Mucin 4

Mucin-4 (MUC-4) is a mucin protein that in humans is encoded by the MUC4 gene.[3] Like other mucins, MUC-4 is a high-molecular weight glycoprotein.[4]

MUC4
Identifiers
AliasesMUC4, ASGP, HSA276359, MUC-4, mucin 4, cell surface associated
External IDsOMIM: 158372 GeneCards: MUC4
Orthologs
SpeciesHumanMouse
Entrez

4585

n/a

Ensembl

n/a

UniProt

Q99102

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RefSeq (mRNA)

n/a

RefSeq (protein)

NP_001309397
NP_004523
NP_060876
NP_612154

n/a

Location (UCSC)Chr 3: 195.75 – 195.81 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

The major constituents of mucus, 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.[5]

MUC-4 has been found to play various roles in the progression of cancer, 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 for the actual protein, and up to 4,650 kDa with glycosylation.[6]

Structure

MUC4 is an O-glycoprotein that can reach up to 2 micrometers outside the cell.[6] 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.[7] This beta subunit is considered an oncogene, whose role in cancer is increasingly being recognized particularly due to its involvement in signalling pathways, particularly with ErbB2 (Her2).[7] This subunit serves as a ligand for ErbB2, which is suggested to cause the repression of apoptosis found in many cancer cells.[8]

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.[6] The heavy glycosylation may also serve as a reservoir for growth factors, which may become released upon degradation.[9]

The two subunits of MUC4 are transcribed from a single gene[8] made of 25 exons and with its exon/intron structure identical to that of the mouse gene.[10] Over 24 splice variants have been found for MUC4 using commercial mRNAs or total RNAs extracted from cancer cell lines.[6][11] Some predicted forms are soluble, while others are membrane bound. However, most of these splice variants are likely artefactual. [12] Many polymorphisms are observed in the tandem repeat region of the alpha subunit, which has a variable number of repeats.[13][14]

Function

Normal

In normal functioning, MUC-4 is known to play anti-adhesive roles in the body, such as in lubricating the reproductive lining.[15] It is also found in the respiratory tract - particularly in the trachea and lung - and the digestive tract - in the esophagus and colon - as well as in the visual and auditory systems.[6] 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.[8] It is found to be overexpressed during the luteal phase of menstruation.[16] MUC-4 may also have a role in fetal morphogenic development.[6] MUC-4 is not found in the gallbladder, pancreas, or liver except in abnormal conditions such as cancer. MUC-4, however, may normally be found in bodily fluids like saliva, tears, and milk.[9] In the soluble form, MUC-4 appears to lubricate the epithelial mucosa.[8]

Disease

MUC-4 is thought to play a role in cancer progression by repressing apoptosis and consequently increasing tumor cell proliferation.[17] The molecular mechanism is thought to be through a MUC-4 complex with ERBB2 receptors, which alters downstream signaling and down regulates CDKN1B.[17] The beta subunit of MUC-4 appears to serve as a ligand that causes the phosphorylation of ErbB2, but does not activate the MAPK or AKT pathways.[18] MUC-4 may also affect HER2 signaling, and result in its stabilization.[6][19] 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, 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.[4] 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.[4] Scientists have recently experimented with MUC4 inhibition in pancreatic cancer using drug delivery methods such as microRNAs.[20] Such efforts have been successful at reducing EGF receptor 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 in pancreatic ductal adenocarcinoma cells through increased expression of MUC4.[21]

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 present in gastroesophageal reflux disease 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.[22]

Breast

Unlike pancreatic and esophageal cancers, MUC4 expression is suppressed in the primary tumor when compared to normal cells.[23] 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[23]

Other

MUC4 is found to be overexpressed in papillary thyroid carcinoma, and could serve as a potential marker of malignancy and prognosis.[24] MUC-4 is also found to be a very sensitive and specific marker in low-grade fibromyxoid sarcoma.[25]

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,[15] as well as dysplastic cervical disorders.[26] MUC-4 also has important roles in inflammatory bowel disease such as Crohn's disease and is found to be overexpressed in ulcerative colitis.[27]

References
  1. ENSG00000145113, ENSG00000273822, ENSG00000278303, ENSG00000273984, ENSG00000276613, ENSG00000277585, ENSG00000275164 GRCh38: Ensembl release 89: ENSG00000278468, ENSG00000145113, ENSG00000273822, ENSG00000278303, ENSG00000273984, ENSG00000276613, ENSG00000277585, ENSG00000275164 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. Porchet N, Nguyen VC, Dufosse J, Audie JP, Guyonnet-Duperat V, Gross MS, Denis C, Degand P, Bernheim A, Aubert JP (May 1991). "Molecular cloning and chromosomal localization of a novel human tracheo-bronchial mucin cDNA containing tandemly repeated sequences of 48 base pairs". Biochem Biophys Res Commun. 175 (2): 414–22. doi:10.1016/0006-291X(91)91580-6. PMID 1673336.
  4. Srivastava SK, Bhardwaj A, Singh S, Arora S, Wang B, Grizzle WE, Singh AP (December 2011). "MicroRNA-150 directly targets MUC-4 and suppresses growth and malignant behavior of pancreatic cancer cells". Carcinogenesis. 32 (12): 1832–9. doi:10.1093/carcin/bgr223. PMC 3220613. PMID 21983127.
  5. "Entrez Gene: MUC-4 mucin 4, cell surface associated".
  6. "MUC4 (mucin 4, cell surface associated)". Atlas of Genetics and Cytogenetics in Oncology and Haematology. AtlasGeneticsOncology.org.
  7. Albrecht H, Carraway KL (June 2011). "MUC1 and MUC4: switching the emphasis from large to small". Cancer Biother. Radiopharm. 26 (3): 261–71. doi:10.1089/cbr.2011.1017. PMC 3128783. PMID 21728842.
  8. Carraway KL, Perez A, Idris N, et al. (2003). "MUC4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive". Prog. Nucleic Acid Res. Mol. Biol. Progress in Nucleic Acid Research and Molecular Biology. 71: 149–85. doi:10.1016/S0079-6603(02)71043-X. ISBN 9780125400718. PMID 12102554.
  9. Chaturvedi P, Singh AP, Batra SK (April 2008). "Structure, evolution, and biology of the MUC-4 mucin". FASEB J. 22 (4): 966–81. doi:10.1096/fj.07-9673rev. PMC 2835492. PMID 18024835.
  10. Desseyn JL, Clavereau I, Laine A (2002). "Cloning, chromosomal localization and characterization of the murine mucin gene orthologous to human MUC4". Eur. J. Biochem. 269 (13): 3150–9. doi:10.1046/j.1432-1033.2002.02988.x. PMID 12084055.
  11. Escande F, Lemaitre L, Moniaux N, et al. (2002). "Genomic organization of MUC4 mucin gene. Towards the characterization of splice variants". Eur. J. Biochem. 269 (15): 3637–44. doi:10.1046/j.1432-1033.2002.03032.x. PMID 12153560.
  12. Desseyn JL, Tetaert S, Gouyer V (December 2007). "Architecture of the large membrane-bound mucins". Gene. 410 (2): 215–222. doi:10.1016/j.gene.2007.12.014. PMID 18242885.
  13. Gross MS, Guyonnet-Duperat V, Porchet N, et al. (1992). "Mucin 4 (MUC4) gene: regional assignment (3q29) and RFLP analysis". Ann. Genet. 35 (1): 21–6. PMID 1351710.
  14. Nollet S, Moniaux N, Maury J, et al. (1998). "Human mucin gene MUC4: organization of its 5'-region and polymorphism of its central tandem repeat array". Biochem. J. 332. ( Pt 3) (Pt 3): 739–48. doi:10.1042/bj3320739. PMC 1219535. PMID 9620877.
  15. Chang CY, Chang HW, Chen CM, Lin CY, Chen CP, Lai CH, Lin WY, Liu HP, Sheu JJ, Tsai FJ (2011). "MUC4 gene polymorphisms associate with endometriosis development and endometriosis-related infertility". BMC Med. 9: 19. doi:10.1186/1741-7015-9-19. PMC 3052195. PMID 21349170.
  16. Audie JP, Tetaert D, Pigny P, et al. (1995). "Mucin gene expression in the human endocervix". Hum. Reprod. 10 (1): 98–102. doi:10.1093/humrep/10.1.98. PMID 7745080.
  17. "MUC4 Gene". GeneCards. Weizmann Institute of Science.
  18. Jepson S, Komatsu M, Haq B, et al. (2002). "MUC4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27(kip), but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways". Oncogene. 21 (49): 7524–32. doi:10.1038/sj.onc.1205970. PMID 12386815.
  19. Chaturvedi P, Singh AP, Chakraborty S, Chauhan SC, Bafna S, Meza JL, Singh PK, Hollingsworth MA, Mehta PP, Batra SK (2008). "MUC-4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells". Cancer Res. 68 (7): 2065–70. doi:10.1158/0008-5472.CAN-07-6041. PMC 2835497. PMID 18381409.
  20. Singh AP, Moniaux N, Chauhan SC, Meza JL, Batra SK (January 2004). "Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis". Cancer Res. 64 (2): 622–30. doi:10.1158/0008-5472.CAN-03-2636. PMID 14744777.
  21. 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
  22. Bruyère E, Jonckheere N, Frénois F, Mariette C, Van Seuningen I (September 2011). "The MUC-4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein". Biochem. Biophys. Res. Commun. 413 (2): 325–9. doi:10.1016/j.bbrc.2011.08.095. PMID 21889495. S2CID 25816150.
  23. Workman HC, Miller JK, Ingalla EQ, Kaur RP, Yamamoto DI, Beckett LA, Young LJ, Cardiff RD, Borowsky AD, Carraway KL, Sweeney C, Carraway KL (2009). "The membrane mucin MUC-4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells". Breast Cancer Res. 11 (5): R70. doi:10.1186/bcr2364. PMC 2790847. PMID 19761616.
  24. Nam KH, Noh TW, Chung SH, Lee SH, Lee MK, Hong SW, Chung WY, Lee EJ, Park CS (July 2011). "Expression of the membrane mucins MUC4 and MUC15, potential markers of malignancy and prognosis, in papillary thyroid carcinoma". Thyroid. 21 (7): 745–50. doi:10.1089/thy.2010.0339. PMID 21615302.
  25. Doyle LA, Möller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL (May 2011). "MUC-4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma". Am. J. Surg. Pathol. 35 (5): 733–41. doi:10.1097/PAS.0b013e318210c268. PMID 21415703. S2CID 205920712.
  26. López-Ferrer A, Alameda F, Barranco C, et al. (2001). "MUC-4 expression is increased in dysplastic cervical disorders". Hum. Pathol. 32 (11): 1197–202. doi:10.1053/hupa.2001.28938. PMID 11727258.
  27. Shirazi T, Longman RJ, Corfield AP, Probert CS (August 2000). "Mucins and inflammatory bowel disease". Postgrad Med J. 76 (898): 473–8. doi:10.1136/pmj.76.898.473. PMC 1741691. PMID 10908374.
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