gene for congenital tufting enteropathy". Gastroenterology. 135 (2): 429–37. doi:10.1053/j.gastro.2008.05.036. PMC   2574708 . PMID   18572020.

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