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MUC13 (mucin 13, cell surface associated)
Diane Maher, Brij Gupta, Mara Ebeling, Satoshi Nagata, Meena Jaggi, Subhash C Chauhan
Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57105,
USA (DM, BG, ME, SN, MJ, SCC); Department of OB/GYN, and Basic Biomedical Science Division,
Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA (MJ, SCC)
Published in Atlas Database: January 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/MUC13ID41454ch3q21.html
DOI: 10.4267/2042/44884
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: DRCC1; FLJ20063; MUC-13; RECC
HGNC (Hugo): MUC13
Location: 3q21.2
Note: MUC13 is a membrane bound mucin exhibiting
abundant O- and N-glycosylation. The aberrant
expression and localization of MUC13 may be
involved in cancer pathobiology and could be a
potential diagnostic/prognostic biomarker of cancer as
well as a target for antibody guided therapy for cancer
treatment.
Description
Human MUC13 was originally identified as a ortholog
of the previously identified murine MUC13 (Williams
et al., 2001). Based on fluorescence in situ
hybridization, MUC13 was originally identified at
location 3q13.3 (Williams et al., 2001); however,
MUC13 is now reported to be located on chromosome
3; location 3q21.2, MUC13 is flanked by ITGB5 (beta
5 integrin) and HEG-1 (Heart of Glass), each
transcribed from the reverse strand.
Schematic diagram of the genomic MUC13 DNA (including neighboring genes) and the transcript of MUC13. MUC13 is located on
chromosome 3 between ITGB5 and HEG-1. These 3 genes are transcribed from the reverse strand. The MUC13 transcript contains 12
exons and the final mRNA consists of 2,876 base pairs (Figure modified from Ensembl).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
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MUC13 (mucin 13, cell surface associated)
Maher D, et al.
Interestingly, HEG and MUC13 share some molecular
features, suggesting they may be evolutionarily related
(Lang et al., 2006).
invasion of the cancer cells (Hollingsworth and
Swanson, 2004).
Description
Transcription
MUC13 is a recently identified membrane bound
mucin (Williams et al., 2001). At the N-terminus, a
signal peptide shuttles the protein into the secretary
pathway. The signal peptide is followed by a large
serine-threonine rich tandem repeat domain (TD).
Composed of 10 degenerate tandem repeats, the tandem
repeat domain provides a scaffold on which cells build
oligosaccharide structures. O-glycosylation with
complex oligosaccharides is crucial to mucin structure
and function. The central region of MUC13 contains
three epidermal growth factor (EGF)-like domains
(EGF1, EGF2 and EGF3), suggesting that MUC13 may
play an important role in a signaling cascade. A sea
urchin sperm protein enterokinase arginine (SEA)
module is present between EGF1 and EGF2 like
domains, providing a cleavage site which separates
MUC13 into an extracellular a subunit and a
transmembrane beta subunit.
It is expected that the SEA domain is cleaved while in
transport to the cell surface and that after cleavage, the
alpha and beta subunits are covalently bound together.
Adjacent to the EGF3-like domain is a short
transmembrane domain (TM), followed by a 69 amino
acid long cytoplasmic domain (CD) (Williams et al.,
2001; Shimamura et al., 2005).
The predominate MUC13 transcript (exact match
between Ensembl and Havana) contains 12 exons and
encodes 511 amino acids. Splice variants have been
detected and may alter the length of the tandem repeat
domain (Lang et al., 2006); however they have not
been well studied for MUC13.
Protein
Note
Members of the mucin family are characterized by a
hallmark feature: the presence of a tandem repeat
domain, consisting of a protein backbone which acts as
a scaffold for a large number of complex O-linked
carbohydrate side chains (Williams et al., 2001). In
general, mucins have important biological roles in the
lubrication and protection of normal epithelial tissues.
In normal tissue, mucins are expressed in a tissue type
dependent manner; however, for many types of cancer,
mucin expression becomes altered (down-regulated,
up-regulated or newly expressed). The mucin's
ectodomain may protrude more than 200-2000 nm
above the cell surface and can effectively block cellcell adhesion. Therefore, the over-expression of mucins
may be implicated in the exfoliation, dissemination and
Schematic diagram and annotated amino acid sequence of MUC13. Left: a schematic diagram shows the structural features of
MUC13, highlighting the signal peptide, mucin repeat domain, SEA module, EGF-like domains, transmembrane region and the
cytoplasmic domain. Right: The annotated amino acid sequence shows the extensive post-translation modifications that MUC13
undergoes (O-glycosylation, N-glycosylation and predicted disulfide bonds). The signal peptide, SEA module and Transmembrane
sequences are indicated by pink, red and green font, respectively.
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MUC13 (mucin 13, cell surface associated)
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Within the cytoplasmic domain of MUC13, there are
several potential phosphorylation sites (8 serine and 2
tyrosine residues) and a protein kinase C consensus
phosphorylation motif, further supporting the
hypothesis that MUC13 may be involved in cell
signaling pathways.
diagnosed with ovarian cancer and 14600 women will
die due to this disease (Jemal et al., 2009). A high
percent of women with ovarian cancer are diagnosed at
an advanced stage (67%) and have a 5 year survival
rate of only 46% (Jemal et al., 2009).
Oncogenesis
In a recently published report, we analyzed the
expression profile and functions of MUC13 to elucidate
its potential role in ovarian cancer diagnosis and
pathogenesis. We determined the expression profile of
MUC13 by immunohistochemistry, using ovarian
cancer tissue microarrays and 56 additional epithelial
ovarian cancer (EOC) samples. The expression of
MUC13 was significantly (p<0.005) higher in cancer
samples compared to the normal ovary/benign tissues.
Among all ovarian cancer types, MUC13 expression
was highest in EOC. Exogenous expression of full
length MUC13 induced morphological changes,
including scattering of cells, marked reduction in cellcell adhesion and significant (p<0.05) increases in cell
motility and proliferation. Additionally, we observed
increased tumorigenesis in a xenograft mouse model
system. These cellular characteristics were correlated
with up-regulation of HER2, p21-activated kinase1
(PAK1) and p38 protein expression. These changes
were abrogated through c-jun NH2-terminal kinase
(JNK) chemical inhibitor (SP600125) or JNK2 siRNA.
Our findings demonstrate the aberrant expression of
MUC13 in ovarian cancer and show that its expression
alters the cellular characteristics of SKOV-3 cells. This
implies a significant role of MUC13 in ovarian cancer.
Expression
Among normal tissues, MUC13 mRNA and/or protein
has been detected in the large intestine, trachea, kidney,
small intestine, gastric epithelium and esophagus
(Williams et al., 2001). MUC13 is normally localized
to the apical surface of epithelial cells lining the
mucosal surface. In ovarian, gastric and colon cancers,
MUC13
expression
(determined
by
immunohistochemical analysis) is increased compared
to expression levels of non-neoplastic tissues
(Shimamura et al., 2005; Walsh et al., 2007; Chauhan
et al., 2009).
Localisation
MUC13 is a transmembrane glycoprotein present at the
apical surface in normal cells. In cancer cells, MUC13
is over-expressed and aberrantly located in the
cytoplasm and occasionally in the nucleus (Williams et
al., 2001; Chauhan et al., unpublished data).
Function
Under normal physiological conditions, mucins,
including MUC13, protect the epithelial surface of
mucosal surfaces (gastrointestinal tract, respiratory
tract and reproductive tract). Mucins create a physical
barrier from the extracellular environment and protect
epithelial tissues from noxious and toxic substances.
When aberrantly expressed, MUC13 has oncogenic
functions which are described below.
Colon cancer
Disease
Colon cancer is the third leading cause of cancer
related deaths among men and women worldwide, with
an estimated 639000 deaths in 2004 (WHO, 2009). In
the United States in 2009, approximately 106000
people were diagnosed with colon cancer and 49900
people died, making colon cancer the second leading
cause of deaths among all cancers (Jemal et al., 2009).
Colon cancer has an overall survival rate of 49%,
which is drastically dependent on the stage of diagnosis
(Jemal, et al., 2009). For example, if colon cancer is
detected in an early stage, prior to metastasis, survival
is 90%; however, if colon cancer is not treated until an
advanced stage (with metastasis to distant organs),
survival decreases to approximately 10% (Jemal et al.,
2009).
Oncogenesis
Walsh et al studied the expression of MUC13 in
various stages of colon cancer (99 samples) (Walsh et
al., 2007). Using immunohistochemical analysis,
MUC13 was detected predominantly on the apical
surface, with some cytoplasmic staining, of glands in
normal colon. Scoring of the normal tissue was not
done for this study, so it is difficult to state a
comparison of MUC13 staining between normal and
Homology
MUC13 is known to have orthologs in mice, rats,
chickens, dogs, cows, chimpanzees and even fish
(Williams et al., 2001; Lang et al., 2006; NCBI:
homologene). Additional putative orthologs are likely
in a variety of different species and can be viewed via
Ensembl.
Mutations
Note
While a variety of Single Nucleotide Polymorphisms
(SNPs) have been identified, the clinical significance
has not yet been determined (NCBI: SNPs).
Implicated in
Ovarian cancer
Disease
Ovarian cancer is the most lethal gynecological cancer
and the fifth most common cause of cancer mortality in
women in the United States (Jemal et al., 2009). In
2009, it is estimated that 21550 women will be
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
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MUC13 (mucin 13, cell surface associated)
Maher D, et al.
tissues. However, MUC13 staining in gastric cancer
tissue was positive in 64.9% of cases and the cellular
localization of MUC13 was dependent upon the
histological type of gastric cancer. MUC13 was also
detected in 9 out of 10 cases of intestinal metaplasia
(precancerous lesions of intestinal type gastric cancer).
When correlated with clinicopathological factors,
MUC13 expression only correlated significantly with
intestinal types of gastric cancer. MUC13 expression
did not correlate with the expression of other mucins
(MUC2, MUC5AC, MUC6 and CD10), suggesting that
MUC13 may be regulated in a different manner then
other mucins markers for gastric cancer (Shimamura et
al., 2005).
cancer cells. However, MUC13 was highly expressed
in most of the colon tumors, with 81% of well
differentiated adenocarcinomas exhibiting strong
MUC13 staining. Interestingly, although the
significance is not yet known, this study also found that
tumors originating from the left side of the patient's
body had a higher proportion of MUC13-positive
cancer cells. Mucinous tumors expressed MUC13, but
at a lower staining intensity (50% indicating strong
staining) compared to adenocarcinomas. While MUC13
was most intense on the apical surface, it was also
detected in the cytoplasm. Basolateral staining was
detected in 24% of the cases, most frequently in poorly
differentiated tumors (55% of poorly differentiated
tumors showed basolateral staining). Although not
statistically significant, there was a trend toward poorer
survival in patients with tumors showing basolateral
MUC13 expression. Taken together, these observations
suggest aberrant expression of MUC13 may affect
colon cancer pathogenesis. In contrast to these results,
Packer et al reported that the RNA level of MUC13
was decreased in colon cancer; however this was a
small study with only 23 samples of colon cancer and 6
normal colon tissues (Packer et al., 2004). In our own
studies, we have observed the over-expression of
MUC13 in colon and pancreatic cancer compared to
normal colon and pancreas (unpublished data). Taken
together, these data suggest that MUC13 may be a
potential diagnostic/prognostic biomarker for colon,
pancreatic and ovarian cancers. Additionally, due to its
cell surface expression, MUC13 may be a suitable
target for antibody guided therapy for cancer treatment.
References
Williams SJ, Wreschner DH, Tran M, Eyre HJ, Sutherland GR,
McGuckin MA. Muc13, a novel human cell surface mucin
expressed by epithelial and hemopoietic cells. J Biol Chem.
2001 May 25;276(21):18327-36
Hollingsworth MA, Swanson BJ. Mucins in cancer: protection
and control of the cell surface. Nat Rev Cancer. 2004
Jan;4(1):45-60
Packer LM, Williams SJ, Callaghan S, Gotley DC, McGuckin
MA. Expression of the cell surface mucin gene family in
adenocarcinomas. Int J Oncol. 2004 Oct;25(4):1119-26
Shimamura T, Ito H, Shibahara J, Watanabe A, Hippo Y,
Taniguchi H, Chen Y, Kashima T, Ohtomo T, Tanioka F,
Iwanari H, Kodama T, Kazui T, Sugimura H, Fukayama M,
Aburatani H. Overexpression of MUC13 is associated with
intestinal-type gastric cancer. Cancer Sci. 2005 May;96(5):26573
Lang T, Hansson GC, Samuelsson T. 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. BMC Genomics. 2006
Aug 3;7:197
Gastric cancer
Disease
Gastric cancer is the second most common cause of
cancer related deaths worldwide, accounting for
approximately 803000 deaths each year (WHO, 2009).
In the United States, 21130 people were diagnosed with
gastric cancer and 10620 died due to gastric cancer
(Jemal et al., 2009). When diagnosed with localized
gastric cancer, the survival rate is approximately 60%;
however, if gastric cancer has metastasized to distant
sites, the survival rate is very low (4%) (Jemal et al.,
2009).
Oncogenesis
Shimamura et al detected an increased expression of
MUC13 at both mRNA and protein levels (Shimamura
et al., 2005). In normal tissue, MUC13 protein was
detected at the luminal surface of crypts in both the
small and large intestines, but not in normal gastric
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
Walsh MD, Young JP, Leggett BA, Williams SH, Jass JR,
McGuckin MA. The MUC13 cell surface mucin is highly
expressed by human colorectal carcinomas. Hum Pathol. 2007
Jun;38(6):883-92
Chauhan SC, Vannatta K, Ebeling MC, Vinayek N, Watanabe
A, Pandey KK, Bell MC, Koch MD, Aburatani H, Lio Y, Jaggi M.
Expression and functions of transmembrane mucin MUC13 in
ovarian cancer. Cancer Res. 2009 Feb 1;69(3):765-74
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer
statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
This article should be referenced as such:
Maher D, Gupta B, Ebeling M, Nagata S, Jaggi M, Chauhan
SC. MUC13 (mucin 13, cell surface associated). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(11):1020-1023.
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