SIMULTANEOUSLY BOTH EXPRESSION OF LMP-1
AND METHYLATION OF E-CADHERIN:
MOLECULAR BIOMARKER IN STAGE IV OF
NASOPHARYNGEAL CARCINOMA PATIENTS
Lao TD1, Truong PK1, Thieu HH1, Nguyen DH2, Nguyen MT3, Le TAH1,*
*Corresponding Author: Associate Professor Thuy A.H. Le, Department of Pharmaceutical and Medical
Biotechnology, Ho Chi Minh City Open University, 35-37 Ho Hao Hon Street, Ho Chi Minh City,
Vietnam. Tel.: +84-905-784-471. E-mail: thuy.lha@ou.edu.vn
page: 57
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DISCUSSION
In this study, we pointed out the significantly high
expression of LMP-1 in NPC biopsy samples, accounting
for 76.34%, compared to no expression in non-cancerous
samples. The increased expression of LMP-1 was strongly
associated with NPC risk, with statistical significance,
based on the calculated OR value of 638.73 (p <0.05).
Thus, all these results imply that the oncogenic role of
LMP-1 in NPC was well evaluated in this case/control.
According to the etiological factor, as previously reported,
LMP-1 is an integral membrane protein that plays a key
role in EBV-mediated oncogenesis involved in many signal
pathways, including nuclear factor-κ-light-chain-enhancer
of activated B cells (NF-κB), c-Jun N-terminal kinase
(JNK), p38 mitogen-activated protein (MAP) pathway
[20-22]. Moreover, LMP-1 is capable of inducing a range
of phenotypic changes in epithelial cells [23]. In the latent
stage of NPC, the expression of LMP-1 are expressed in
EBV-associated malignant type II, exemplified by NPC,
contribute to cell survival, and NPC metastasis [11,24].
Thus, the LMP-1 gene, which encoded the LMP-1 protein,
performed the oncogenic function in the case of EBVassociated
malignancies, including NPC, has been identified
as the meaningful diagnosis biomarker as well as potential
therapeutic molecule target for NPC. Additionally,
the finding of LMP-1 characteristics was again confirmed
in the current case-control study, and it may open up the
treatment approach for NPC therapy based on the inhibitor
of LMP-1 expression in EBV-associated NPC. The inactivation
of the E-cadherin gene through the methylation of
its promoter has been postulated as the metastasis-associated
factor of NPC development and progression [14-17,25].
In this study, the methylation of the E-cadherin gene was examined by the nested-MSP method, which shows an
advantage in the hypermethylation analysis by increased
MSP sensitivity of approximately 50-fold [26]. Here, we
found that the hypermeth-ylation of the E-cadherin gene
promoter in 73.12% NPC biopsy samples, which was
significantly higher than in control samples, accounting
for 30.00%. This frequency of methylated E-cadherin
gene in the current study was similar to that previously
reported by Niemhom et al. [15], Ayadi et al. [16], and
higher than the study by Ran et al. [17]. Even though the
differences in E-cadherin methylation frequencies exist,
they met the common point where the methylation of the
E-cadherin gene was significantly associated with the risk
of NPC based on the calculated OR (OR >1.0, p <0.05).
Therefore, we believe that the aberrant methylation of the
E-cadherin gene is significant in NPC and may serve as
the promising biomarker that could be potentially used
for diagnosis of NPC.
To answer whether or not there was the association
between the expression of LMP-1 and methylation of
E-cadherin in NPC tumorigenesis, the statistical analysis
was performed between the expression of LMP-1 and
E-cadherin methylation in 93 clinical NPC biopsy samples.
Our results reported that there was strongly correlation between
the LMP-1 expression and E-cadherin methylation
in NPC samples (p <0.0001). Especially, the status of both
gene positive was significantly associated with the stage
of NPC, in which the highest frequency of 37.63% (35 of
93) NPC samples were positive for both LMP-1 expression
and methylation of E-cadherin was observed. Additionally,
in the stage IV, we found that in case of LMP-1-positive
samples, 35 cases of 37 samples (counting for 94.60%)
were positive for methylation of E-cadherin. Whereas,
we found that 7 of 15 cases (counting for 46.67%), 19 of
33 cases (counting for 57.58%) in the stage II and stage
4, respectively, were positive for both genes. Therefore,
it could be concluded that the expression of LMP-1 and
methylation of E-cadherin are more likely to be positive
in the stage IV than the early stage of NPC. Based on these
finding, it could be induced that the expression of LMP-1,
which profound effects on the proliferation of NPC cells
as well as the highly invasive, malignant growth of NPC
tumors, and addition of epigenetics change, methylation
of E-cadherin, a main key mediator of cell-cell adhesion,
are likely to be a major contributing factor to the advance
stage of nasopharyngeal tumor. These finding was similar
to pervious study, the LMP-1 have an ability to down regulation
of expression of E-cadherin through the pathway
of E-cadherin/β-catenin, in our study the inactivation of
E-cadherin caused by the epigenetics event, resulting in
enhancement of invasive capacity of metastasis of NPC
cells [27]. E-cadherin, which is the important factor responsible
for the development and metastasis of nasopharyngeal
tumor, may combine to act in a complex sequential
process of nasopharyngeal tumorigenesis that culminates
in metastasis of EBV-infected tumor cells. Therefore, these
combination testing will be used as a parameter in the
diagnosis of NPC in further studies.
In this study, the E-cadherin gene has been reported
to be a candidate therapeutic target in human cancers, such
as hepatocellular carcinoma [28], nasopharyngeal cancer
[17], breast cancer [29]. Especially, growing evidence
supported epigenetics drug (epi-drug) has been generated
and developed to explore the epigenetics reversion
to treat human cancers. Giving the example, the inhibitors
of DNA meth-ylation drugs, such as 5-azacytidine,
5-aza-2’-deoxycytidine, etc. acts as a potent inhibitor of
the DNA demeth-ylase, enzymes that catalyze the process
of DNA methylation [30]. In other study, they reported
that 5-aza-2’-deoxycytidine could restore the E-cadherinsilenced
lung cancer and metastasis of cancer cell [31].
Concerning to viral therapy, as reported, LMP-1 gene, and
its encoded protein play an oncogenic role in NPC, including
the proliferation as well as the metastasis of NPC cells,
whereby evidence of its expression can only be inferred
by its inhibition being detrimental to the growth of the
cell, therefore, LMP1 may be a value therapeutic molecule
target in the treatment of EBV associated disease, including
NPC [32]. Therefore, the re-activation of E-cadherin,
especially combined with viral therapy, will be a candidate
therapeutic target in NPC. This study is believed to show
the relationship between LMP-1 expression, E-cadherin
gene methylation reinforced the basis for pursuing LMP1
and E-cadherin as a therapeutic molecule target in NPC.
As reported, the striking different expression of LMP-1
and aberrant methylation of E-cadherin, therefore, towards
to activation of tumor suppressive E-cadherin and/
or inhibition of oncogenic LMP-1 expression may open
up the molecule-biomarker for the development of therapeutics
for NPC. This suggested a clinical trial could be
performed on the group of NPC patients with advance
stage to improve their survival and recovery. Therefore,
it is necessary to design such a study to consider the effect
treatment on two criteria described above by the treatment
which focused on each molecular target or both targets.
Conclusions. Our data indicated that the LMP-1
expression and E-cadherin methylation were significantly
correlated with the risk of NPC. The frequency
of LMP-1 expression and E-cadherin methylation were
higher in NPC biopsy samples, counting for 76.34% and
73.12%, respectively, compared to non-cancerous samples.
Additionally, the strong association between the LMP-1
expression and E-cadherin methylation was observed in
NPC samples. The status of both gene positive was sig nificantly associated with the stage of NPC, in which the
highest frequency of 37.63% (35 of 93) NPC samples were
positive for both LMP-1 expression and methylation of
E-cadherin, was reported. In summary, the authors of this
paper demonstrated that the relationship between LMP-1
expression, E-cadherin gene methylation reinforced the
basis for pursuing LMP1 and E-cadherin as a molecule
biomarker in NPC.
Acknowledgments. We wish to express our thanks
to the research project sponsored by Ho Chi Minh City
Department of Science and Technology, Vietnam; Ho Chi
Minh City Open University, Vietnam. We also thank all the
recruited participants in this work and all the staff members
of Otorhinolaryngology in Cho Ray Hospital, Ho Chi Minh
City, for collecting the samples used in these studies.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
Funding. This project is funded by Ho Chi Minh
City Department of Science and Technology [Grant No.
42/2017/HD-SKHCN] and Ho Chi Minh City Open
University [Grant No. 2018.02.1].
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