MUC6 (mucin 6, oligomeric mucus/gel-forming)

2009-12-01 Lara Cobler , Marta Garrido , Carme de Bolós Affiliation

Programa de Recerca en Cancer, IMIM-Hospital del Mar, Dr Aiguader, 88, 08003, Barcelona, Spain

Identity

HGNC

MUC6

LOCATION

11p15.5

IMAGE

LEGEND

Location of MUC6 gene.

LOCUSID

4588

ALIAS

MUC-6

FUSION GENES

Show Gene Fusions

DNA/RNA

Genomic organization of MUC6 gene (not to scale).

Description

MUC6 gene approximately extends 24 kb-long on the chromosome 11 in the region p15.5. The central region has sequences repeated in tandem (TR) with a consensus motif composed of 507 pb. The variable number of TR (VNTR) diverges between 15 and 26, and the difference in distinct alleles is 5 kb long. Some data suggest that short MUC6 alleles are associated with Helicobacter pylori infection and gastric cancer.

Transcription

MUC6 gene is composed of 33 exons and the mRNA length is approximately 8 kb. The 5 flanking region of the MUC6 gene contains a TATA box at -35/-29 and potential transcription factor binding sites are described for NFkappaB and Sp family members.
Although MUC6 promoter contains a high percentage of CpG dinucleotides (up to 75%) and a CpG island, its regulation is not influenced by epigenetics.
At present no splice variants forms have been reported.

Proteins

Schematic representation of MUC6 peptide structure (not to scale).

Description

At the N-terminal region D1, D2, D and D3 domains similar to von Willebrand factor (vWF) are present.
The TR domain composes the central region. The 169 amino acid consensus sequence has a high content of Thr-Ser-Pro containing numerous potential O-glycosilation sites.
The C-terminal region consists in two distinct regions. One with a high Thr-Ser-Pro content (STP domain), very similar to the tandem repeat region in amino acid composition, and the other region that has a high content of cystein residues. This domain has approximately 25% similarity to the CK domain of the 11p15 human mucins MUC2, MUC5AC, MUC5B and the vWF.

Expression

MUC6 was initially isolated from a gastric cDNA library, and it is expressed in the deep gland cells. It is the only mucin produced by acinar cells of the duodenal Brüners glands and it is also expressed in pancreas, endocervix and gallbladder.
Under pathological conditions, MUC6 expression can be altered, as it is reported below.

Function

MUC6, together with MUC5AC, is the major component of the protective layer over the gastric surface where it acts as a selective diffusion barrier for HCl. Furthermore, the O-glycans found in the MUC6 TR have antimicrobial activity against Helicobacter pylori, inhibiting the biosynthesis of cholesteryl-alpha-D-glucopyranoside, a major cell wall component.

Homology

Several orthologues of MUC6 have been identified in Mus musculus, Rattus norvegicus, Pan troglodytes and Equus caballus. The chicken and mouse Muc6 have similar domain structures with human MUC6. Furthermore, the tissue-specific expression is conserved in murine organisms.

Implicated in

Entity name

Gastric cancer

Disease

Gastric cancer remains the second leading cause related death and the fourth most common cancer in the world, although its incidence is gradually decreasing.

Prognosis

MUC6 is highly expressed in gastric mucosa and in intestinal metaplasia MUC6 levels are decreased: In incomplete metaplasia and type I complete metaplasia MUC6 is not detected, whereas it is found in type II and type III complete intestinal metaplasia. MUC6 expression is lower in intestinal-type of gastric carcinomas than in adenomas or normal mucosa suggesting that the downregulation of MUC6 may contribute to the malignant transformation of gastric epithelial cells.
MUC6 is expressed in diffuse-type gastric carcinoma and its levels are greater in early carcinomas than in advanced carcinomas, showing no relationship with the depth of the carcinoma cells invasion.

Entity name

Colon cancer

Disease

Colorectal cancer is one of the commonest cancers and the third leading cause of cancer death. However, its incidence has decreased due to a most effective intervention and life-style changes in the western countries.

Prognosis

Although in normal colon mucosa MUC6 is not expressed, it is upregulated through the adenoma-carcinoma sequence, together with the downregulation of MUC2.

Entity name

Salivary glands tumors

Disease

Salivary gland tumors are relatively uncommon. However, mucoepidermoid carcinoma is the most frequent malignant tumor of salivary glands.

Prognosis

Normal salivary glands do not express MUC6 whereas in mucoepidermoid carcinomas MUC6 is detected preferentially in mucous cells.

Entity name

Esophagus adenocarcinoma

Disease

The frequency of adenocarcinoma of the esophagus is increasing in the western world from a result of a higher prevalence in Barretts mucosa.

Prognosis

MUC6 showed a decrease in expression with progression from Barretts esophagus to dysplasia and to adenocarcinoma.

Entity name

Pancreatic cancer

Disease

Pancreas cancer is a very aggressive tumor with a 5-year survival of less than 5%, and approximately 85% of them correspond to ductal adenocarcinomas.

Prognosis

In normal pancreatic epithelium MUC6 is only expressed in ductal and in a minority of centroacinar cells. However, it is upregulated at early stages of pancreatic carcinogenesis and in pancreatic cancer. MUC6 expression has been related to clinicopathological factors and patient prognosis and survival in invasive ductal carcinoma.

Entity name

Biliary tract cancer

Disease

Biliary tract carcinomas are uncommon tumors that include cholangiocarcinomas and gallbladder carcinomas. These tumors have a poor prognosis: more than 80% of the patients are unresectable with a 6-9 month survival, and this rate is increased to 5 year after surgery.

Prognosis

MUC6 is expressed in normal gallbladder mucosa. However in adenomas, dysplasias and carcinomas, MUC6 tends to decrease and its expression is related to non-invasive growth. MUC6 is expressed frequently in pseudopyloric gland metaplasia as well as dysplasia and carcinoma.

Entity name

Lung cancer

Disease

Lung cancer is the leading cause of cancer-related mortality worldwide. Despite of this its incidence is decreasing.

Prognosis

MUC6 is not expressed in normal respiratory epithelium, but it has been focally detected in normal and distal epithelium from cancer patients. MUC6 levels increase significantly in the progression from atypical adenomatous hyperplasia, through bronchio alveolar carcinoma, to adenocarcinoma with mixed subtypes, suggesting that its expression might be associated with the progression of the lung adenocarcinoma. No expression of MUC6 is found in squamous lesions.

Entity name

Breast cancer

Disease

Breast cancer is the most common cancer worldwide and the leading cause of cancer mortality in women.

Prognosis

MUC6 is generally not detected in normal breast epithelium but it is overexpressed in benign breast disease (fibrocystic disease without atypia and atypical fibrocystic disease) and in breast carcinoma.

Entity name

Endometrial adenocarcinoma

Disease

Endometrial carcinoma is the most common malignant neoplasm of the female genital tract in developed countries, and it occurs predominantly after menopause.

Prognosis

MUC6 is not expressed in normal endometrial epithelium. However during endometrial neoplasia transformation, increased levels of MUC6 are detected: from simple hyperplasia, to complex hyperplasia, and in endometrial adenocarcinomas a MUC6 upregulation is found.

Entity name

Uterine cervix adenocarcinoma

Disease

Adenocarcinoma is the second most common malignancy of the uterine cervix. Its incidence has been increasing and constitutes 10-20% of invasive cervical cancers.

Prognosis

Although MUC6 is not expressed in normal cervical epithelium, in adenocarcinomas from uterine cervix; MUC6 can be detected at different levels associated to the histological type.

Bibliography

Pubmed ID	Last Year	Title	Authors
17197898	2007	Mucin genes (MUC2, MUC4, MUC5AC, and MUC6) detection in normal and pathological endometrial tissues.	Alameda F et al
15897748	2005	Expression of membrane-bound mucins (MUC1 and MUC4) and secreted mucins (MUC2, MUC5AC, MUC5B, MUC6 and MUC7) in mucoepidermoid carcinomas of salivary glands.	Alos L et al
16487661	2006	Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases.	Andrianifahanana M et al
15151204	2004	Expression of MUC1, MUC2, MUC5AC, and MUC6 in atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, adenocarcinoma with mixed subtypes, and mucinous bronchioloalveolar carcinoma of the lung.	Awaya H et al
10209489	1998	The MUC6 secretory mucin gene is expressed in a wide variety of epithelial tissues.	Bartman AE et al
1448168	1992	Viscous fingering of HCl through gastric mucin.	Bhaskar KR et al
11101634	2000	Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. I. Stomach. A relationship to gastric carcinoma.	Buisine MP et al
17401217	2007	Mucin expression profile in Barrett's, dysplasia, adenocarcinoma sequence in the esophagus.	Burjonrappa SC et al
15260848	2004	Phenotypic alterations of mucins and cytokeratins during gallbladder carcinogenesis.	Chang HJ et al
11274635	2001	Mucinous bronchioloalveolar carcinomas display a specific pattern of mucin gene expression among primary lung adenocarcinomas.	Copin MC et al
7657100	1995	MUC6 apomucin shows a distinct normal tissue distribution that correlates with Lewis antigen expression in the human stomach.	De Bolós C et al
14984930	2004	The mouse secreted gel-forming mucin gene cluster.	Escande F et al
9419405	1997	MUC6 gene polymorphism in healthy individuals and in gastric cancer patients from northern Portugal.	Garcia E et al
16803685	2006	CDX2 expression is increased in gastric cancers with less invasiveness and intestinal mucin phenotype.	Ha Kim G et al
15235131	2003	Expression of MUC5AC and MUC6 in invasive ductal carcinoma of the pancreas and relationship with prognosis.	Jinfeng M et al
15310903	2004	Natural antibiotic function of a human gastric mucin against Helicobacter pylori infection.	Kawakubo M et al
16887038	2006	An inventory of mucin genes in the chicken genome shows that the mucin domain of Muc13 is encoded by multiple exons and that ovomucin is part of a locus of related gel-forming mucins.	Lang T et al
11152646	2001	Mucins as differentiation markers in bronchial epithelium. Squamous cell carcinoma and adenocarcinoma display similar expression patterns.	López-Ferrer A et al
15143335	2004	Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and 'adenoma malignum'.	Mikami Y et al
14623937	2003	Expression of gastric gland mucous cell-type mucin in normal and neoplastic human tissues.	Nakajima K et al
17009402	2006	Short mucin 6 alleles are associated with H pylori infection.	Nguyen TV et al
19639217	2009	Expression of MUC1, MUC2, MUC5AC and MUC6 in cholangiocarcinoma: prognostic impact.	Park SY et al
11253133	2001	Immunohistochemical study of the expression of MUC5AC and MUC6 in breast carcinomas and adjacent breast tissues.	Pereira MB et al
8975711	1996	Human mucin genes assigned to 11p15.5: identification and organization of a cluster of genes.	Pigny P et al
10681391	2000	Immunohistochemical study of the expression of MUC6 mucin and co-expression of other secreted mucins (MUC5AC and MUC2) in human gastric carcinomas.	Reis CA et al
15979574	2005	Upregulation of MUC6 mucin gene expression by NFkappaB and Sp factors.	Sakai H et al
10227723	1999	Expression of MUC2, MUC5AC and MUC6 apomucins in carcinoma, dysplasia and non-dysplastic epithelia of the gallbladder.	Sasaki M et al
9195947	1997	The carboxyl-terminal sequence of the human secretory mucin, MUC6. Analysis Of the primary amino acid sequence.	Toribara NW et al
9544852	1998	Variable number tandem repeat polymorphism of the mucin genes located in the complex on 11p15.5.	Vinall LE et al
17471237	2007	Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells.	Vincent A et al
16456183	2006	Regulation of mucin genes in chronic inflammatory airway diseases.	Voynow JA et al
16807756	2006	MUC6 down-regulation correlates with gastric carcinoma progression and a poor prognosis: an immunohistochemical study with tissue microarrays.	Zheng H et al
11578953	2001	Regulation of mucin and glycoconjugate expression: from normal epithelium to gastric tumors.	de Bolos C et al

Other Information

Locus ID:

NCBI: 4588
MIM: 158374
HGNC: 7517
Ensembl: ENSG00000184956

Variants:

dbSNP: 4588
ClinVar: 4588
TCGA: ENSG00000184956
COSMIC: MUC6

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000184956	ENST00000421673	Q6W4X9
ENSG00000184956	ENST00000525923	E9PJC5
ENSG00000184956	ENST00000527242	H0YEZ6
ENSG00000184956	ENST00000532016	H0YDA7

Expression (GTEx)

100

150

200

250

300

350

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
O-linked glycosylation	REACTOME	R-HSA-5173105
O-linked glycosylation of mucins	REACTOME	R-HSA-913709
Termination of O-glycan biosynthesis	REACTOME	R-HSA-977068
Disease	REACTOME	R-HSA-1643685
Diseases of glycosylation	REACTOME	R-HSA-3781865
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
C-type lectin receptors (CLRs)	REACTOME	R-HSA-5621481
Dectin-2 family	REACTOME	R-HSA-5621480
Diseases associated with O-glycosylation of proteins	REACTOME	R-HSA-3906995
Defective C1GALT1C1 causes Tn polyagglutination syndrome (TNPS)	REACTOME	R-HSA-5083632
Defective GALNT3 causes familial hyperphosphatemic tumoral calcinosis (HFTC)	REACTOME	R-HSA-5083625
Defective GALNT12 causes colorectal cancer 1 (CRCS1)	REACTOME	R-HSA-5083636

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
12360467	2002	Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas.	70
23446997	2013	Aberrant expression of mucin core proteins and o-linked glycans associated with progression of pancreatic cancer.	55
17471237	2007	Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells.	43
23807779	2013	Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype.	43
11988092	2002	Gastric MUC5AC and MUC6 are large oligomeric mucins that differ in size, glycosylation and tissue distribution.	37
16475027	2005	MUC1, MUC2, MUC4, MUC5AC and MUC6 expression in the progression of prostate cancer.	35
19682628	2009	Mucin 6 in seminal plasma binds DC-SIGN and potently blocks dendritic cell mediated transfer of HIV-1 to CD4(+) T-lymphocytes.	26
20139757	2010	Preferential expression of MUC6 in oncocytic and pancreatobiliary types of intraductal papillary neoplasms highlights a pyloropancreatic pathway, distinct from the intestinal pathway, in pancreatic carcinogenesis.	26
19924550	2010	A comprehensive analysis of common genetic variation in MUC1, MUC5AC, MUC6 genes and risk of stomach cancer.	22
21851820	2011	MUC6 mucin expression inhibits tumor cell invasion.	22

Citation

Lara Cobler ; Marta Garrido ; Carme de Bolós

MUC6 (mucin 6, oligomeric mucus/gel-forming)

Atlas Genet Cytogenet Oncol Haematol. 2009-12-01

Online version: http://atlasgeneticsoncology.org/gene/44115/muc6