ONCOLOGY LETTERS 3: 1017-1022, 2012
Abstract. The effects of the interaction between KLF4 and
β-catenin may be significant in human carcinogenesis and
tumor development. This study aimed to determine whether
the expression of KLF4 and β-catenin in gastric cancer tissues
is associated with clinicopathological characteristics. Western
blot analysis and immunohistochemistry were performed to
detect KLF4 and β-catenin expression in tumor and corre-
sponding non-cancerous tissues from 49 patients. The data
revealed that KLF4 expression was significantly reduced
in gastric cancer tissues compared with normal tissues. By
contrast, the expression of the β-catenin protein was signifi-
cantly increased in all tumor tissues, but was not expressed
in distant normal mucosae. The altered expression of the
KLF4 and β-catenin proteins was associated with advanced
tumor stage and gastric cancer. In addition, the expression of
the KLF4 and β-catenin proteins was inversely associated in
moderately differentiated human gastric cancers. This study
showed that β-catenin expression is significantly increased
and KLF4 protein expression is markedly decreased in gastric
cancer tissues, thus showing that the expression of KLF4 is
inversely correlated with that of β-catenin in gastric cancer.
The altered expression of the two proteins is associated with
advanced tumor stage in gastric cancer.
Gastric cancer remains the fourth most common malignancy
and the second leading cause of cancer-related mortality
worldwide, despite a steady decline in incidence over the
past several decades (1). In recent years, the survival rate of
gastric cancer has significantly improved due to advances in
treatments, including surgery, chemotherapy and radiotherapy.
However, approximately 800,000 individuals still succumb
to gastric carcinoma each year worldwide. Clinically, early
gastric cancer is often asymptomatic or causes non-specific
symptoms; when symptoms occur, the cancer has often
reached an advanced stage. This results in the poor short-term
survival rate of gastric cancer patients due to primary tumor
invasion and metastasis (2). Similar to other types of cancer,
tumor invasion and metastasis are serious clinical problems
and are the most notable properties of aggressive gastric carci-
noma. Gastric cancer development is often associated with a
number of molecular abnormalities, including the inactivation
of various tumor suppressor genes and/or activation of various
oncogenes (3,4). A number of these genes have been investi-
gated as biological markers for the prediction of gastric cancer
staging and lymph node metastasis, but the potential roles of
these genes in the etiology of gastric cancer remain poorly
understood. Investigations into the molecular alterations in
gastric cancer may provide novel insights into the mechanisms
responsible for stomach carcinogenesis and lead to the devel-
opment of biomarkers for the early detection of gastric cancer
and the prediction of its prognosis.
Krüppel-like factor 4, (KLF4) is a newly identified
zinc-finger transcription factor (5). Similar to all Krüppel-like
factors, KLF4 has three zinc-finger domains in its C-terminus
and is involved in various cell and developmental processes,
including cell terminal differentiation and carcinogenesis (6).
The results of previous studies have shown that the expres-
sion level of KLF4 is high in the epithelial cells of the skin,
lung and gastrointestinal tract and is particularly elevated in
terminally differentiated and postmitotic epithelial cells (7).
Other studies have found that KLF4 expression is associ-
ated with the growth arrest of cultured cells (8) and KLF4
overexpression reduces colorectal cancer colony formation,
migration and invasion. By contrast, a decrease or loss of
KLF4 expression frequently occurs in various types of cancer,
including cancers of the colorectum (9,10), stomach (11),
esophagus (12), prostate (13) and lung (14). The expression
levels of KLF4 were found to be inversely associated with
the size of intestinal adenoma in animal experiments (11). In
addition, the results of studies have shown that a decreased
KLF4 expression is associated with poor survival and it is
used as an independent prognostic marker in primary gastric
Altered expression of Krüppel-like factor 4
and β-catenin in human gastric cancer
N. ZHANG*, J. ZHANG*, Z.W. WANG, L. ZHA and Z. HUANG
Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University,
Chongqing 400016, P.R. China
Received December 10, 2011; Accepted February 10, 2012
Correspondence to: Dr Zi-Wei Wang, Department of General
Surgery, The First Affiliated Hospital, Chongqing Medical
University, No. 1 Youyi Rd., Yuzhong District, Chongqing 400016,
Key words: Krüppel-like factor 4, β-catenin, immunohistochemistry,
tumor cell differentiation
ZHANG et al: KLF4 AND β-CATENIN EXPRESSION IN GASTRIC CANCER
cancer (11). However, certain studies have shown that KLF4
expression is increased in breast ductal cell carcinoma (15)
and oral squamous cell carcinoma (16) for as yet unknown
reasons. Additionally, KLF4-knockout mouse studies have
demonstrated that KLF4 may activate mucosal cell differen-
tiation and induce precancerous changes in the stomach (17).
These studies demonstrate the importance of KLF4 in various
types of cancer, including gastric cancer, although the role of
KLF4 in the staging and lymph node metastasis of gastric
cancer remains to be determined.
β-catenin is a multifunctional protein involved in
cadherin-mediated cell adhesion at the plasma membrane and
transcriptional regulation in the nucleus (18), that is involved in
a number of cell processes, including embryogenesis, tumori-
genesis and tumor progression (19). In the cytoplasm of normal
epithelium, the levels of β-catenin are regulated by the phos-
phorylation of its N-terminal serine and threonine residues
by the APC-Axin-GSK-3β complex. When β-catenin overex-
pression and its accumulation results in β-catenin-lymphoid
enhancer factor (LEF)/T-cell factor (TCF) complex formation
in the nucleus, β-catenin acts as a transcription factor, acti-
vating target genes such as cyclin-D1 and c-Myc (20). Thus,
β-catenin has been confirmed as an oncogene in a variety of
tumors (21,22). In a number of types of aggressive and lethal
cancer, the aberrant quantity and localization of β-catenin may
weaken cell-cell junctions and promote the dedifferentiation,
hyperproliferation, invasion and metastasis of tumor cells in
different types of cancer, including gastric cancer, lung cancer
and breast cancer (20). A high level of β-catenin activity is
significantly correlated with the invasion and progression of a
number of types of cancer (23,24) and is used as an independent
prognostic indicator for these cancers (25). KLF4 is known to
be a novel antagonist of β-catenin in the nucleus. Crosstalk
between KLF4 and β-catenin occurs in normal intestinal
mucosae and colorectal cancer and is involved in the homeo-
stasis of intestinal mucosae (26,27). Therefore, the aim of this
study was to investigate the expression levels of the KLF4 and
β-catenin proteins in moderately differentiated gastric cancer
tissues and determine whether their expression is associated
with gastric cancer staging and lymph node metastasis.
Materials and methods
Tissue specimens. Forty-nine moderately differentiated
specimens were obtained from gastric cancer patients who
had undergone standard D2 radical gastric resection in the
Department of Gastrointestinal Surgery, The First Affiliated
Hospital of Chongqing Medical University (Chongqing, China)
between November 2009 and May 2010. The clinicopatho-
logical data are shown in Table I. Staging of the tumors was
performed according to the gastric cancer staging standard of
the International Union Against Cancer (UICC). No patients
underwent chemotherapy or radiotherapy prior to surgery. A
matched distant non-cancerous sample (5 cm away from the
lesion) was also obtained from each patient and used as a
control. Informed consent and permission to use their tissue
in research was obtained from each patient. This study was
performed in compliance with the Declaration of Helsinki
with the approval of the Ethics Committee of Chongqing
Immunohistochemistry. Formalin-fixed and paraffin-
embedded tumor specimens were prepared, cut into 5-µm
sections and mounted onto poly-L-lysine coated glass slides.
The tissue sections were stained immunohistochemically
with antigen retrieval methods (28) using a rabbit polyclonal
antibody against human KLF4 (1:200 dilution, Abcam
Biotechnology, Cambridge, UK) and a mouse monoclonal
antibody against human β-catenin (1:200 dilution, Millipore
Biotechnology, Boston, MA, USA). Positive staining was a
reddish-brown precipitate in the nuclei and cytoplasm (29).
The expression of KLF4 and β-catenin proteins was reviewed
and scored according to the following grading system:
staining intensity was categorized as negative (-), weak (+),
moderate (++) or strong (+++). The percentage of staining was
categorized as no staining (-), <10% of tumor cell stained (+),
10-40% (++), 40-70% (+++) and >70% (++++). To simultane-
ously gauge the staining intensity and uniformity, the average
values for the intensity in each slice were multiplied by the
average values for the percentage area stained in each slice to
derive a composite histoscore (histoscore = intensity x area).
Protein extraction and western blotting. To confirm the quality
of the antibody, we randomly selected seven cases from the
49 patients for protein extraction and western blot analysis.
Samples (50 mg) of each tumor and normal mucosa tissue
were minced, washed three times with ice-cold PBS, gently
centrifuged and soaked in 500 ml of hypotonic buffer (1 mM
NaHCO2) containing 2 mM phenylmethanesulfonyl fluoride
(PMSF) for 30 min, followed by centrifugation at 15,000 x g
for 15 min. The supernatant was measured for protein concen-
tration with a protein assay kit (Bio-Rad, Hercules, CA, USA).
The protein samples were mixed with sample loading buffer
(30% glycerol, 6% sodium-dodecylsulfate (SDS), 62.5 mM
Tris-HCl, pH 6.8), separated by 10% SDS-PAGE and trans-
ferred to a PVDF membrane (Millipore). The membrane
was then blocked using 5% skimmed milk, incubated with
the appropriate primary antibodies and then incubated with
secondary antibodies coupled with horseradish peroxidase
(HRP) (Amersham, Arlington Heights, IL, USA). The protein
bands were finally visualized with an enhanced chemilumi-
nescence (ECL) reagent (Beyotime Institute of Biotechnology,
Statistical analysis. Statistical analysis was performed using
SPSS 17.0 for Windows (SPSS, Chicago, IL, USA) to assess
the immunohistochemical data of KLF4 and β-catenin expres-
sion between gastric carcinoma and paired normal tissues with
the Chi-square test and with the Student's t-test for western
bloting data (data reported as the mean ± SD). The asso-
ciation between KLF4 and β-catenin was evaluated using the
Spearman's correlation test. P<0.05 was considered to indicate
a statistically significant difference.
Expression of KLF4 and β-catenin proteins in gastric
cancer and distant normal tissue. In this study, we first
assessed the expression of the KLF4 and β-catenin proteins
in gastric cancer tissues and distant normal mucosae using
western blotting. We found that the antibodies against the two
ONCOLOGY LETTERS 3: 1017-1022, 2012
proteins were specific, indicating that they were suitable for
immuno histochemistry. Western blotting revealed that KLF4
was highly expressed in the normal tissues, whereas all the
tumor tissues had a reduced KLF4 expression. By contrast, the
expression of the β-catenin protein was significantly increased
in all tumor tissues compared with the distant normal mucosae
(Fig. 1). The alteration of the expression of the two proteins
was statistically significant (P<0.01 for the two proteins).
Immunohistochemical analysis of KLF4 and β-catenin
expression in gastric cancer tissues and distant normal
mucosae. We analyzed the expression of the KLF4 and
β-catenin proteins in paraffin-embedded cancer and
paired-non-cancerous tissues from 49 cases of moderately
differentiated gastric adenocarcinomas. The immunohisto-
chemical data showed that 34/49 (69.4%) gastric cancer tissues
were positive for β-catenin, whereas only 22/49 (44.90%) of
the distant normal mucosae expressed the β-catenin protein.
Moreover, β-catenin was located in the nucleus. By contrast,
positive staining of the KLF4 protein was found in only seven
gastric cancer samples (7/49, 14.29%), whereas 40/49 (82.6%)
of the normal gastric mucosae expressed the KLF4 protein.
Compared with the normal mucosae, KLF4 expression was
significantly decreased in gastric cancer patients (P=0.0001;
Fig. 2). The increased β-catenin expression in gastric cancer
tissues was also statistically significant (P=0.014; Fig. 3). We
then associated the expression of the two proteins with the
clinicopathological data of the patients (Table I) and found
that the decreased expression of KLF4, but increased levels
of β-catenin, were associated with advanced tumor stage
(P=0.041 and P=0.034, respectively). However, KLF4 and
β-catenin expression in cancer tissues was not significantly
associated with age (P=0.85 and P=0.98, respectively) or
gender (P=0.686 and P=0.78, respectively). In addition, we
Figure 1. Western blotting of KLF4 and β-catenin in tumor tissues and matched distant non-cancerous tissues. (A) KLF4 expression. (B) β-catenin expression.
The bands were densitometrically scanned and β-actin was used as an internal control. The statistical analysis with the relative protein expression levels of
KLF4 and β-catenin are shown in the graphs.
ZHANG et al: KLF4 AND β-CATENIN EXPRESSION IN GASTRIC CANCER
found a significant inverse correlation between KLF4 and
β-catenin expression in moderately differentiated human
gastric cancers (rs=-0.488; P<0.001).
In this study, we analyzed the expression of the KLF4 and
β-catenin proteins in gastric cancer and corresponding normal
tissues. The immunohistochemical data have shown that
β-catenin expression was upregulated in gastric cancer tissues
compared with distant normal mucosae, whereas the expres-
sion of KLF4 protein was significantly decreased in gastric
cancer samples compared with normal gastric mucosae. The
altered expression of KLF4 and β-catenin was associated with
the advanced tumor stage of gastric cancer. In addition, the
expression of the KLF4 protein was inversely correlated with
Figure 2. Expression of KLF4 protein in human gastric adenocarcinoma and matched distant non-cancerous tissues by immunohistochemistry. (A) Strong
KLF4 expression (+++) in distant non-cancerous tissues. (B) Positive KLF4 expression (++) in different stages of gastric cancer. (C) Weakly positive KLF4
expression (+) in different stages of gastric cancer. (D) Negative KLF4 expression (-) in different stages of gastric cancer. Original magnification, x200.
Figure 3. Expression of β-catenin protein in human gastric adenocarcinoma and matched distant non-cancerous tissues by immunohistochemistry. (A)
Weak β-catenin expression (+) in distant non-cancerous tissues. (B) Weak β-catenin expression (+) in different stages of gastric cancer. (C) Weakly positive
β-catenin expression (++) in different stages of gastric cancer. (D) Strongly positive β-catenin expression (+++) in different stages of gastric cancer. Original
Table I. Clinical characteristics and the expression of KLF4 and β-catenin in 49 gastric carcinoma patients.
Positive Positive rate (%)
Positive Positive rate (%) P-value P-value
15.38 0.98 0.85
14.71 0.78 0.686
6.25 0.242 0.041
Lymph node metastasis
7.69 0.034 0.086
Staging was performed according to the gastric cancer staging standard of the International Union Against Cancer (UICC).
ONCOLOGY LETTERS 3: 1017-1022, 2012
that of β-catenin in moderately differentiated human gastric
cancers. The data from the current study demonstrate that the
expression of the β-catenin protein is significantly increased,
whereas that of the KLF4 protein is markedly decreased, in
gastric cancer tissues, and that the expression of KLF4 is
inversely associated with that of β-catenin. The altered expres-
sion of the two proteins is associated with advanced tumor
stage in gastric cancer. More studies are needed to verify the
value of these two proteins as biomarkers for the prediction of
gastric cancer progression.
The results of previous studies have shown that KLF4
is highly expressed in gastrointestinal epithelial cells and is
associated with growth arrest (8), by blocking G1/S progres-
sion of the cell cycle, and terminal differentiation (30,31).
The studies published currently have speculated that KLF4
is involved in the maintenance of gastric mucosa homeo-
stasis (11). However, depending upon molecular events, KLF4
may act as either a tumor suppressor gene or an oncogene in
different cells (32,33). For example, the number of goblet cells
in the colon is substantially decreased in KLF4-null mice (34),
which may be a significant event in colorectal tumor develop-
ment. Nevertheless, the levels of KLF4 RNA and protein are
significantly reduced in the dysplastic epithelium, adenoma-
tous polyps and colon cancers, indicating the involvement of
KLF4 in colorectal carcinogenesis (35). On the other hand, an
inverse correlation has also been found between KLF4 and the
size of multiple intestinal adenomas in mice (36). The altera-
tion of KLF4 expression leads to aberrant proliferation and
differentiation in gastric and colonic epithelium (17,34). Low
levels or the loss of KLF4 expression in a number of types
of cancer (9-14) have been reported and increasing evidence
suggests that KLF4 is a putative tumor suppressor in the
digestive tract, including the stomach and colon (9,11). KLF4
knockout mice exhibit defects in gastric differentiation and
have precancerous changes in the stomach (11,17). In addi-
tion, the overexpression of KLF4 in a colon cancer cell line
induced colon cancer cell growth arrest (30), reduced colony
formation, cell migration and invasion and repressed β-catenin
transcription in colon cancer HT29 cells (37). These results
suggest that KLF4 is a tumor suppressor gene and is involved
in the progression and development of gastric tumors. In the
current study, we found that the KLF4 protein was predomi-
nantly expressed in gastric non-neoplastic epithelium, but was
substantially decreased or lost in gastric tumor specimens.
β-catenin is a crucial part of the cell-cell adhesion complex
associated with cadherins (e.g., α-, β- and E-cadherin).
β-catenin has been found to mediate intercellular adhe-
sion (18), as well as to regulate cell growth and differentiation.
β-catenin is a key downstream molecule in the Wnt signaling
pathway and binds to the TCF/LEF transcription factors to
regulate and activate the transcription of target genes that
are involved in embryo development, tissue self-renewal and
cancer (38). β-catenin is pivotal in intracellular signaling and
is a key element in one of the most significant pathways in
epithelial carcinogenesis (39,40). β-catenin has been identified
as an oncogene in a variety of tumors in numerous previous
studies (23,41). In a number of types of aggressive and lethal
cancer, aberrant β-catenin expression may weaken cell-cell
junctions and promote carcinoma cell dedifferentiation, hyper-
proliferation, invasion and metastasis, characteristics that are
commonly found in a number of tumors, including gastric,
lung and breast cancers (42). A high level of β-catenin activity
is significantly correlated with the invasiveness and progres-
sion of numerous tumors, including gastric cancer (8,23,24).
Previous studies have confirmed that β-catenin is an indepen-
dent prognostic indicator for these carcinomas and is closely
correlated with tumor progression (25,41). However, it has been
reported that KLF4 regulates Wnt/β-catenin signaling, which
is significant in the homeostasis of the normal intestine, and
indicates important implications in cancer research (26,27).
In the present study, we investigated the expression levels of
KLF4 and β-catenin and the potential association between
KLF4 and β-catenin expression in human gastric cancer and
corresponding normal tissue. This study identified patterns in
the expression of KLF4 and β-catenin. Notably, the expression
of the β-catenin protein was found to be inversely associated
with KLF4 expression, suggesting that a decrease in the expres-
sion of KLF4 reduces its ability to inhibit β-catenin expression
levels. The overexpression of β-catenin is commonly observed
in colorectal cancers, while KLF4 expression is decreased in a
variety of types of cancer (9-14). Our data are consistent with
those published in other studies (9-14).
In the current study, the altered expression of these two
proteins was associated with certain clinicopathological
parameters. For example, reduced KLF4 expression was
associated with advanced TNM stage of gastric cancer, while
the expression of β-catenin was associated with lymph node
metastasis of gastric cancer. To the best of our knowledge, this
is the first study showing an inverse correlation between KLF4
and β-catenin expression in gastric cancer, which may lead to
a fuller understanding of the interaction between KLF4 and
β-catenin, thereby widening diagnosis and treatment options
for gastric cancer. Although novel, these data should be further
verified with a larger sample size. In addition, future studies
are required to investigate the molecular link between KLF4
and β-catenin proteins and further evaluate them as potential
biomarkers for gastric cancer development and progression.
This study was supported in part by a grant from the 2010
Annual Medical Research Projects of the Chongqing
Municipal Health Bureau (no. 2010-1-19).
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