[Chinese Journal of Cancer 27:10, 337-342; October 2008]; ©2008 Sun Yat-Sen University Cancer Center

Basic Research Paper

Correlation of Epstein-Barr virus-encoded latent membrane protein

1 (LMP1) to fascin and phosphorylated Stat3 in nasopharyngeal
carcinoma
Qiu-Yu Liu,1 An-Jia Han,1,* Shu-Yuan You,1 Yu Dong,1 Qing-Xu Yang,2 Jue-Heng Wu3,4 and Meng-Feng Li3,4
1Department of Pathology; The First Affiliated Hospital; Sun Yat-sen University; Guangzhou, Guangdong P.R. China; 2Department of Pathology; Central People’s Hospital of
Huizhou city; Huizhou, Guangdong P.R. China; 3Department of Microbiology; Zhongshan School of Medicine; 4Ministry of Education Key Laboratory of Tropical Diseases Control
Research; Sun Yat-sen University; Guangzhou, Guangdong P.R. China

Key words: nasopharyngeal carcinoma, Epstein-Barr virus, latent membrane protein 1; Fascin, signal transducers and activators of
transcription (Stat)

Background and Objective: Latent membrane protein 1 (LMP1)
of Epstein-Barr (EB) virus is an important oncogene. Fascin is an
actin cross-linking protein involved in cell migration and adhesion.
Phosphorylated signal transducer and activator of transcription
3 (pStat3) is a member of STATs family, which is closely related
to tumorigenesis. This study was to investigate expressions of
LMP1, Fascin and pStat3 in nasopharyngeal carcinoma (NPC)
tissues and the corresponding lymph node metastatic carcinoma,
thus to explore the correlation of these genes to the initiation
and progression of NPC. Methods: Expressions of EBV-encoded
small RNA (EBER), LMP1, Fascin, pStat3, p53, Ki-67 and Bcl-2
were detected in 43 NPC tissues (21 with and 22 without lymph
node metastases) and 21 corresponding lymph node metastases
using in situ hybridization or immunohistochemistry (IHC). Data
were statistically analyzed. Expressions of pStat3 and Fascin were
measured in the NPC cell line CNE1 transfected with the LMP1-
expressing plasmid using western blot. Results: Positive EBER
expression was detected in all 43 NPC tissues and 21 lymph node
metastases of NPC. The expression rates of LMP1, Fascin, pStat3,
p53, Ki-67, and Bcl-2 were 69.8% (30/43), 93.0% (40/43), 72.1%
(31/43), 90.7% (39/43), 88.4% (38/43) and 88.4%(38/43) in 43
NPC tissues, respectively. LMP1 expression was positively corre-
lated with the expression level of Fascin, pStat3, p53, Ki-67 and
Bcl-2 in 43 NPC cases (p < 0.05). LMP1 was found in 10 out of
21 (46.7%) lymph node metastases of NPC. In addition, LMP1
*Correspondence to: An-Jia Han; Department of Pathology; The First Affiliated
Hospital; Sun Yat-sen University; Guangzhou, Guangdong 510080 P.R. China; Tel.:
86.20.87331784; Email: anjiahan@hotmail.com
Submitted: 06/12/07; Revised: 07/09/08; Accepted: 07/20/08
This paper was translated into English from its original publication in Chinese.
Translated by: Hua He on 08/15/08.
The original Chinese version of this paper is published in: Ai Zheng (Chinese
Journal of Cancer), 27(10); http://www.cjcsysu.cn/cn/article.asp?id=13773
Previously published online as a Chinese Journal of Cancer E-publication:
http://www.landesbioscience.com/journals/cjc/article/7974
expression dramatically increased pStat3 and Fascin in CNE1 cells.
Conclusions: LMP1 is expressed in lymph node metastases in
NPC. The expression of LMP1 is positively correlated with Fascin,
pStat3 and the proliferation index of tumor cells. Moreover, LMP1
up-regulates pStat3 and Fascin in NPC cells.
Epstein-Barr virus (EBV) is the pathogen of infective nono-
nucleosis and is related to many kinds of human malignant tumors.
It is believed that the onset of nasopharyngeal carcinoma (NPC)
is closely associated with EBV infection. EB virus latently exists in
NPC and expresses a small amount of proteins, such as (1) EB virus
nuclear antigen 1 (EBNA1), which is considered to play a role in the
maintenance of latent infection of EBV and its DNA replication;
(2) latent membrane protein (LMP), including LMP1 (35–65%)
and LMP2; and (3) two EBV-encoded non-poly-A tail small RNAs,
EBER1 and EBER2.
It is shown that LMP1, a product encoded by EB viral gene, can
lead to malignant transformation of rat fibroblasts, primary B cells
and human epithelial cells. LMP1 can also produce oncogenicity in
nude mice.1,2 Recent studies reveal that LMP1 is involved in the
activation of transcription factors, such as nuclear factor-κB (NF-κB)
and activator protein 1 (AP-1), which could activate their target genes
to prompt cell survival, adhesion, invasiveness and angiogenesis, as
well as participate in biological reactions, such as cell proliferation,
differentiation, transformation and apoptosis.2
Fascin, a 55 ku cytoskeletal protein capable of binding to F-actin,
was found in the cytoplasm of sea urchin oocytes by Bryan at el.3
in the 1970's. Human Fascin, located on chromosome 7p22, was
cloned from human dermoid tumor in 1990s.4 Human Fascin gene
belongs to the gene family of Fascins, which encods three protein
products, Fascin 1, Fascin 2 and Fascin 3. Fascin 1, which was firstly
found, is expressed in most human tissues and is the most studied
one among the three. Fascin 2 and Fascin 3 are found specifically
expressed in retinal photoreceptor cells and testis, respectively.5
Fascin is found highly expressed in many malignant tumor tissues,
including invasive urothelial carcinoma, breast cancer, non small-cell
lung cancer, and tumor cells of epithelial origin, including uterine

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 Correlation of Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) to fascin and phosphorylated Stat3 in nasopharyngeal carcinoma
Table 1 Dilutions of primary antibodies, antigen retrieval solution and positive control tissues
for immunohistochemistry assay
cervix cancer HeLa, gastric cancer AGS, colorectal cancer LIM1215
and SW480 cells.4-6
Signal transducers and activators of transcription (STATs), found
by Decker at el.7 in 1991 when they studied gene expression induced
by γ-interferon, is an important signaling molecule. Han et al.8
found abnormal activation of Stat3, such phosphorylated Stat3
(pStat3) in NPC cells.
Mosialos et al.9 exhibited that transformation of B lymphocyte by
EBV resulted in upregulation of Fascin. Gries et al.10 reported that
EBV latent membrane protein 1 (LMP1) activated Stat3 and Stat1
by binding to JAK3. This study was to investigate expressions of
LMP1, Fascin and pStat3 in NPC, thus to explore their correlations
to the initiation and progression of NPC.
Materials and Methods
Materials. Twenty-one tissue specimens of NPC and the corre-
sponding metastatic lymph node specimens were obtained from
paraffin blocks archived before 2004 in the Department of Pathology,
Central Hospital of Huizhou, Guangdong province. Twenty-two
NPC tissue specimens without lymph node metastasis were obtained
from paraffin blocks archived between January 2006 and July 2006
in the Department of Pathology, the First Affiliated Hospital of Sun
Yat-sen University. None of the cases received radiotherapy or chemo-
therapy. Of the 43 patients, 28 were males and 15 were females. The
patients were aged 28–73 years old, with the median age of 50. All
patients were of Guangdong origin and spoke Cantonese.
According to WHO histological classification (2005) for upper
respiratory tumors and otoncus, all the 43 NPC cases in this study
were classified as nonkeratinizing carcinoma, including 40 nasopha-
ryngeal undifferentiated nonkeratinizing and three nasopharyngeal
differentiated nonkeratinizing NPC. Pre-infiltrative changes were
observed in some cases, including atypical hyperplasia to different
extents, or preinvasive carcinoma in covering epithelium or recess
epithelium of the nasopharynx.
EBV EBER in situ hybridization was performed using Epstein-
Barr Virus Probe ISH Kit (No. NCL-EBV-K) purchased from
Novocastra. Immunohistochemistry (IHC) was performed using
LSAB2 System-HRP enhanced kit (No. K0673) from DAKO
company. Anti-LMP1 (CS 1-4), anti-Fascin, anti-p53 (DO-7), anti-
Ki-67 and anti-Bcl-2 monoclonal antibodies were purchased from
DAKO (No. M0897, No. M3567, No. M7001, No. M7240 and
No. M0887). Anti-pStat3 antibody (Ser727) was purchased from
Cell Signaling Technology (No. 9134).
338
EB virus positive cell line B95-8 and EB virus negative nasopha-
ryngeal carcinoma cell line CNE1 were used as control.
Methods. In situ molecular hybridization was performed
according to the instruction provided by the manufacture. Briefly,
paraffin-embedded tissue sections (about 3 μm thick) were fixed in
10% neutral formalin, mounted on polylysine pretreated slides and
dried at 65°C. The sections were subjected to routine deparaffinage
and gradient ethanol hydration, followed by digestion with different
concentrations of protease K (5 µg/mL, 10 µg/mL, and 15 µg/mL)
in turn at 37°C for 30 min each. After gradient ethanol dehydration,
sections were incubated with EBV probe at 37°C for 2 h, followed
by blocking at room temperature for 10 min. Then the sections were
incubated with rabbit F (ab’) anti-FITC/AP at room temperature for
30 min, followed by incubation with alkaline phosphatase substrate
buffer (pH 9.0) at room temperature for 5 min. The binding sites
were visualized after incubation with a mixture of the substrate and
levamisole at room temperature away from light. Color intensity was
controlled under the microscope. Finally, the sections were counter-
stained by Mayer’s hematoxylin and mounted by neutral gum. The
control probe provided by the kit was used as the negative control.
IHC was performed according to the instruction of the enhanced
IHC kit. Briefly, paraffin-embedded tissue sections (about 3 μm thick)
were fixed in 10% neutral formalin, mounted on polylysine pretreated
slides, and dried at 65°C. The sections were subjected to routine
deparaffinage, gradient ethanol hydration and microwave antigen
repair for 10 min. After incubation with 3% H2O2 at room tempera-
ture for 15 min to quench endogenous peroxidase activity, sections
were incubated with primary antibodies at the optimized dilution at
4°C overnight, followed by incubation with biotinylated secondary
antibodies at room temperature for 30 min. After incubation with the
streptavidin-antibiotin-peroxidase complex at room temperature for
30 min, the binding sites were visualized after DAB staining. Color
intensity was controlled under the microscope. Finally, the sections
were counterstained by Mayer’s hematoxylin and mounted by neutral
gum. For each batch of the staining, PBS, instead of the primary anti-
body, was used as negative control. The tissue section recommended
in the instruction was used as the positive control. The optimal dilu-
tion of the primary antibody, antigen repair solution and positive
control used in the study are shown in Table 1.
The full-length of LMP1 cDNA was amplified from B95-8 cells
using 5'-CGG GAT CCA TGG AAC ACG ACC TTG AGA GGG
GCC-3' as the upstream primer, and 5'-GCT CTA GAT TAG TCA
TAG TAG CTT AGC TGA ACTG-3' as the downstream primer.
The cDNA was cloned into a pcDNA3.1 vector with HA tag.
Chinese Journal of Cancer 2008; Vol. 27 Issue 10
 Correlation of Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) to fascin and phosphorylated Stat3 in nasopharyngeal carcinoma

Positive clones were validated by sequencing. LMP1-

expressing plasmid and the empty plasmid were
transfected into CEN1 cells using Lipofactamine
2000. Cells were harvested and lysed 24 h later. After
protein quantification, expressions of Fascin and
pStat3 were detected by western blot. α-tubulin was
used as the internal reference.
Results judgments. Positive hybridization for
EBER was presented as violet blue particles in the
nucleus. All six indices, LMP1, Fascin, p53, Ki-67,
Bcl-2 and pStat3, detected by IHC were presented
as yellowish-brown particles. Staining of LMP1 Figure 1. EBER expression in NPC tissues and lymph node metastases in NPC. (A) EBER
appeared on the cell membrane or/and in the expression in NPC tissues (x 400); (B) EBER expression in lymph node metastases (x 200).The
cytoplasm, staining of Fasicn and Bcl-2 was in the positive staining is purple/blue in nuclei.
cytoplasm, and staining of p53, Ki-67 and pStat3
was in the nucleus. Clear appearance of LMP1 staining under a light
microscope was considered as positive expression of LMP. The rest five
indices were judged based on the staining intensity and the number
of positive cells.11,12 Staining intensity was scored as 0 (no detectable
stain), 1 (yellowish fine particles), 2 (yellowish brown particles) and
3 (brownish yellow particles). The percentage of positive cells was
scored as 0 ( < 25%), 1 (25–49%), and 3 ( > 50%). The sum of
the two scores was regarded as the final score to classify the results
into negative (< 3) and positive (≥ 3). At least 5–10 high power
visual fields were randomly selected for each section to calculate the
mean value.
Statistical Analysis. χ2 test was performed using SPSS 11.5. The
significance level was α = 0.05.

Results
EBER expression in NPC tissues and the corresponding
metastatic lymph nodes. The expression rates of EBER in 43 NPC
tissues and 21 metastatic lymph nodes were both 100%. Positive
staining of EBER was observed in the nuclei of most cancer cells
(Fig. 1 A and B). Pre-infiltrative changes, including atypical hyper-
plasia at different degrees or preinvasive carcinoma of nasopharyngeal
covering epithelium or recess epithelium, appeared around the
cancer nest of some NPC tissues. Proliferation of some epithelium
was not obvious. There were only two to three layers of covering
epithelium. Some epithelial surfaces were still covered with ciliated
columnar epithelial cells. However, the basal cells were found to
have heteromorphism, presenting as disturbed arrangements, loss
of polarity, large and darkly stained nucleus. Positive expression of
EBER was also detected in different amount of allotypic nucleus in
these pre-infiltrative lesions. Moreover, positive EBER were found in
a few infiltrative lymphocytes in the cancer nest and/or mesenchymal
of the cancer nest.
Expressions of LMP1, Fascin, pStat3, p53, Ki-67 and Bcl-2.
Positive LMP1 staining was located on the cell membrane and/
or in the cytoplasm of cancer cells, presenting as focal or patchy
staining (Fig. 2). In different cases or even different areas of cancer
nest of the same case, the distribution of positive LMP1 staining
was not completely consistent. LMP1 expression was also detected
in metastatic lymph node of NPC, and the positive rate was 46.7%
(10/21).
Positive Fascin staining was distributed in the cytoplasm of cancer
cells and manifested as yellowish brown particles (Fig. 3). In different
Figure 2. LMP1 expression in NPC tissues (x 400). The positive staining is
brown in the cellular membrane and/or cytoplasm.
cases or even different areas of cancer nest of the same case, the distri-
bution of Fascin staining was not completely consistent. Fascin was
also expressed in normal covering epithelium and recess epithelium
around NPC tissues, but was mainly limited to basal cells. Fascin
expression was observed in almost the full-length of epithelium,
when pre-infiltrative changes appeared. Furthermore, weak staining
of Fascin was detected in interstitial lymphocytes, plasmocytes, and
vascular endothelial cells inside or around the cancer nest.
Positive expression of pStat3 was mainly distributed in the nucleus
of cancer cells, also in the cytoplasm with different intensity (Fig 4).
In different cases or even different areas of cancer nest of the same
case, the distribution of pStat3 was not completely consistent. pStat3
was found expressed in almost the full length of covering epithelium
and recess epithelium around NPC tissues before the presence of
pre-infiltrative changes. Furthermore, pStat3 expression was also
observed, mainly in the cytoplasm, of some interstitial lymphocytes,
plasmocytes inside and around the cancer nest, yet with much weaker
intensity compared to that in cancer cells.
Positive staining of p53 and Ki-67 was located in the nucleus
of cancer cells, while that of Bcl-2 was in the cytoplasm. Similar to
other three indices, the distribution of p53, Ki-67 and Bcl-2 was
not completely consistent in different cases or even different areas of
cancer nest of the same case.

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 Correlation of Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) to fascin and phosphorylated Stat3 in nasopharyngeal carcinoma

Figure 3. Fascin expression in NPC tissues (x 400). The positive staining is Figure 4. pStat3 expression in NPC tissues (x 400). The positive staining is
brown in the cytoplasm. brown mainly in nuclei.

Table 2 Expression of six proteins in NPC and lymph node metastases [cases (%)]

ap = 0.05, bp < 0.05, NPC tissues with lymph node metastases vs. NPC tissues without lymph node metastases.

Table 3 Relationship between LMP1 and Fascin, p53, Ki-67, Bcl-2 and pStat3 in 43 cases of NPC tissues [cases (%)]

ap < 0.05, vs. LMP1.

When the above mentioned proteins appeared in metastatic lymph
nodes, they were also detected in the corresponding primary foci of
NPC; differences in Ki-67 and pStat3 expressions were significant
between NPC tissues complicated with lymph node metastasis
and those were not (p ≤ 0.05). However, there were no significant
differences in the expression of these six indices compared with their
corresponding metastatic lymph node tissues (Table 2).
Correlation of LMP1 to Fascin, pStat3, p53, Ki-67 and Bcl-2. In
43 cases of primary NPC, positive expressions of Fascin, pStat3, p53,
Ki-67 and Bcl-2 in the LMP1 positive group were compared with
those in the LMP1 negative group (Table 3). The expression of LMP1
was positively correlated with that of Fascin (χ2 = 7.442, p = 0.023),
pStat3 (χ2 = 6.857, p=0.009), p53 (χ2 = 4.242, p = 0.039), Ki-67 (χ2
= 4.242, p = 0.039) and Bcl-2 (χ2 = 4.521, p=0.033) (Table 3).
Effect of LMP1 expression on pStat3 and Fascin in CNE1 cells.
LMP1 expressing plasmid and the empty vector were transfected
into CNE1 cells. Western blot showed that, 24 h after transfection,
the expression of Fascin and pStat3 in LMP1 transfected group was
significantly higher than that in the empty vector group (Fig. 5).
Discussion
The present study assessed the expression of EBV LMP1 in
primary NPC and the corresponding lymph node metastatic carci-
noma. Results showed that LMP1 was highly expressed in lymph
node metastatic tissues of NPC, suggesting a role of LMP1 in the
infiltration and metastasis of NPC. Further investigation on the
correlation of LMP1 expression to Fascin, pStat3, p53, Ki-67 and
Bcl-2 expression in NPC tissues revealed that there was a significant
association between LMP1 and the five proteins.
Fascin expression in NPC tissues in relation with LMP1
expression. Our results showed that Fascin was expressed in 85.7%
(18/21) of NPC tissues complicated with lymph node metastasis, in
90.5% (19/21) of the corresponding lymph node metastatic tissues,
and in 100% (22/22) of NPC tissues not complicated with lymph

340 Chinese Journal of Cancer 2008; Vol. 27 Issue 10

 Correlation of Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) to fascin and phosphorylated Stat3 in nasopharyngeal carcinoma
Figure 5. Expressions of Fascin and pStat3 in CNE1 cells transfected with
LMP1-expressing plasmid detected by Western blot.
node metastasis. Fascin was mainly distributed in the cytoplasm of
cancer cells. It is notable that Fascin expression was positive in pre-
infiltrative lesions of some NPC tissues. Positive staining of Fascin
was predominantly distributed in the basal cell layer of allotypic
epithelium. These cells showed some atypia heteromorphism, which
implies that the expression of Fascin may be up-regulated during
malignant transformation of NPC. Additionally, the distribution
of positive Fascin exhibited heterogeneity. Mosialos et al.9 found
that the expression of Fascin was up-regulated in EBV transfected B
lymphocytes. However, the relationship of Fascin with EBV related
nasopharyngeal epithelial tumor is still unclear. This study showed
that there was a significant positive correlation (p < 0.05) between
Fascin expression and LMP1 in NPC tissues. In vitro experiments
also confirmed that LMP1 could significantly up-regulate the
expression of Fascin in NPC cells. It is proposed that LMP1 may be
involved in migration and distant dissemination of cancer cells via
up-regulation of Fascin. However the molecular mechanism needs
further investigation.
pStat3 expression in NPC tissues in relation with LMP1
expression. We found that pStat3 was expressed in most cases of
NPC and the corresponding lymph node metastatic carcinoma.
Positive staining of pStat3 was mainly distributed in the nucleus of
cancer cells and occasionally in the cytoplasm of a few cancer cells.
Gries et al.10 reported that LMP1 activated Stat3 and Stat1 by binding
with JAK3, and activated Stat3 had oncogene-like functions.13 Chen
et al.14 demonstrated combination of activated Stat3 with EB virus
Qp (BamHI Q promoter) and LMP1 L1-TR promoter, thus to
up-regulate the expression of EBV EBNA1 and LMP1. There was a
significant positive correlation (p < 0.05) between the expression of
LMP1 to pStat3 in 43 cases of NPC, which was also confirmed by in
vitro experiments. Therefore, we suggest that LMP1 can up-regulate
the expression of pStat3 in NPC cells through activating Stat3 and
subsequently participating in the malignant biological behavior of
cancer cells.
LMP1 expression in NPC tissues in relation with p53, Ki-67
and Bcl-2 expression. The main function of wild type p53 is to keep
cell cycle at the G1 phase, thus to win time to repair damaged DNA.
However, other factors, such as gene mutation, may deactivate p53
and lead to malignant transformation of the cells. Although, there
is little chance (~10%) of p53 gene mutation in NPC, abnormal
protein accumulation is quite usual.15 Counting mitoses, prolifer-
ating cell nuclear antigen (PCNA), and Ki-67 are common indices
which reflect the degree of cell proliferation. Mitosis is a small part
www.landesbioscience.com
of the whole cell cycle. The half life of PCNA exceeds the whole cell
cycle time, which means that cells may also express PCNA even if
they are not within the cell cycle. Therefore, neither of these two
indices can accurately reflect cell proliferation. Expression of Ki-67
is limited to the whole cell cycle, making it a reliable index to reflect
cell proliferation. Bcl-2 and its gene family are main genes regulating
apoptosis. Bcl-2 can promote cell survival and inhibit apoptosis. Our
study revealed positive correlations of LMP1 to p53, Ki-67 and Bcl-2
in 43 cases of primary NPC (p < 0.05). Our findings are consistent
with previous reports, suggesting a close correlation of LMP1 with
proliferation and apoptosis in NPC tissues.
Expression characteristics of six indices in NPC and lymph
node metastatic carcinoma. The positive expression rates of the six
measured indices were basically consistent in the primary NPC and
the corresponding lymph node metastatic carcinoma. There was no
significant difference in positive expression rates of LMP1, Fascin,
p53 and Bcl-2 between NPC tissues complicated with lymph node
metastasis and those without. In the mean time, the positive expres-
sion rates of Ki-67 and pStat3 in NPC tissues complicated with
lymph node metastasis was significantly lower than that in NPC
tissues not complicated with lymph node metastasis. This result
needs further validation using a large sample study.
In summary, EBV LMP1 is highly expressed in lymph node
metastasis of NPC. The expressions of Fascin and pStat3 in NPC
tissues have positive correlations with LMP1. Furthermore, LMP1
can significantly up-regulate the expression of Fascin and pStat3 in
NPC cells, suggesting that LMP1 may be involved in the malignant
transformation of nasopharyngeal epithelial cells, as well as in infil-
tration and metastasis of cancer cells. In addition, the expression of
LMP1 in NPC tissues is closely related to the proliferation of cancer
cells.
Acknowledgements
Grants: National Natural Science Foundation of China (No.
30300382); Guangzhou Municipal Science and Technology Research
Project (No.2006Z3E4081); Guangdong Provincial Natural Science
Foundation Research Team Project
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