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MUC2 and MUC6 apomucins expression in human gastric neoplasm: An

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Med Oncol (2011) 28:S207–S213
DOI 10.1007/s12032-010-9699-5
ORIGINALPAPER
MUC2 and MUC6 apomucins expression in human gastric
neoplasm: an immunohistochemical analysis
Abdul-Zaher M. Khattab • Wesam A. Nasif •
Mahmoud Lotfy
Received: 6 June 2010 / Accepted: 17 September 2010 / Published online: 29 September 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Apomucins play important biological roles in
cell–cell and cell–extracellular matrix interactions, in cell
signaling, and in biological properties of cancer cells. Their
specific pattern of expression during the different steps of
tumor progression toward adenocarcinoma suggests that
they play significant roles in tumorigenesis. The family of
secreted mucins, gel-forming components of viscoelastic
mucus gels protecting the epithelia, includes mucins
MUC2 and MUC6. Their principle function is to contribute
in mucus formation by forming a tridimensional network
via oligomerization domains to protect underlying epithelia
against diverse injuries. The current study was investigated
the expression of MUC2 and MUC6 in patients with gastric
carcinoma. MUC2 and MUC6 expressions were detected
immunohistochemically in gastric cancer biopsies using
specific monoclonal antibodies. The results showed that in
our gastric carcinoma cases, MUC2 expression was
detected in 78.6% of cases. MUC2 expression is increased
from well differentiated to moderately differentiated to
poorly differentiated gastric adenocarcinoma. On the other
hand, MUC6 was detected in 32% of cases. The expression
of MUC2 is increasing, which is accompanied by an altered
A.-Z. M. Khattab
Pathology Department, Faculty of Medicine,
Zagazig University, Zagazig, Egypt
W. A. Nasif
M. Lotfy (&)
Molecular and Cellular Biology Department, Genetic
Engineering and Biotechnology Research Institute, Minufiya
University, P.O. 22857-79, Sadat City, Minufiya, Egypt
e-mail: mlotfy2000@yahoo.com
Present Address:
M. Lotfy
Department of Applied Medical Sciences,
Jouf University, P.O. 1300, Qurayat, Saudi Arabia
expression of MUC6 in gastric cancer. Therefore, it is
concluded that the expression pattern of secreted mucins
including MUC2 and MUC6 is altered apparently in gastric
carcinoma.
Keywords Gastric cancer
Immunohistochemistry

MUC2
MUC6
Introduction
Mucins are high molecular weight glycoproteins consisting
of a mucin core protein (apomucin) and O-linked oligo-
saccharides synthesized by a broad range of epithelial tis-
sues and are coded by MUC genes [1]. Epithelial mucins
in the gastrointestinal tract (GIT) were classified into
two distinct families: secretory gel-forming (MUC2,
MUC5AC, MUC5B, and MUC6) and membrane bound
mucins. Members of each family possess common struc-
tural characteristics and at least some common functions
[2]. In general, mucins have the unique function of pro-
tecting and lubricating epithelial surfaces, but nowadays,
they have also been implicated in additional diverse roles,
such as growth, fetal development, inflammation, epithelial
renewal and differentiation, epithelial integrity, carcino-
genesis, and metastasis [3–5]. Altered expression of mucin
epitopes have been described in colon and stomach cancers
and correlated with decreased survival [6, 7].
The normal gastric mucosa shows cell-type-specific
expression of MUC1, MUC5AC, and MUC6 with the first
two mucins found in the superficial epithelium, while
MUC6 was observed in the deep glands in normal gastric
mucosa restricted to pyloric glands of the antrum and
mucopeptic cells of the neck zone of the body region
[8–10]. The normal gastric mucosa does not express MUC2
123
S208
[11, 12]. MUC2 plays an important role in the differenti-
ation of normal, inflamed, and neoplastic gastric tissues [4].
The two secretory mucins MUC2 and MUC6 have been
reported to be aberrantly expressed during the development
of gastric carcinoma [11]. MUC2 expression has been
related more specifically to the mucinous carcinomas of
WHO classification and to group II of Goseki’s classifi-
cation (high tubular differentiation and high mucin content)
[13, 14]. MUC6 expression was found to decrease in gas-
tric carcinoma [15]. Mucin expression is also altered in the
precancerous condition of gastric carcinoma [16, 17].
MUC1, MUC5AC, MUC6, and MUC2 mucins are coex-
pressed in incomplete intestinal metaplasia, but MUC1,
MUC5AC, and MUC6 mucins are not expressed in com-
plete metaplasia [16, 18, 19]. However, co-expression of
multiple mucins is frequently observed in gastric carcino-
mas [8].
However, a question that remains to be answered is
whether membrane-associated mucins or secretory mucins
have an actual role in carcinogenesis. The expression of
mucin epitopes is frequently modified in carcinomas
mostly because of alterations in glycosylation. Therefore,
immunohistochemical studies using several glycoforms of
mucins have reached conflicting and inconclusive results
concerning the clinical relevance and prognostic signifi-
cance of mucin expression in gastric carcinoma [20].
MUC2 mucin expression in gastric carcinoma has been
thought to be a favorable prognostic factor, but the results
of the relation between MUC2 expression and the patients
overall survival also have remained unclear [21]. The
purpose of the present study was to investigate the
expression pattern of representative secretory mucins
(MUC2 and MUC6) in human chronic gastritis and gas-
tric adenocarcinoma and, moreover, to explore the rele-
vance of this pattern to the key clinicopathological
features.
Patients and methods
Patients
Sampling was performed after informed consent was
obtained from each patient included in the study to use
the samples and clinical data for research purposes after
being informed about the nature of the study. The study
protocol conforms to the most recent ethical guidelines of
the Declaration of Helsinki as reflected in a priori
approval by local ethical committee. It was carried out
during surgical resections for patients with gastric carci-
noma underwent a potentially curative total or partial
gastrectomy. Chronic gastritis samples were collected
during endoscopy. All the information was reviewed such
123
Med Oncol (2011) 28:S207–S213
as age, sex, tumor location, tumor size, histological pro-
liferation, clinical stage, depth of invasion, and metasta-
sis. The current study was pursued on those patients prior
to treatment including neo-adjuvant, radiotherapy and/or
chemotherapy. The cohort comprised 24 men and 10
women with a ratio of 2.4:1. The mean age was
54.7 years old, (range from 37 to 79 years). Formalin-
fixed, paraffin wax-embedded 4-lm sections of gastric
carcinoma samples (N = 28) and chronic gastritis with
intestinal metaplasia (N = 6) were assessed. Staging was
performed based on the international standard TNM
classification [22]. Classification of gastritis was done
according to the revised Sydney classification [23]. The
sections were stained using hematoxylin/eosin and then
examined to confirm the final diagnosis.
Immunohistochemistry
MUC2 and MUC6 expressions were detected by specific
monoclonal antibodies. From each tumor block, 4-lm-
thick sections were cut on neoprene-coated slides. The
immunostaining was performed using the avidin–biotin
complex (ABC) method and an automatic autostainer
(CODE-ON Immuno/DNA slide stainer; Biotek solution,
Santa Barbara, CA). Slides were deparaffinized and
blocked for endogenous peroxidase with 1.75% hydrogen
peroxide in methanol for 20 min. Antigen retrieval was
performed for 15 min using Biogenex Antigen Retrieval
Citra solution in 90°C water bath for 30 min. The slides
were allowed to cool for 20 min before continuing. Slides
were then blocked by normal goat serum for 5 min at
37°C. The monoclonal antibody was applied overnight in
humid medium at room temperature followed by the
biotinylated secondary antibody for 15 min at 37°C and
the ABC complex for 15 min at 37°C (Vectastain Elite
ABC Kit; Vector Laboratories, Burlingame, CA). Diam-
inobenzidine (DAB) was applied for 20 min at room
temperature as chromogen, slides were counterstained
with Mayer’s hematoxylin, dehydrated, and covered by
cover slips. In negative control slides, the same system
was applied with replacement of the monoclonal antibody
by diluted normal bovine serum. All negative control
slides were strictly negative. MUC2 immunostaining was
performed by applying mouse monoclonal antibody
(clone NCL-MUC2, Novocastra Laboratories, Newcastle,
UK) at a dilution of 1:100 and for MUC6 using mono-
clonal antibody (clone NCL-MUC6, Novocastra) at a
dilution of 1:150. Staining results were interpreted as
positive or negative. The analysis was recorded as (?)
(positive cells \25%), (??) (positive cells [25–50%),
(???) (positive cells [50–75%), and (????) (stained
most cells [75%).
Med Oncol (2011) 28:S207–S213
Statistical analysis
The relationships of intestinal metaplasia samples and the
clinicopathological features of gastric cancer with the
expression pattern of MUC2 and MUC6 were analyzed for
significance by chi-square or Fischer exact test as appropri-
ate using SPSS 18 for Windows (SPSS, Chicago, IL, USA).
Statistical significance was considered at P values B 0.05.
Results
Among 34 cases, six were suffering from chronic gastritis
with intestinal metaplasia and the other 28 cases were
suffering from gastric carcinomas. The gastric adenocar-
cinoma lesions were subdivided into 14 well differentiated,
10 moderately differentiated and 4 poorly differentiated.
MUC2 expression was not detected in the normal
mucosa; meanwhile, abundant amount of MUC6 was
detected in the mucous cells in normal gastric mucosa of
the neck zone and antral glands. There was no evidence of
immunoreactivity for MUC2 or MUC6 in the stromal cells
of the tumors. The staining pattern for each mucin in
gastric mucosa undergoing intestinal metaplasia was dis-
tinct. MUC2 staining was very weak and was found only in
the cytoplasm of goblet cells (Fig. 1). Out of six cases of
intestinal metaplasia, four cases (66.7%) were positive for
MUC2. Among this series of 28 gastric carcinomas, there
Fig. 1 a MUC2 staining in intestinal metaplasia (Meyer’s hematox-
ylin counterstain 9200). b MUC2 staining of well-differentiated
gastric carcinoma. c MUC2 staining of moderately differentiated
S209
is a histopathological heterogeneity in the majority of
individual tumors. Immunostaining for MUC2 in gastric
carcinoma was more diffuse pattern in goblet cells. MUC2
positivity was observed in the cytoplasm, in intracellular
mucus vacuoles of tumoral cells, and also in extracellular
mucus (Fig. 1). The overall positivity for MUC2 in gastric
adenocarcinoma was 22 out of 28 samples (78.6%).
On the other hand, the MUC6 was expressed in both
goblet and columnar cells of intestinal metaplasia. The
staining pattern for MUC6 was restricted to the perinuclear
regions of the cells (Fig. 2). The overall reactivity of
MUC6 in intestinal metaplasia was only two cases (33.3%).
As regards MUC6 reactivity in gastric carcinoma, there
was diffuse cytoplasmic pattern in the clusters of the
tumoral cells (Fig. 2), and out of 28, nine cases (32%) were
positive for MUC6 (P = 0.059). Thus, it seems clear that
there was a decrease in the MUC6 expression was followed
by an increase in the expression of MUC2 (Fig. 3). No
significant difference in the expression of mucins MUC2 or
MUC6 was seen in gastric carcinoma among the different
groups of patients studied, with respect to patient sex,
tumor location, invasion, staging, or metastasis. There was
no significant difference in the expression of MUC2 and
MUC6 among the three Lauren types: namely, intestinal,
diffuse, and mixed type (Tables 1, 2).
High intensity of MUC2 immunostaining (in more than
30% of the tumoral cells) was detected in the mucinous
subtype. MUC2 was expressed in 10 out of 14 (71.4%)
gastric carcinoma. d MUC2 staining of poorly differentiated gastric
carcinoma (Meyer’s hematoxylin counterstain 9100)
123
S210
Fig. 2 a MUC6 staining in intestinal metaplasia (Meyer’s hematox-
ylin counterstain 9200). b MUC6 staining of well-differentiated
gastric carcinoma. c MUC6 staining of moderately differentiated
Fig. 3 The positive and negative samples (presented as percent) for
MUC2 and MUC6 expression in patients with gastric cancer
cases of well differentiated, eight out of ten (80%) cases of
moderately differentiated, and four (100%) cases of poorly
differentiated tumors (Fig. 1). Thus, it seems clear that
MUC2 reactivity was increasing with increasing the
123
Med Oncol (2011) 28:S207–S213
gastric carcinoma. d MUC6 staining of poorly differentiated gastric
carcinoma (Meyer’s hematoxylin counterstain 9100)
differentiation grade of gastric adenocarcinoma, despite the
difference is not significant (P [ 0.05). On the other hand,
MUC6 positivity was detected in four (28.6%) cases of
well-differentiated, in three (30%) cases of moderately
differentiated, and in two cases (50%) of poorly differen-
tiated gastric adenocarcinoma (P [ 0.05). Finally, there
was not a significant difference in both MUC2 and MUC6
expression between the intestinal metaplasia and gastric
cancer samples (P [ 0.05).
Discussion
Mucins are high molecular weight glycoproteins that are
involved in regulating diverse cellular activities. Impor-
tantly, in various cancers, burgeoning evidence indicates
that the deregulated expression and structural modifications
of mucins can impact the cancer progression [24]. The
alterations in the composition of mucin-type glycoproteins
were reported in inflammatory and malignant diseases of
the stomach; in the latter, altered carbohydrate and peptide
moieties of mucins may constitute as a significant molec-
ular event [25].
Intestinal metaplasia is one of the lesions identified in
the cascade of events that precedes the development of
gastric carcinoma [26, 27]. Altered mucin expression pat-
terns have been reported previously in intestinal metapla-
sia, including the lower expression level of MUC1,
MUC5AC, and MUC6 [28] and de novo expression of
Med Oncol (2011) 28:S207–S213 S211

Table 1 The relationship between MUC2 expression and the clini- Table 2 The relationship between MUC6 expression and the clini-
copathological features of gastric cancer copathological features of gastric cancer
Variables Total MUC2 (?) MUC2 (-) P value Variables Total MUC6 (?) MUC6 (-) P value
No % No % No % No %

Age (years) Age (years)

B55 13 9 69.2 4 30.8 NS B55 13 3 23.1 10 76.9 NS
C5 15 13 86.7 2 13.3 C55 15 6 40 9 60
Sex Sex
Male 21 15 71.4 6 28.6 NS Male 21 7 33.3 14 66.7 NS
Female 7 7 100 0 0 Female 7 2 28.6 5 71.4
Size (cm) Size (cm)
\5 18 14 77.8 4 22.2 NS \5 18 6 33.3 12 66.7 NS
[5 10 8 80 2 20 [5 10 3 30 7 70
Stage Stage
Stage I & II 13 10 76.9 3 23.1 NS Stage I & II 13 5 38.5 8 61.5 NS
Stage III & IV 15 12 80 3 20 Stage III & IV 15 4 26.7 11 73.3
Tumor site Tumor site
Fundus 4 3 75 1 25 NS Fundus 4 2 50 2 50 NS
Body 6 5 83.3 1 16.7 Body 6 2 33.3 4 66.7
Antrum 18 14 77.8 4 22.2 Antrum 18 5 27.8 13 72.2
Metastasis Metastasis
Present 13 10 76.9 3 23.1 NS Present 13 5 38.5 8 61.5 NS
Absent 15 12 80 3 20 Absent 15 4 26.7 11 73.3
Lymphatic invasion Lymphatic invasion
Present 8 6 75 2 25 NS Present 8 3 37.5 5 62.5 NS
Absent 20 16 80 4 20 Absent 20 6 30 14 70
Tumor types Tumor types
Intestinal 7 5 71.4 2 28.6 NS Intestinal 7 3 42.9 4 57.1 NS
Diffuse 16 12 75 4 25 Diffuse 16 4 25 12 75
Mixed 5 5 100 0 0 Mixed 5 2 40 3 60

NS Non-significant for comparison between positive and negative NS Non-significant for comparison between positive and negative
MUC2 MUC6

MUC2 [29, 30]. In the present study, a distinct staining
pattern was observed for the investigated mucins in intes-
tinal metaplasia. MUC2 expression was detected in 66.7%
of cases with intestinal metaplasia. On the other hand,
MUC6 expression was documented in 33.3% of cases, and
these results are consistent with previous reports [5, 6, and
11]. MUC2 staining was depicted only in goblet cells,
whereas the MUC6 was expressed in both goblet and
columnar cells. Furthermore, MUC6 expression was
restricted to the perinuclear regions of the cells, whereas
MUC2 expression was illustrated in the cytoplasm [31, 32].
Thus, an evident shift in mucin expression was showed in
intestinal metasplasia that was evidenced by the detection
of MUC2 increasing and MUC6 decreasing [6]. In agree-
ment with previous studies [28, 33, 34], it was observed
that the expression of MUC6 in mucous cells of the neck
zone and antral gland. Moreover, MUC2 expression was
not detected in normal gastric mucosa.
In the current study, MUC2 and MUC6 expressions in
gastric carcinoma were documented in 78.6 and 32% of
cases, respectively. The expression of MUC2 and MUC6
was detected in 81 and 39%, respectively, in cases with
gastric carcinomas [35]. Conflicting reports are existed
regarding the frequency of MUC2 and MUC6 expressions
in gastric carcinoma [2, 4, 8, 32, 35], and this discrepancy
may largely due to the antibody specificity [36, 37]. Nev-
ertheless, the trend was a decrease in the MUC6 and an
increase of MUC2 expression. In the present study, no
significant difference was observed between the expression
of MUC2 and MUC6 in gastric carcinomas samples with
the patients and tumor characteristics such as sex, tumor
location, lymphatic invasion, clinical staging, metastasis,
and the three Lauren types, namely intestinal, diffuse, and
mixed type. These findings are comparable with data
obtained by others [2, 8] and in contrast with results
obtained by other investigators [38–40].

123
S212
High intensity MUC2 immunostaining was detected in
poorly differentiated mucinous gastric carcinoma. Reis
et al. [8] described that all gastric carcinomas that were
expressing MUC2 in more than 50% of the cells were of
the mucinous type according to the WHO classification.
MUC2 reactivity was increasing with increasing the grade
of differentiation. The MUC2 expression was not associ-
ated with a particular subtype of gastric carcinoma what-
ever the classification [35]. On the other hand, some
investigators stated that the co-expression of mucins was
correlated with the histomorphological type and stage of
the tumors [8]. The expression of MUC6 in our series was
not significantly associated with any histological type of
the gastric carcinomas, a result in accordance with previous
studies [16, 34]. In agreement with Leteurtre et al. [35], no
statistical difference was detected between MUC6 reac-
tivity and histologic grade of gastric adenocarcinoma.
There are many reports that correlate the expressions of
MUC2 and MUC6 with the poor prognosis in gastric car-
cinoma, and other reports showed no correlation [41–43].
The importance of mucins in GIT tumorigenesis was
obtained from mucin knockout mice experiments. It was
found that the loss of MUC2 in the intestine leads to an
abnormal morphology marked by an increase in thickness
of the gut mucosa, flattening and ulceration of epithelial
cells, general loss of architecture, a mild increase in
inflammatory cells, and an increase in proliferation. Fur-
thermore, It was showed that changes in the mucus com-
position, caused by MUC2 deficiency, lead to inflammation
of the colon and that deficiency of MUC2 contributes to the
onset and/or perpetuation of inflammatory bowel diseases
[44]. Moreover, in a more recent study, it was documented
that the MUC2 gene deficiency in mice impairs host
resistance to an enteric parasitic infection [45]. Alterations
or absence of MUC2 production can lead to colon carci-
noma [46], ulcerative colitis [47], and celiac disease [48].
In conclusion, our results revealed that the expression
pattern of the secreted mucins including MUC2 and MUC6
is altered apparently in gastric carcinoma, and such
molecular alteration is a potential event in gastric tumori-
genesis. Nevertheless, these findings will be confirmed in a
future study based mainly on large number of patients with
gastric cancer.
Conflict of interest None Declared.
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