J. Biomedical Science and Engineering, 2011, 4, 483-489
doi:10.4236/jbise.2011.47061 Published Online July 2011 (http://www.SciRP.org/journal/jbise/
JBiSE
).
Published Online July 2011 in SciRes. http://www.scirp.org/journal/JBiSE
The clinical significance of CD97, NF-kB and COX-2 in
gastric MALT lymphomas
Shao-Liang Han*, Jun Cheng, Xiu-Ling Wu, Zeng-Rong Jia, Peng-Fei Wang, Zhan-Wei Wang
Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.
Received 12 August 2010; revised 9 September 2010; accepted 20 October 2010.
ABSTRACT
Background and Objectives: Increased expression of
the CD97, nuclear factor-kB (NF-kB) and cyclooxy-
genase-2 (COX-2) has been found to play an impor-
tant role in development of many cancers, including
gastric neoplasm. However, the expression and bio-
logical behavior of CD97, NF-kB and COX-2 in gas-
tric MALT (mucosa-associated lymphoid tissue)
lymphoma has not been well investigated. Methods:
The expressions of CD97, COX-2 and NF-kB in 47
cases of gastric MALT lymphoma were detected im-
munohistochemically, and the relevance between
their expressions and the biological behavior was
analyzed retrospectively. Results: 1) The expressions
of CD97, NF-kB and COX-2 were 87.2%, 36.2% and
48.9%, respectively; 2) The difference of CD97 ex-
pression between depth of invasion limited in mucosa
and submucosa and beyond muscularis propria was
significant (100.0% vs. 71.4%, P < 0.01). Moreover,
the expression of nuclear CD97 between stage IIE, III,
IV and stage I patients showed significant difference
(96.4% vs. 73.7%, P < 0.05); 3) The expression of
NF-kB was significantly correlated with tumor size,
depth of invasion and stage; 4) The expression of
COX-2 was significantly correlated with Helicobacter
pylori infection, clinical stage, depth of invasion
and tumor size (P < 0.05). Conclusions: Expressions
of CD97, NF-κB and COX-2 were correlated with
tumor invasion and metastasis in gastric MALT lym-
phoma.
Keywords: Stomach Neoplasm; CD97; Nuclear
Factor-Kb (NF-Kb); Cyclooxygenase-2 (COX-2); Mu-
cosa-Associated Lymphoid Tissue (MALT) Lymphoma
1. INTRODUCTION
Gastric mucosa associated lymphoid tissue (MALT)
lymphoma has recently been incorporated into the World
Health Organization (WHO) lymphoma classification,
termed as extranodal marginal zone B-cell lymphoma of
MALT-type [1,2]. Low grade gastric MALT lymphoma
is a neoplasia with a very indolent course and an excel-
lent prognosis, and it has a tendency to remain localized
to the gastric wall and seldom involve lymph nodes and
bone marrow [1-5]. As with other malignancies, the ac-
cumulation of genetic abnormalities is required for ma-
lignant transformation of human lymphocytes.
CD97 is known as a leukocyte-restricted, cell surface
glycoprotein expressed constitutively by human granu-
locytes, monocytes, and, at low levels, resting T and B
cells [6], and it regulates the expression of genes that are
involved in inflammation, cell proliferation, and apop-
tosis [7]. Recent studies suggest that CD97 expression
correlates with tumor dedifferentiation, migration, and
invasion in many tumors, such as thyroid, colorectal, and
gastric cancer [8-15]. Furthermore, CD97 has features of
a multifunctional protein that may play a role in signal
transduction associated with the development or estab-
lishment of the inflammatory processes [6,7]. However,
CD97 has never been systemically investigated in gastric
MALT lymphoma.
Nuclear factor kappa B (NF-kB), a transcription factor,
plays an important role in carcinogenesis as well as in
the regulation of immune and inflammatory responses,
and it induces the expression of diverse target genes that
promote cell proliferation, regulate apoptosis, facilitate
angiogenesis and stimulate invasion and metastasis
[16-25]. And the transcription factor NF-kB is a tightly
regulated positive mediator of T- and B-cell develop-
ment, proliferation, and survival [16-22,24,26-29]. Vari-
ous molecular events lead to deregulation of NF-kB sig-
naling in Hodgkin disease and a variety of T- and B-cell
non-Hodgkin lymphomas either up-stream or down-
stream of the central IkppaB kinase. These alterations
are prerequisites for lymphoma cell cycling and block-
age of apoptosis.
Epidemiological and clinical studies demonstrated a link
between gastric MALT lymphoma and chronic infection

S.-L. Han et al. / J. Biomedical Science and Engineering 4 (2011) 483-489 484
with Helicobacter pylori (H pylori) [30]. Cyclooxy-
genase-2 (COX-2) is one of important enzymes that medi-
ate inflammatory processes. In recent years, it has been
demonstrated that both COX-2 play an important role in
various tumors, including gastric lymphoma [3,31-36].
Cyclooxygenase-2 (COX-2) is a key biosynthetic enzyme
of COX enzyme family, which is the rate-limiting enzyme
for prostaglandin H synthesis. It is an inducible enzyme,
and normally absent in cells, but its expression is rapidly
and transiently induced in response to growth factors, tu-
mor promoters or cytokines, and it has an important role in
the development and progression of various malignancies
[31-34,36]. COX-2 has been studied in solid tumors;
however, there is little data on the potential role of COX-2
in gastric MALT lymphoma pathogenesis. In this study, we
conducted to determine the expressions of CD97, NF-kB
and COX-2 with the clinicopathological data in 47 gastric
MALT lymphomas and 10 adjacent mucosal specimens by
using immunohistochemistry.
2. MATERIAL AND METHODS
2.1. Patients and Specimens
A total of 47 Chinese patients with gastric MALT lym-
phoma, who were treated surgically from January 1994 to
May 2007 at the University Hospital of Wenzhou Medical
College, participated in this study. All the patients were
pathologically confirmed as low grade gastric MALT
lymphoma. The diagnosis of low grade gastric MALT
lymphoma was made according to the criteria of Isaacson
[1,2], which are composed of centrocyte-like cells, lym-
phoid follicles and plasma cell differentiation, and scoring
system of Wotherspoon et al. [5], and the stains of immu-
nohistochemical markers, such as leukocyte common an-
tigen (LCA), L26, CD5 and CD10 was performed. The
initial staging procedures included a complex physical
examination, chest roentgenogram, bone marrow examina-
tion, abdominal CT scan and endoscopy. Normal gastric
mucosal samples were located at least 8 cm from the mar-
gin of the tumors of surgical specimens. The average age
was 56.4 years, ranging from 32 years to 81years, and the
ratio of male to female was 30 to 17.
2.2. Immunohistochemistry
The expressions of CD97, NF-kB and COX-2 were stud-
ied by immunohistochemicl Envision method according
to the manufacturer’s recommendations. Briefly, all the
tissue specimens were preserved with 10% v/v formalin
and embedded in paraffin. Sections (5-μm-thick) were
cut, placed on glass slides, and depaffinized. One section
from each block was stained with hematoxylin-eosin for
evaluating the diagnosis of gastric MALT lymphoma.
After depaffinization and dehydration, the tissue sections
were subjected to microwave oven treatment in 0.01
mol/L sodium citrate buffer (pH 6.0) for 8 minutes at
600W and then exposed to 0.3% H2O2 for 30 minutes to
block endogenous peroxidase. After washing with PBS,
sections were incubated in PBS supplemented with 10%
goat serum for 20 min at room temperature to block
non-specific binding of secondary antibody, then incu-
bated overnight at 4˚C with CD97 (1:50), NF-kB (1:100)
and COX-2 (1:50) in PBS containing 1% bovine serum
albumin. After rinsing three times in PBS, sections were
treated with biotinylated anti-immunoglobulin for 1h at
room temperature, then washed again and reacted with
the streptavidinbiotin system by using 0.04% 3, 3’-dia-
minobenzidine tetrahydrochloride for1min as chromogen.
Negative control was established by replacing the pri-
mary antibody with PBS.
The primary antibody of rabbit polyclonal CD97
(ab13345) was purchased from Cambridge Science Park
(Abcam plc332, Cambridge, UK), monoclonal mouse
anti-human NF-kB oncoprotein were purchased from
Beijing Zhongshan Godden Bridge Biotechnology Co.
LTD., and rabbit polyclonal anti-human COX-2 IgG
from (Santa Cruz, CA, USA).
2.3. Evaluation of Immunohistochemical
Staining
Immunoreactivity was scored semiquantitatively by two
independent investigators who were unaware of the his-
tological results using a light microscope in the terms of
proportion of cells in gastric MALT lymphoma tissues.
The criteria for grade referenced to the report of Wu et al.
[37]: grade 0, stained cells accounted for less than 10%;
grade 1, between 10% and 29%; grade 2, between 30%
and 49%; and grade 3, more than 50%. Grades 1 through
3 were considered positive. And the level of staining
intensity was estimated to grades between 0 and 3 (0,
negative; 1, weak; 2, moderate; 3, strong staining).
CD97-positive tumors were further examined for the
presence of more strongly stained scattered cells or scat-
tered cell groups near or on the invasion front.
2.4. Statistical Analysis
Statistical analysis was performed with SSPS 13.0; the
parameters were compared with the χ2 test. Spearman cor-
relation test was used for the correlation between positive
rates. A level of P 0.05 was considered significant.
3. RESULTS
3.1. CD97 Protein Expression Correlates with
Clinicopathological Variables
Forty-one of 47 gastric MALT lymphoma tissues
showed CD97 positive staining, including 8 weak, 15
moderate and 18 strong staining (Figure 1(a)). All three
cases with large cell differentiation stained strongly,
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S.-L. Han et al. / J. Biomedical Science and Engineering 4 (2011) 483-489 485
whereas, in normal gastric mucosa tissue, no immuno-
reactivity of CD97 was found. The relationship between
CD97 protein expression and a number of clinical in-
dexes, including depth of tumor invasion and clinical
staging, as well as patient’s age and sex, tumor size, and
H pylori infection, were also investigated and summa-
rized in Table 1. The difference of CD97 expression
between depth of invasion limited in mucosa and sub-
mucosa and beyond muscularis propria was significant
(100.0%, 26/26 vs. 71.4%, 15/21, P < 0.01). Moreover,
the expression of nuclear CD97 between stage IIE, III,
IV and stage I patients showed significant difference (27
of 28, 96.4% vs. 14 of 19, 73.7%, P < 0.05), but not with
the age and gender of patients, H pylori infection, and
tumor size (P > 0.05, Table 1).
JBiSE
There was no correlation between CD97 and NK-kB
(r = 0.243, P = 1.00) or COX-2 expression (r = 0.263, P
= 0.74).
3.2. NF-kB Protein Expression Correlates with
Clinicopathological Variables
In this study, no immunoreactivity of NF-kB was found
in all normal gastric mucosa tissues, the positive expres-
sion of NF-kB protein (Figure 1(b)) in the patients with
gastric MALT lymphoma was 36.2% (17/47), moreover,
tumors with low expression of NF-kB were significantly
smaller in size (17 of 47, 36.2%, P < 0.05) than those
with high expression (9 of 21, 42.8% and 5 of 7, 71.4%).
The incidence of deeper invasion was significantly
higher (P < 0.05) than that in tumor with low expression
(13 of 26, 50% vs. 4 of 21, 26.7%). Furthermore, the
expression of nuclear NF-kB between stage IIE, IV and
stage I and stage II patients showed significant differ-
ence(16 of 19, 84.2% vs. 4 of 19, 21.1% vs. 4 of 15,
26.7%, P < 0.05).Whereas, not with the age and gender
of patients, or H pylori infection (P > 0.05, Table 1).
3.3. COX-2 Protein Expression Correlates with
Clinicopathological Variables
Twenty-three of 47 gastric MALT lymphoma tissues
showed COX-2 positive staining, immunohistochemi-
cally, COX-2 was stained diffusely in cytoplasm of the
tumor cells (Figure 1(c)). In contrast, no or very faint
signal was found in neighboring normal tissues. The
expression of COX-2 gastric MALT lymphoma patients
with H pylori infection was significantly higher than
those in patients without H pylori infection (19 of 29,
65.5% vs. 4 of 18, 22.2%) (P<0.05), moreover, COX-2
expression was significantly correlated with clinical
stage, depth of invasion, tumor size (P<0.05). Univariate
factor analysis showed that the overall survival of gastric
MALT lymphoma patients with positive COX-2 protein
Figure 1. (a) Strong immunohistological stain of CD97 in gastric MALT lymphoma
(original magnification × 200). (b) The gastric MALT lymphoma stained NF-kB
nuclear immunity (original magnification × 200). (c) Strong immunohistological
stain of COX-2 in gastric MALT lymphoma (original magnification × 200).

S.-L. Han et al. / J. Biomedical Science and Engineering 4 (2011) 483-489 486
Table 1. The relationship between CD97, NF-kB and COX-2 positive expression and the clinico-
pathological factors in gastric MALT lymphoma.
Clinicopathological factors CD97 positive
expression (%)
NF-kB positive
nuclear expression (%) COX-2 expression (%)
Age
>60year (n = 20)
≤60year (n = 27)
18 (90.0%)
23 (85.2%)
11 (55.0%)
10 (43.5%)
10 (50.0%)
13 (48.1%)
Sex
male (n = 30)
female (n = 17)
26 (86.7%)
15 (88.2%)
13 (50.0%)
8 (53.3%)
14 (46.7%)
9 (52.9%)
H pylori infection
yes (n = 29)
no (n = 18)
24 (82.8%)
17 (94.4%)
10 (41.7%)
7 (29.9%)
10 (34.5%) **
14 (77.8%)
Tumor size
≤5 cm (n =19)
5 - 10 cm (n = 21)
>10 cm (n = 7)
14 (73.7%)
20 (95.2%)
7 (100.0%)
3 (15.7%)
9 (42.8%)*
5 (71.4%) **
14 (73.7%)*
10 (35.7%)
Depth of invasion
m + sm (n = 21)
pm + s (n = 26)
15 (71.4%) **
26 (100.0%)
4 (19.0%)*
13 (50.0%)
15 (71.4%)*
9 (34.6%)
Staging
stage I (n = 19)
stage II (n = 15)
stage IIE + IV (n = 13)
14 (73.7%)*
14 (93.3%)
13 (100.0%)
4 (21.1%)*
4 (26.7%)*
9 (69.2%)
12 (63.2%)*
9 (60.0%)
2 (15.4%)
Tumor recurrence
yes (n = 4)
no (n = 43)
3 (75.0%)
38 (88.4%)
3 (33.3%)
14 (36.8%)
5 (29.4%)*
19 (63.3%)
Note: *P < 0.05; **P < 0.01
(59.9 months) was shorter than that of patients with
negative COX-2 protein (77.8 months), but this differ-
ence was no statistically significant (P > 0.05).
There was a significant correlation between COX-2
and NK-kB expression (r = 0.442, P = 0.02).
4. DISCUSSION
Normal human gastric mucosa is devoid of MALT, and
MALT accumulates within gastric mucosa as a result of
long-standing H pylori infection in a subset of infected
patients, and from this acquired MALT, low-grade B cell
MALT lymphoma may eventually develop [1-3,5]. H
pylori can be demonstrated in the gastric mucosa of the
majority of cases of gastric MALT lymphoma [23,30].
Additionally, eradication of H pylori was reported to
result in the complete regression of the majority of these
tumors [5,38]. However, the exact mechanism responsi-
ble for the development of MALT lymphoma still re-
mains obscure.
It has been showed that expression of CD97 was
found in various epithelial tumours, for example, thyroid,
colorectal, gastric, oesophageal and pancreatic carcino-
mas [30-36,39]. A study from Steinert et al. [14] sug-
gests a strong correlation between the appearance of
moderate of severe tumor budding and accumulating of
CD97 in these scattered tumor cells. Recent studies sug-
gest that molecule CD97 are contributing to cell-matrix
and cell to cell interactions and identify a subset of car-
cinoma cells prone to invade focally, spread, and metas-
tasis in colorectal cancer [10,12]. In addition, the level of
CD97 in cancer cell line correlates with migration and
invasion in vitro, and this result was confirmed in
CD97-inducible Tet-off HT1080 cells [14]. However,
there is no data on CD97 expression in MALT lym-
phoma. Our observation for the first time demonstrated
that CD97 protein was strongly expressed in 87.2% gas-
tric MALT lymphoma tissues, moreover, CD97 protein
was diffusely expressed in the gastric MALT lymphoma
tissues, and very highly expressed in the tumor with
large cell differentiation, but it remarkably differed from
the characteristics of CD97 in gastric or colorectal can-
cer tissues [12,14]. Moreover, our data showed that
CD97 protein expression was inversely correlated with
tumor size, depth of invasion and clinical staging in gas-
tric MALT lymphoma (P < 0.01 or 0.05), namely, the
immunoassaying of CD97 in gastric MALT lymphoma
suggests that CD97 expression may play an important
role in the development and aggressiveness of gastric
MALT lymphoma.
NF-kB is a family of important transcription factors
that regulate B-cell development, maintenance, and
stimulation [19,20,23,25] ;it is constitutively present in
the cytosol and inactivated by its association with IkB
family inhibitors [17,22]. B-cell receptor signaling and
some tumor necrosis factor (TNF) cytokine signaling
induce NF-kB activation through the NF-kB1 pathway
[24], where phosphorylation of the NF-kB inhibitor IkB
by the IkB kinase (IKK) complex allows the cytoplasmic
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S.-L. Han et al. / J. Biomedical Science and Engineering 4 (2011) 483-489 487
NF-kB proteins p65 and p50 to translocate to the nucleus
when their nuclear localization sequence (NLS) is ex-
posed. Once phosphorylated, IkB is targeted for ubiquit-
ination and degradation by the 26S proteasome, allowing
translocation of NF-kB into the nucleus where it binds to
specific DNA sequences in the promoters of target genes,
thereby stimulating transcription [16,21]. Recently, ge-
netic and biochemical evidence has accumulated, sug-
gesting that constitutive activation of NF-kB proteins
plays an important role in the development/progression
of B and T cell lymphoid malignancies [19,22,29]. In
particular, genetic and molecular alterations of NF-kB
family members and their transcriptional target genes
have been implicated in the development of diffuse large
B cell lymphoma and mucosa-associated lymphoid tis-
sue lymphoma. Various molecular events lead to de-
regulation of NF-kB signaling in Hodgkin disease and a
variety of T- and B-cell non-Hodgkin lymphomas either
up-stream or downstream of the central IkappaB kinase.
Although NF-kB proteins represent an integrating point
of several pathways, potentially contributing to several
diseases, their unique activation depends on cell type
and stimulus [26,28].
H pylori activate the alternative NF-kB pathway in B
lymphocytes. The effects on chemokine production and
antiapoptosis mediated by H. pylori-induced processing
of NF-kB2/p100 to p52 may drive lymphocytes to ac-
quire malignant potential [10]. Merzianu M et al. [27]
reported that nuclear expression of the p65 subunit of
NF-kB in lymphoplasmacytic lymphoma was 34%, sug-
gesting that NF-kB is active in these tumors. In this
study, expression of NF-kB was examined in gastric
MALT lymphoma, and found NF-kB nuclear expression
was inversely correlated with tumor volume, depth of
tumor invasion and clinical staging in gastric MALT
lymphoma. These results suggest that nuclear expression
of NF-kB involve in the tumorogenesis and development
of gastric MALT lymphoma and inhibition of NF-kB
pathway may be an alternative for prevention and treat-
ment of this disease.
Cyclooxgenases (COXs) are the key enzymes in ara-
chidonate metabolism and catalyze the biosynthesis of
prostaglandin H2, which is the precursor for prostanoids.
There are at least two isoformers, COX-1 and COX-2,
the former, which is constitutively expressed in many
tissues, and involved in the homeostasis of various
physiologic functions, and the latter, which is involved
in many inflammatory reactions with its expression rap-
idly induced by growth factors, tumor promoters or cy-
tokines [30,33]. Under normal conditions, COX-2 is
absent in tissue cells. Over-expression of COX-2 in ade-
nocarcinoma cells has also been linked to increased an-
giogenesis and metastasis [32-34]. COX-2 can be regu-
lated at both transcriptional and posttranscriptional lev-
els [33]. The transcriptional activation of COX-2 is me-
diated by the binding of inducible transcriptional factors
to cis-acting elements in the COX-2 promoter. Binding
sites for the regulatory elements, including NF-kB, nu-
clear factor for interleukin-6 (NF-IL-6), cyclic AMP
response element (CRE), PEA-3, SP-1, activator pro-
tein-2 (AP-2), and T-cell factor 4 (TCF-4), have been
identified in the 5’-flanking region of the COX-2 gene
[19,20,29]. COX-2 has been found to be overexpressed
in various B-cell lymphoma cell lines [32,34,36,40].
With respect to lymphoma, Paydas et al.’s study sug-
gested that there was an important association between
aggressive histology and COX-2 expression: COX-2 was
negative in about half of the cases with indolent mor-
phology, while two thirds of the COX-2 positive cases
had aggressive histology (P = 0.036) [32]. Furthermore,
though the difference was not significant statistically, the
overall survival of COX-2-positive patients was less
than for those without COX-2 expression [31]. Our
study showed COX-2 positive staining, and the expres-
sion of COX-2 gastric MALT lymphoma patients with H
pylori infection was significantly higher than those in
patients without H pylori infection (P < 0.05), moreover,
COX-2 expression was significantly correlated with
clinical stage, depth of invasion, tumor size in gastric
MALT lymphoma(P < 0.05), and gastric MALT lym-
phoma patients with positive COX-2 protein lived
shorter than patients with negative COX-2 protein (P >
0.05) in univariate factor analysis. This is in agreement
with the report of Yang et al. [41], the COX-2 expression
correlated with clinical stage and COX-2 negative pa-
tients had lower survival than COX-2 positive patients (p
= 0.014). Lymphoma cells treated with COX-2 inhibitor
(celecoxib) revealed apoptotic induction of greater than
85% in all cell lines examined at 50 microM celecoxib,
these findings suggest that increased COX-2 expression
and activity, contributes to the pathogenesis of B cell
lymphomas and point to a possible role for COX-2 inhi-
bition in their treatment [34]. These findings suggest that
increased COX-2 expression and activity, contributes to
the pathogenesis of gastric MALT lymphomas and point
to a possible role for COX-2 inhibition in their treat-
ment.
COX-2 over-expression parallels NF-kB expression in
oral precancer and cancer[40], and synchronism between
individual expressions may denote a regulatory role of
the latter in COX-2 tansactivation[41]. Our results indi-
cate that there was a significant correlation between
COX-2 and NK-kB Expression (r = 0.02, P < 0.05), but
no correlation was found between CD97 and NK-kB (r =
1.00, P > 0.05) or COX-2 expression (r = 0.74, P > 0.05).
Taken together, our findings was the first to indicate
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S.-L. Han et al. / J. Biomedical Science and Engineering 4 (2011) 483-489 488
that CD97 strongly expressed in gastric MALT lym-
phoma tissues, and expressions of CD97, NF-kB and
COX-2 may play a synergistic role in the pathogenesis
of gastric MALT lymphoma, moreover, their expressions
were correlated with tumor invasion and metastasis.
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