Dig Dis Sci (2007) 52:536–542
DOI 10.1007/s10620-006-9316-9
ORIGINAL ARTICLE
Altered Expression of a Li-Cadherin in Gastric Cancer
and Intestinal Metaplasia
Weiguo Dong · Qiongfang Yu · Yu Xu
Received: 1 January 2006 / Accepted: 14 March 2006 / Published online: 17 January 2007


C Springer Science+Business Media, Inc. 2007
Abstract The aims of this study were to examine Li-
cadherin expression in 74 gastric carcinoma tissues, 10 cases
with normal gastric tissues, and 21 cases with intestinal
metaplasia and to investigate the role of Li-cadherin in cell
differentiation, cancer invasion, and metastasis. Expression
of Li-cadherin was analyzed by immunohistochemistry and
semiquantitative polymerase chain reactio and correlated
with clinicopathological parameters. Immunohistochemistry
showed that Li-cadherin was mainly present on the cell mem-
brane and there was no staining for liver–intestine cadherin in
normal tissues. The reduction of Li-cadherin mRNA expres-
sion was inversely correlated with the grade of differentiation
(P < 0.05). Significant differences in the expression of liver–
intestine cadherin were found in lymphatic metastasis of the
tumors (P < 0.05), but the expression of liver–intestine cad-
herin was not associated with gender (P = 0.748), serosal
invasion (P = 0.136), TNM stage (P = 0.172), Helicobacter
pylori infection (P = 0.572), liver metastasis (P = 0.374), or
peritoneal metastasis (P = 0.621). Multivariate analysis re-
vealed that the expression of Li-cadherin is an important
predictor of lymph node metastasis. We conclude that there
is a significant correlation between Li-cadherin expression
and the differentiation of gastric carcinoma, and Li-cadherin
can be a good marker to detect gastric cancer at early stages.
Increased Li-cadherin expression may contribute to gastric
cancer invasion to lymph nodes.
W. Dong (
) · Q. Yu · Y. Xu
Department of Gastroenterology,
Renmin Hospital of Wuhan University,
JieFang Road, 238 WuHan,
430060, People’s Republic of China
e-mail: dongwg@public.wh.hb.cn
Springer
Keywords Gastric cancer . Intestinal metaplasia .
Li-cadherin . Immunohistochemistry . Semiquantitative
polymerase chain reaction . Multivariate analysis
Introduction
Cadherins are transmembrane glycoproteins responsible for
Ca2+ -dependent cell–cell adhesion, and they are a family
of Ca2+ -dependent homotypic cell–cell adhesion molecules
that are involved in the maintenance of tissues struc-
ture and morphogenesis [1, 2]. The cadherin family con-
sists of type I classic cadherins, type II classic cadherins,
desmosomal cadherins, and modified classic cadherins [2].
Among many types of cell–cell adhesion molecules, cad-
herins play a critical role in establishing adherens-type junc-
tions by mediating Ca2+ -dependent cell–cell adhesion [4–
6]. There is increasing evidence that cadherin-mediated cell
adhesion additionally plays a crucial role in carcinoma cell
behavior [7, 8].
Li-cadherin, also called human peptide transporter-1
(HPT-1), is a structurally unique member of the cadherin
superfamily [9–11] which is solely expressed in liver and in-
testine of the rat, thus it was assigned the name Li-cadherin
[12]. Four major characteristics make this protein unique
among the classical type I cadherins. First, in contrast to clas-
sical cadherins and to desmosomal cadherins, the extracel-
lular portion of Li-cadherin consists of seven instead of five
structurally defined cadherin repeats. Second, Li-cadherin
contains the sequence motif AAL in place of the HAV mo-
tif conserved among classical cadherins. Third, compared
with the classical type I cadherins, the Li-cadherin of the
cytoplasmic tail has only 20 amino acid residues rather
than 150 to 160 amino acid residues. Fourth, these amino
acid residues display no significant homology to classical
Dig Dis Sci (2007) 52:536–542 537

cadherins [13]. In contrast to classical cadherins, cell–cell

adhesion mediated by Li-cadherin is independent of any in-
teraction with cytoplasmic components. But Li-cadherin was
able to induce Ca2+ -dependent homophilic cell–cell adhe-
sion in Drosophila S2 cells [14]. The adhesive mechanism
of Li-cadherin remains to be demonstrated.
Studies of ductal adenocarcinoma of the pancreas have
shown that Li-cadherin expression was seen focally in nor-
mal pancreatic ducts. In carcinoma, Li-cadherin is expressed
strongly in well-differentiated carcinoma cases, whereas
it is expressed less or not at all in less differentiated ar-
eas and poorly differentiated carcinoma cases. Furthermore,
galectin-3 was identified as being coimmunoprecipitated
with Li-cadherin and this interaction was inhibited by lac- Fig. 1 Immunohistochemical staining with Li-cadherin in chronic
atrophic gastritis with intestinal metaplasia: dark-brown staining in a
tose in a dose-dependent manner. Because galectin-3 has cell membrane distribution. (SP; original magnification, ×400.)
been observed to have a similar expression pattern to Li-
cadherin in ductal adenocarcinoma of the pancreas, the ex-
to May 2004. In this study, patients who had undergone ad-
pression of Li-cadherin and this interaction could have some
juvant therapies either before or after surgery were excluded.
role in ductal adenocarcinoma of the pancreas [15]. A study
The clinical typing of tumors was done following the guide-
of human colorectal cancer showed that reduced Li-cadherin
lines of the International Union Against Cancer [18]. The
expression was significantly associated with a high tumor
materials were obtained immediately after the surgical pro-
grade, lymphatic invasion, lymph node metastasis, and an
cedure and were cut in half. One half was fixed in formalin
advanced pTNM stage. These results suggest that analysis
and embedded in paraffin blocks for morphological and im-
of Li-cadherin expression may help to indicate the biologi-
munohistochemical examinations. The other half was frozen
cal aggressiveness of malignancy [16]. Li-cadherin is overex- ◦
in liquid nitrogen and stored at − 80 C before mRNA isola-
pressed in hepatocellular carcinoma (HCC) tissues compared
tion. All present studies were performed retrospectively us-
with noncancerous tissues, predominantly in the cytoplasm
ing frozen tissues and paraffin-embedded tissues from these
of HCC cells. It is predominantly expressed in cytoplasm of
patients.
HCC cells, contrary to that of E-cadherin immunostaining
Immunohistochemical staining. Formalin-fixed and
in the plasma membrane region [17]. But hitherto, the real
paraffin-embedded sections, 4 mm thick, were cut and
function of Li-cadherin in tumor development has not been
mounted on aminopropyltriethoxysilane-treated slides. The
fully understood.
slides were routinely deparaffinized with xylene and
In this study, we examined the expression of Li-cadherin
rehydrated with a series of ethanol washes. Endogenous
in 74 gastric carcinoma tissues, 10 normal gastric tissues, and
peroxidase activity was blocked by incubation in 3% hy-
21 cases with intestinal metaplasia by immunohistochem-
drogen peroxide methanol for 10 min. After washing with
istry methods of S-P and semiquantitative polymerase chain
reaction (PCR). We also evaluated the role of Li-cadherin in
gastric tumor differentiation and analyzed the associations
between the expression of Li-cadherin and clinicopatholog-
ical factors.

Materials and Methods

Specimens. Seventy-four primary gastric cancerous tissues

(48 male and 26 female; ages, 25 to 78 years; mean,
53.7 years) were as follows: well, moderately, and poorly
differentiated adenocarcinoma in 20, 16 and 38 cases,
respectively, 54 cases with metastatic lymph nodes and
20 cases with no metastatic lymph nodes. Twenty-one cases
Fig. 2 Immunohistochemical staining with Li-cadherin in well-
of chronic atrophic gastritis with intestinal metaplasia and 10
differentiated gastric cancerous tissue: brown-yellow staining in a cell
cases with normal gastric tissues were obtained from patients membrane distribution. (SP; original magnification, ×400.)
at Renmin Hospital of Wuhan University from October 1999

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538 Dig Dis Sci (2007) 52:536–542

Fig. 3 Immunohistochemical staining with Li-cadherin in moderately

differentiated gastric cancerous tissue: yellow staining in a cell mem-
brane distribution. (SP; original magnification, ×400.)

phosphate-bufered saline (PBS), the sections were subjected

to antigen retrieval in boiling sodium citrate buffer (0.01 mM;
pH 6.0) for 10 min in a microwave oven set at 95–100◦ C.
After the sections were cooled at room temperature, the
specimens were saturated in 10% normal goat serum (S-P
immunohistochemical kit; Fujian Maixin Biological Tech-
nology Ltd., Fujian, China) for 5 min and incubated at room
temperature for 60 min with the primary antibody, anti-Li-
cadherin (anti-Li-cadherin goat polyclonal Li-cadherin pri-
mary antibody; Santa Cruz Biotechnology, Santa Cruz, CA,
USA), at a 1:100 dilution. After the sections were washing
in PBS, a biotinylated rabbit antibody to goat immunoglob-
ulin (S-P immunohistochemical kit) was applied, followed
by incubation at room temperature for 10 min. Immuno-
histochemical reactions were developed in freshly prepared
3,30-diamino-benzidine tetrahydrochloride (DAB kit; Fujian
Maixin Biological Technology Ltd.) for immune complex
visualization and then counterstained with hematoxylin for
30 sec. Slides were counterstained in hematoxylin and de-
hydrated through a graded alcohol series terminating with
xylene. Formalin-fixed and paraffin-embeded sections of hu-
man gastric tissues with strong staining served as a positive
Fig. 4 Immunohistochemical staining with Li-cadherin in poorly dif-
ferentiated gastric cancer tissue: light-yellow staining in a cell mem-
brane distribution. (SP; original magnification, ×400.)
Fig. 5 Semiquantitative RT-PCR analysis of Li-cadherin in gastric can-
cer and chronic atrophic gastritis with intestinal metaplasia. (A) Chronic
atrophic gastritis with intestinal metaplasia; (B) well-differentiated gas-
tric cancerous tissue; (C) moderately differentiated gastric cancerous
tissue; (D) poorly differentiated gastric cancer tissue; (E) normal gastric
tissue
control, and PBS in lieu of anti-Li-cadherin as a negative
control. Stained slides were examined microscopically by
two immunohistochemistry experts. Staining was considered
negative when there were up to 10% focally distributed pos-
itive cells or when no positive cell membrane staining could
be identified. When more than 10% of tumor cells showed
cell membrane-positive immunostaining, the staining was
considered positive.
Semiquantitative polymerase chain reaction. Total RNA
from tissue specimens was isolated using TRIzol reagent
(Invitrogen Corp.) according to the manufacturer’s instruc-
tions. The RNA concentration was determined by spec-
trophotometer and adjusted to a concentration of 200 ng/ml.
RT-PCR was performed using Takara RNA PCR kit (AMV)
version 2.1 (Takara Dalian Inc., Dalian, China) under
the following conditions: 0.8 µg total RNA was reverse-
transcribed with random primer at 55◦ C for 30 min in
a 20-µl solution, and the reaction was terminated by

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Dig Dis Sci (2007) 52:536–542 539

Table 1 Expression of Li-cadherin in gastric cancer mucosal tissues by 35 cycles at 94◦ C for 50 sec, 62◦ C for 50 sec, and 72◦ C
Li-cadherin for 60 sec, followed by an additional 10 min at 72◦ C for
No. of Li-cadherin/β-actin one cycle. In all experiments, a negative control reaction
Histotype patients mRNA level P value was performed by replacing the cDNA template with sterile
water. PCR products were separated on 2.0% agarose gels,
Intestinal metaplasia 21 1.1740 ± 0.1418
and the density of each PCR product was determined using
Differentiation
Well differentiated 20 1.0956 ± 0.0627 a 2UVTM Transilluminator (Model LM-26E; Upland, CA,
Moderately USA). Messenger RNA (mRNA) expression of each sample
Differentiated 16 1.0490 ± 0.0842 was determined in at least two independent experiments us-
Poorly differentiated 38 0.9083 ± 0.1313 0.000 ing β-actin as an internal standard. In the present study, we
used the expression ratio (Li-cadherin/β-actin) as measured
by densitometry to evaluate gene expression. The results are
expressed as the mean ± standard deviation (SD) for gastric
incubating the mixture at 99◦ C for 5 min. To ensure the
cancer tissues and intestinal metaplasia.
fidelity of mRNA extraction and reverse transcription, all
Statistical analysis. All analyses were performed using the
samples were subjected to PCR amplification with β-actin.
SPSS software package, version 13.0 (SPSS Inc., Chicago,
The primer sequences for Li-cadherin gene were as follows:
IL, USA). Data consisting of continuous variables were an-
forward primer, 5 -CAGTGTTGTCTCATAGAACTGCC-3 ,
alyzed using the independent-sample t-test for two groups,
and reverse primer, 5 -GTTCTCATTGAAGCGTGGGT-3
one-way analysis of variance (ANOVA), and least-significant
(268 bp). Cycling conditions were as follows: initial denat-
difference (LSD) for three groups. The chi-square test or
uration at 94◦ C for 5 min, followed by 35 cycles at 94◦ C for
Fisher’s exact test was used to evaluate the significance of
45 sec, 53◦ C for 45 sec, and 72◦ C for 50 sec, followed by an
associations between lymph node metastasis and expression
additional 10 min at 72◦ C for one cycle. Primer sequences for
of Li-cadherin and clinicopathologic factors. Multivariate lo-
the β-actin gene were as follows: forward primer, 5 -CGA
gistic stepwise regression analysis was used to identify the
GCG GGA AAT CGT GCG TGA CAT TAA GGA GA-3 ;
most significant predictor of lymph node metastasis in the
and reverse primer, 5 -CGT CAT ACT CCT GCT TGC TGA
74 patients with gastric cancer. Probability values below 5%
TCC ACA TCT GC-3 (479 bp). Cycling conditions were
were considered statistically significant.
as follows: initial denaturation at 94◦ C for 5 min, followed

Fig. 6 Li-cadherin/β-actin
expression levels in samples
from well (n = 20)-, moderately
(n = 16), and poorly (n = 38)
differentiated gastric cancerous
tissues and intestinal metaplasia
(n = 21)

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540 Dig Dis Sci (2007) 52:536–542

Results Table 2 Correlation between Li-cadherin expression and clin-

icopathological characteristics
Expression of Li-cadherin protein. Immunohistochemistry Li-cadherin
showed that Li-cadherin was mainly present on the cell No. of Li-cadherin/β-actin
membrane. Staining of light yellow, dark yellow, brown, and Factor patients (%) mRNA levels P value
brown yellow in a low-power field and diffuse or granular Gender
staining in a high-power field was detected under microscopy Male 48 (64.9) 0.9852 ± 0.1273
in poorly, moderately, and well-differentiated gastric cancer- Female 26 (35.1) 0.9957 ± 0.1508 0.748a
ous tissues and intestinal metaplasia (Figs. 1–4). The highest Serosal invasion
expression of Li-cadherin protein was observed in intestinal Negative 29 (39.2) 1.0188 ± 0.1100
metaplasia. Li-cadherin was absent in normal gastric tissues. Positive 45 (60.8) 0.9704 ± 0.1485 0.136a
Fifty-eight positive-staining specimens occurred in 74 gas- TNM staging
I 16 (21.6) 0.9849 ± 0.1384
tric cancerous tissues and the total positive rate was 78.4%.
II 17 (23.0) 0.9789 ± 0.1628
Li-cadherin mRNA expression levels in gastric tissues. III 26 (35.1) 1.0307 ± 0.1003
Immunohistochemistry showed that Li-cadherin was absent IV 15 (20.3) 0.9341 ± 0.1452 0.172b
in normal gastric tissues, so we did not compare Li-cadherin Helicobacter pylori infection
mRNA expression in normal gastric tissues to that in the other Negative 33 (44.6) 0.9801 ± 0.1413
gastric cancerous tissues. To investigate the mRNA expres- Positive 41 (55.4) 0.9981 ± 0.1321 0.572a
sion levels of Li-cadherin, we performed semiquantitative Lymph node metastasis
Negative 20 (27.0) 0.9338 ± 0.1247
PCR using 74 gastric cancerous tissues and 21 cases with
Positive 54 (73.0) 1.0144 ± 0.1346 0.026a
intestinal metaplasia. Figure 5 shows examples of RT-PCR Liver metastasis
results for poorly, moderately, and well-differentiated gastric Negative 69 (93.2) 0.9855 ± 0.1344
cancerous tissues and intestinal metaplasia, respectively. In- Positive 5 (6.8) 1.0419 ± 0.1644 0.374a
testinal metaplasia showed increased Li-cadherin expression Peritoneal metastasis
compared to gastric cancerous tissues (P < 0.05, ANOVA). Negative 61 (82.4) 0.9857 ± 0.1332
Li-cadherin mRNA expression in the the well-, moderately, Positive 13 (17.6) 1.0064 ± 01532 0.621a
and poorly differentiated gastric cancerous tissues was sig- Total 74 – –
nificantly down-expressed compared to that in intestinal a
Statistical significance was evaluated by independent-sample
metaplasia, with P = 0.033, P = 0.002, and P = 0.000, re- t-test.
b
spectively (LSD) (Table 1). LSD also showed significant dif- Statistical significance was evaluated by ANOVA.
ferences in mRNA expression among the gastric cancerous
tissues (well-differentiated gastric cancer vs. moderately dif-
ferentiated gastric cancer, P = 0.233; well-differentiated gas- Multivariate analysis by logistic stepwise regression analy-
tric cancer vs. poorly differentiated gastric cancer, P = 0.000; sis revealed that expression of Li-cadherin was an important
moderately differentiated gastric cancer vs. poorly differen- predictor of lymph node metastasis (Table 3).
tiated gastric cancer, P = 0.000) (Fig. 6).
Li-cadherin mRNA expression levels and clinicopatho-
logical factors in gastric cancer. The relationship between Discussion
Li-cadherin mRNA expression and the clinicopathological
factors of gastric cancer patients is summarized in Table 2. In this study, Li-cadherin was mainly present on the
Statistically significant links were found between high Li- cell membrane and absent in normal gastric tissues, and
cadherin mRNA levels and lymph node metastasis (P < the positive rate for Li-cadherin was 78.4%. Expression
0.05). With the exception of lymph node metastasis, no cor- of Li-cadherin protein observed by immunohistochemistry
relation was observed between Li-cadherin mRNA levels showed a reduction of Li-cadherin expression among differ-
and the studied clinicopathological factors. ently differentiated gastric cancers and intestinal metapla-
Risk factors for lymph node metastasis by logistic regres- sia. Li-cadherin/β-actin mRNA levels in intestinal metapla-
sion analysis. To determine which feature is an independent sia and well-, moderately, and poorly differentiated gastric
prognostic variable in predicting nodal metastases, a mul- cancerous tissues were 1.1740 ± 0.1418, 1.0956 ± 0.0627,
tivariate analysis was performed using a logistic regression 1.0490 ± 0.0842, and 0.9083 ± 0.1313, respectively. The
model. Univariate analysis showed that serosal invasion, his- above data indicate that Li-cadherin mRNA expression lev-
tologic type, and expression of Li-cadherin correlated with els are significantly higher in chronic atrophic gastritis
lymph node metastasis, and gender, Helicobacter pylori in- with intestinal metaplasia than in gastric cancer. The level
fection, liver metastasis, and peritoneal metastasis did not. of Li-cadherin mRNA was lower in poorly differentiated

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Dig Dis Sci (2007) 52:536–542 541

Table 3 Multivariate analysis with respect to lymph node metastasis in gastric cancer (logistic stepwise regression analysis)

Univariate analysis
Lymph node metastasis
Negative Positive Multivariate analysis
Factor N % N % P valuea P valueb Odds ratio 95.0% confidence interval

Gender
Male 15 31.3 33 68.7
Female 5 19.2 21 80.8 0.266
Serosal invasion
Negative 12 41.4 17 58.6
Positive 8 17.8 37 82.2 0.026 0.308
Histologic type
Well differentiated 9 45.0 11 55.0 0.128
Moderately differentiated 6 37.5 10 62.5 0.051
Poorly differentiated 5 13.2 33 86.8 0.020 0.051
Helicobacter pylori infection
Negative 9 27.3 24 72.7
Positive 11 26.8 30 73.2 0.966
Liver metastasis
Negative 18 26.1 51 73.9
Positive 2 40.0 3 60.0 0.877
Peritoneal metastasis
Negative 18 29.5 43 70.5
Positive 2 15.4 11 84.6 0.486
Li-cadherin
Negative 8 50.0 8 50.0
Positive 12 20.07 46 79.3 0.019 0.024 3.83 1.192–12.325
a
Statistical significance was evaluated by chi-square test.
b
Statistical significance was evaluated by multivariate logistic stepwise regression analysis.

tumors than in well- and moderately differentiated tumors.
The data in Table 1 reveal that the levels of Li-cadherin
mRNA expression were markedly correlated with the gastric
cancer differentiation grade (P < 0.05). This result sug-
gests that Li-cadherin expression levels are associated with
the biological characteristics of a tumor such as tumor in-
vasiveness in gastric cancer patients. The role of intesti-
nal metaplasia as a precancerous lesion is widely accepted,
so the semiquantitative PCR results provide evidence that
the expression of Li-cadherin is an early event in gastric
cancer. Our data demonstrate a decrease in the expression
of Li-cadherin in the differently differentiated gastric can-
cerous tissues. Thus, decreased expression of Li-cadherin
could be a further factor to detect the histotype of gastric
cancerous tissues. We also found that the location and ten-
dency of Li-cadherin expression are the same as those of
E-cadherin expression in gastric cancer, and Li-cadherin was
found to be complementary to the co-expressed E-cadherin
[11]. A detailed study is still needed to clarify the corre-
lation of E-cadherin and Li-cadherin expression in gastric
cancer.
At present, it is not known whether Li-cadherin is a metas-
tasis protein in gastric cancer. But there was a tendency to-
ward higher Li-cadherin expression levels in gastric cancers
with lymph node metastasis compared to those without. This
finding is consistent with previous reports [19] which re-
vealed that Li-cadherin expression is an independent factors
associated with lymph node metastasis. In addition, a mul-
tivariable regression model showed that the expression of
Li-cadherin might be a powerful discriminator between gas-
tric cancers with lymph node metastasis and those without.
Some clinicopathologic factors were found to be correlated
with prognosis in gastric cancer; for example, the prognosis
of patients with gastric cancer was most strongly influenced
by lymph node involvement [20]. These results suggest that
patients with high Li-cadherin expression have a significantly
poorer prognosis than patients with low Li-cadherin expres-
sion. Further investigations are required to determine the
mechanism for the relationship between lymph node metas-
tasis and Li-cadherin expression.
The main role of Li-cadherin in gastric cancer is not clear.
But our data show two different tendencies of Li-cadherin ex-
pression. First, decreasing Li-cadherin expression levels are
correlated with tumor invasiveness in gastric cancer patients.
Second, patients with higher Li-cadherin expression levels
have a significantly poorer prognosis than patients with low
Li-cadherin expression. We do not yet have enough evidence
to state that the mechanism of altered Li-cadherin expression

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542
is involved in gastric cancer, or in its proliferation and metas-
tasis. Further studies are needed to explore the function of
Li-cadherin in detail.
In conclusion, we have demonstrated a significant corre-
lation between Li-cadherin expression and differentiation of
gastric carcinoma and intestinal metaplasia, and Li-cadherin
expression was strikingly related to lymph node metasta-
sis in gastric cancer. Expression of Li-cadherin might be a
powerful discriminator in gastric cancers with lymph node
metastasis.
In recent years RNA interference has been applied as a
means of assaying gene function. This strategy provides a
novel tool to study the function of Li-cadherin in gastric
cancer. The main function of Li-cadherin in gastric cancer
will be identified, and RNA interference may provide an
important new therapeutic modality for gastric cancer.
Acknowledgments This work was supported by a grant from
the Natural Science Foundation of Hubei Province, China (Project
No.2004AA304B08), as well as by the Department of Surgery, Renmin
Hospital of Wuhan University.
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