carcinoma (NPC), is a highly metastatic epithelial malignancy showing high
prevalence in Southeast Asia and North Africa. It can be
classified into three histological types, namely nonkeratinizing squamous cell
carcinoma, keratinizing squamous cell carcinoma and undifferentiated carcinoma.
At diagnosis, most NPC patients have locally advanced disease, which includes
stages ranging from T2b N0 to T4 N3. Radiotherapy (RT) can effectively control
the early stage of NPC, yielding an excellent
90%-95% of a 5-year local control rate in clinical trials. However,
radiotherapy alone is not the optimal treatment for patients with locally
advanced disease, which is the most frequent clinical presentation at
diagnosis, since it yields an unsatisfactory 5-year survival rate of about 50%[2-3].
Failing to find an early nasopharyngeal carcinoma metastasis is the main reason
of death. So, looking for early markers of specific patients with
nasopharyngeal carcinoma will help early detection, early diagnosis and early
treatment to improve survival rate of patients with nasopharyngeal carcinoma.
The Etiology of NPC Markers
is characterized by its distinct racial and geographical distribution with a
multifactorial etiology. It has been well accepted that, NPC is related to EBV infection,
but environmental and genetics factors also play critical roles.
Among host genetic markers associated with NPC, the highly variable class I
human leukocyte antigen (HLA) genes on chromosome 6 (6p21.3) have shown a
strong and consistent association with NPC risk. It has been observed that, the
frequency of some HLA alleles and/or haplotypes is increased (susceptible) or decreased (protective) in patients with NPC compared
with normal individuals. In the HLA loci, A2, Bw46 were slightly higher than
the non-B17 antigen in nasopharyngeal cancer family two times, which greatly
increased (about 21 times) the risk of suffering from nasopharyngeal.
Nitrosamine has been identified as a carcinogen for NPC, cytochrome P450 2A6 (CYP2A6) played an important role in NPC development.
Relationships between the disease and the CYP2A6 were studied on 74 NPC patients and 137 age-matched
healthy controls by using polymerase chain reaction-restriction fragment length
polymorphism (PCR-RFLP) assay to distinguish between a wide type allele. Overall, a
significant association between CYP2A6
polymorphism and NPC development was observed (P<0.05) .This suggested that
CYP2A6 polymorphism may play
a crucial role in NPC susceptibility and it may be used as a risk marker for
NPC. Old et al for the first time proved that EBV
and nose using immunodiffusion serological relationship pharyngeal cancer. With
the high incidence of nasopharyngeal carcinoma in southern China, EBV is closely related to the prevalence
in Africa is dense with Burkitt lymphoma Cut
of Nasopharyngeal Carcinoma
was the first identified human tumor virus associated with various
malignancies. The fact that EBV genome is present in almost all NPC tissues
renders is an ideal tumor marker for NPC. EBV gains access to the B-cell
compartment, where it drives robust B-cell proliferation through expression of
six EBV nuclear antigens, multiple non-coding RNAs, and two integral membrane
proteins, latent membrane protein (LMP1) and latent membrane protein 2A (LMP2A).
Assessment of immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies responses
to various EBV antigen complexes, usually involving multiple serological assays，the positive rates of EBV
Rta-IgG, VCA-IgA, EA-IgA and EBV DNA in untreated NPC patient group were higher
than those in other two groups. High-titer antibodies to VCA and early antigen,
especially of high IgA class or high titers that persist after therapy, were
found to be associated with a poorer prognosis .
study found that patients with NPC serum EB virus DNA level and clinical
staging and tumor progression was significantly correlated . The
γ-H2AX level was detected by
Gou et al. in NPC cells CNE1 before and after EBV infection using Western
was expressed in most NPC specimens (94%), which was much higher than that in
nasopharyngitis(NPI)(40%), and EBV was presented in 94% of NPC but only 30% in
NPI. Finally, Western blotting showed that γ-H2AX level significantly
increased in CNE1 cells after EBV infection. This study demonstrated that an
intimate connection existed betweenγ-H2AX expression and EBV infection in NPC both in
vivo and in vitro. EBV infection might induce DNA damage in CNE1 cells, which
causes genome instability and initiates or promotes the tumorigenesis and
development of NPC.
The EBV oncogene BARF1 is expressed in a high proportion of NPC. The structure of
the secreted BARF1 glycoprotein expressed in a human cell line was solved by
X-ray crystallography. BARF1 was closely related to glycoprotein CD80
or B71. BARF1 mRNA detection of EBV DNA and molecular level can help
the non-invasive diagnosis of NPC . BARF1 was present in the serum and saliva from North African and Chinese patients
with NPC. The secreted EBV oncoprotein
showed a powerful mitogenic activity in B cells. BARF1 is a particularly
promising marker for all ages of patients with NPC, its mitogenic activity
suggests their implication in the oncogenic
development of NPC.
LMP-1 played an important role in enhancing NPC
cell response to arsenic trioxide (As2O3). The
elongation of telomere length induced by LMP-1 might contribute to the
mechanisms of As2O3 sensitivity. Preclinical studies demonstrated that As2O3
could inhibit LMP-1 expression, dictate apoptosis and alterations of cell cycle distribution
and growth retardation. LMP-1-positive NPC cells were more sensitive to
As2O3 treatment than LMP-1-negative NPC cells . Further study found that As2O3 could
reduce metastatic potential of NPC cells, involving inhibition of MMP-9
expression. LMP-1 were reduced in this process and seemed to enhance
anti-metastatic activity of As2O3 . Of all the EBV-encoded product, latent membrane protein LMP-1 is considered to be an oncogene which playing an essential role in cell transformation and metastasis. The EBV protein, latent
membrane protein 2A (LMP2A), is expressed in NPC and can modulate
epithelial proliferation, transformation and differentiation, and as such may
summary estimates for VCA-IgA in the diagnosis of NPC were: sensitivity 0.91
(95% confidence interval (CI): 0.90 - 0.92), specificity 0.92 (95%CI: 0.92 -
0.93) , positive likelihood ratio 31.65 ( 95%CI: 10.99 - 91.15 ), negative
likelihood ratio 0.10 (95%CI: 0.07 - 0.13) and diagnostic odds ratio 414.59
(95%CI: 174.96 - 982.42). The area under the summary receiver operating
characteristic curves was 0.98. The sensitivity and the specificity of serum VCA-IgA
are very high, suggesting that the presence of VCA-IgA in peripheral blood is a
valuable predictor for NPC, The sensitivity of VCA-IgA and the specificity of
EA-IgA are the highest while detecting solely. Combined determination could
improve the diagnostic sensitivity and accuracy for NPC.
high-throughput approach shows that EBV microRNAs are generally more
up-regulated than microRNAs of human origin. Authors found that their distinct
presence in the serum of NPC patients positively correlated with cellular copy
numbers of EBV microRNAs. Further investigation of potential EBV microRNA
target genes revealed inhibition of tumor suppressor genes (e.g. phosphatase
and tensin homolog deleted on chromosome ten, PTEN) and extensive deregulation of several
pathways frequently involved in NPC (e.g. Wnt signaling), Profiling of
EBV-encoded microRNAs in nasopharyngeal carcinoma reveals potential biomarkers
was established by biopsy of the nasopharyngeal mass. Fused positron emission
tomography/computed tomography is a valuable imaging tool in patients for
staging diagnosis of NPC. However, NPC is commonly diagnosed late due to its
deep location and vague symptoms . By measuring
the nuclear DNA content, DNA diploidy was found to occur earlier in the
progression from premalignant to malignant head and neck squamous cell
carcinomas (including NPC). This finding was promising to demonstrate
methods that were readily applicable for routine diagnostic work . It has been reported that the high sensitivity (81%)
and specificity (0% false positives) of detecting aberrant methylation of CDH13 (encoded a cell adhesion molecule Hcadherin) from
nasopharyngeal swabs suggested it could be utilized as a tool for
samples from NPC patients and healthy subjects with four specific
VCA-IgA/EA-IgA profiles were tested with an anti-EBV Western blot test kit from
EUROIMMUN AG, among the markers screened, EA-D p45-IgG showed a statistically
significant difference (p < 0.05) between NPC and non-NPC subjects with
VCA-IgA positivy. In the verification experiment, the specificity and
sensitivity of EA-D p45-IgG were 75.0% and 90.6 %, respectively. EA-D p45-IgG
might be a potential biomarker for NPC diagnosis. Cf-DNA was
extracted from serum collected from NPC patients and sex-matched healthy
subjects. The promoter hypermethylation status of the five genes (RASSF1, CDKN2A, DLEC1, DAPK1 and UCHL1) was assessed
by methylation-specific PCR after sodium bisulfite conversion. The combination
of four-gene marker - CDKN2A,
DLEC1, DAPK1 and UCHL1 - had the highest sensitivity and specificity in
predicting NPC.Screening DNA hypermethylation of tumor suppressor genes in
serum was a promising approach for the diagnosis of NPC. The
levels of CYFRA21-1 and Tumor Specific Growth Factor (TSGF) in NPC group were
remarkably higher than those in benign nasopharyngeal disease and normal
control groups (P < 0.01). The detection sensitivity is much higher than
other tumor markers. Combined detection of two kinds of serum tumor markers
increases the detective positive rate. CYFRA21-1 and TSGF can serve as the
serum tumor marker in clinical diagnosis of NPC.
necrosis factor a (TNF-a) as another tumor immune cytokine, tumor necrosis with
degradation effects, the content of TNF-a detected in NPC patients and normal
control can be used as one of indicators of the early diagnosis of NPC.
More evidences indicated that inactivation of tumor suppressor genes (TSGs) by
aberrant promoter methylation is an early event during carcinogenesis, The
researchers use the multiplex methylation specific-PCR (MMSP) assay which was
designed to detect tumor-specific methylation status of several NPC-related
genes, they collected paired nasopharyngeal (NP) swabs and NPC biopsies from 49
NPC patients and twenty noncancerous controls. The results showed that MMSP
patterns of NPC swab were largely consistent with those of corresponding
biopsies, MMSP assay is a reliable and potential diagnostic tool for NPC.
A study showed that DNA methylation suppresses BRD7 expression in NPC cells. In
vitro DNA methylation in NPC cells silenced BRD7 promoter activity and
inhibited the binding of the nuclear protein (possibly Sp1) to Sp1 binding
sites in the BRD7 promoter. In contrast, inhibition of DNA methylation augments
induction of endogenous BRD7 mRNA in NPC cells. DNA methylation of BRD7
promoter might serve as a diagnostic marker in NPC. miRNAs and
EBV encoded miRNAs play key roles in almost all the steps of epithelia cell
carcinogenesis, More importantly, some miRNAs could be secreted out and play a
role in the microenvironments. The level of sera miRNAs is correlated with the
copy numbers of host miRNAs in NPC. Promising results of gene therapy have also
been achieved by lentiviral delivered miRNAs. so miRNAs would be potential
biomarkers of early clinical diagnosis of NPC.
The Markers of Targeted Therapies
High-dose radiotherapy with adjunctive
chemotherapy is the primary treatment of NPC. Radiotherapy dose and field margins are
individually tailored to the location and size of the primary tumour and lymph
nodes. New types of treatment are being tested in clinical trials, which
include biological therapy and intensitymodulated radiation therapy. It offer
hope for better control of the disease .
study found that the epidermal growth factor receptor (EGFR) was one of the
most targeted receptors in the field of oncology. It has been highly expressed
in nasopharyngeal , and its expression is often closely associated with a poor
prognosis. Tips for EGFR molecular targeted therapy may improve
the prognosis of patients. Basic research has proved more EGFR antagonist used
alone, in combination with radiotherapy or radiotherapy plus chemotherapy
combined use could significantly inhibit the growth of nasopharyngeal carcinoma
cell lines, proliferation and increased radiation and chemotherapy for
nasopharyngeal carcinoma cells kill strains . The
recombinant plasmid hTERTp/tk/pGL3 was transfected into human NPC HNE1 cells
and the expressions of TK and telomerase were investigated. The targeted
killing effect induced by hTERTp/tk on HNE1 cells was assessed using RT-PCR and
MTT assay. the tumor cell-killing effect of hTERTp/tk/pGL3 was slightly milder
than that of the positive control CMV/tk/pGL3 that produced nonselective cell
killing.it indicated that hTERTp/tk, a tumor-specific expression system, allows
targeted tumor cell killing and reduces the activity of telomerase in NPC cells
in vitro. The antiapoptotic gene bcl-2antisense oligodeoxynucleotide, G3139, was
found to have proapoptotic effects in C666-1 cell line. Combining with
cisplatin, it was curative in C666-1 NPC xenograft tumours in vivo. The sequence-dependency of these effects was
consistent with an antisense mechanism. The result suggested that bcl-2 might represent a biologically relevant target
for the development of novel combinatorial therapies for NPC.
LMP2A is found to play a key role in the
development of NPC. In this study, they inhibited LMP2A gene expression by lentivirus-mediated RNAi and
construct a efficient and stable lentivirus vector, which efficiently
downregulate the expression of LMP2A
gene in infected cell line C666-1, which inhibits the proliferation and colony
formation of C666-1 cells, the result shows that lentivirus-mediated RNAi
knockdown of LMP2A
inhibits the growth of NPC cell line C666-1 in
vitro, and LMP2A may
be a potential target for gene therapy in treatment of NPC. A
study has explored the effects of RNA interference (RNAi) targeting four
different genes (VEGF, c-myc, survivin, hTERT) on the growth and proliferation
of NPC CNE-2Z cells. The inhibitory effect of the plasmids on xenograft tumors
were observed in nude mice.they found that RNA interference targeting multiple
genes can effectively inhibit NPC proliferation and induce apoptosis, which
provides an experiment basis for NPC gene therapy . Pathway
analyses by microarrays revealed that upregulation of NF-κB2 and survivin played central
roles in increasing resistance to apoptosis and demonstrated significant
inhibition of NPC cell proliferation, migration and invasion. These antitumor
effects were associated with induction of G2/M cell cycle arrest and
apoptosis, and downregulation of NF-kappaB target genes (EGFR, cyclin D1 and
survivin). This first demonstration of therapeutic benefits of NF-kappaB
targeting in NPC implicates the importance of targeting this pathway in NPC.
has been reported that frequent down regulation of the microRNA miR-218 in primary NPC tissues and cell
lines plays a critical role in NPC progression. Exogenous expression of miR-218
caused significant toxicity in NPC cells in vitro and delayed tumor growth in
vivo. A negative feedback loop indicated wherein miR-218 regulates NPC cell
migration via the SLIT-ROBO pathway. Our findings define an integrative tumor
suppressor function for miR-218 in
NPC and further suggest that restoring miR-218 expression in NPC might be
useful for its clinical management. To explore the inhibiting
effect of siRNA transfection against Survivin on the growth of nasopharyngeal
carcinoma cells. A study showed that the expression of survivin in xenograft
tumor was significantly inhibited by pshRNA-survivin/shRNA, the apoptosis of
tumor cells was accelerated and the growth speed of NPC cells in xenograft
tumor was retarded. The high expression of nasopharyngeal carcinoma's gene
could significantly be silenced by using technology of RNAi, the growth of
tumors could be inhibited also. It’s a novel treatment that have a good
researchers detected reduced 14-3-3 sigma
expression in 5/6 NPC tumor lines by quantitative reverse transcription PCR (RT-PCR) and Western blotting. By immunohistochemical staining, significant
down-regulation of 14-3-3 sigma was also found in 26/72 (36.1%) primary
tumors of NPC patients, who were treated with curative radiotherapy.
Importantly, they demonstrated that 14-3-3sigma expression is significantly associated
with both overall survival (OS) and cancer-specific survival (CSS), but not
with the clinical staging of NPC patients. In conclusion, low expression of
14-3-3sigma appears to be a valuable marker for better survival in patient with
NPC. These results provide the evidence that 14-3-3 sigma expression is a
significant prognostic factor for NPC patients.
Biomarkers For Prognosis And Progression of Cancer
to clinical data reported by conventional radiotherapy of nasopharyngeal
carcinoma after chemotherapy, early 5-year survival rate of patients with
nasopharyngeal carcinoma 70% -90%, but the 5-year survival in patients with
advanced nasopharyngeal carcinoma is only 20% -30%. Therefore, early diagnosis
huge impact on prognosis of nasopharyngeal carcinoma.It has been reported that
Human leukocyte antigen G (HLA-G) has multiple immune regulatory functions
including the induction of immune tolerance in malignancies. Western assays
showed high HLA-G expression in NPC cell lines, but not in normal
nasopharyngeal epithelium tissue, Moreover, high expression of HLA-G predicted
poor survival of NPC patients. Multivariate analysis indicated that HLA-G was
an independent and unfavorable prognostic factor. Prohibitin-1
(PHB, also known as PHB1) is a pleiotropic protein in cells involved in the
regulation of proliferation, apoptosis, transcription, and mitochondrial
protein folding. The scholars examined PHB mRNA levels using 24 nasopharyngeal
carcinoma (NPC) and eight normal nasopharyngeal epithelium (NPE) tissues. PHB
mRNA and protein expression levels were significantly down regulated in NPC
tissue specimens compared with the NPE samples (P<0.01). In addition,
decreased PHB expression correlates significantly with a poor prognosis,
whereas decreased PHB protein expression is closely associated with advanced
clinical stage and metastasis in NPC lesions. Therefore, Prohibitin-1 is an
important biomarker for nasopharyngeal carcinoma progression and prognosis.
DNA-binding protein inhibitor 2 (ID2) in NPC was significantly increased in NPC
cell’s nucleus when compared with that in normal nasopharynx tissues.
Furthermore, the higher expression level of nuclear ID2 was significantly
associated with tumor size (T classification), lymph node metastasis (N
classification), and clinical stage. The study demonstrated that
over-expression of ID2 protein is an unfavorable prognostic factor which
promotes cell proliferation in NPC.
a cancer-related long non-coding RNA, evaluated its prognostic value for NPC.
Quantified using real-time PCR, which was higher compared with non-cancer
tissue samples. Most importantly, NPC patients with higher HOTAIR levels had a
poor prognosis for overall survival using univariate and multivariate analysis.
HOTAIR is a potential biomarker for the prognosis of NPC, and dysregulation of
HOTAIR might play an important role in NPC progression. The expressions of nm23-H1 and VEGF protein were examined by
immunohistochemistry S-P staining in NPC tissues. The low level expression of
nm23-H1 protein and the high level expression of VEGF protein might be associated with the development and poor
prognosis of NPC. The phosphorylation of eukaryotic translation
initiation factor 4E (eIF4E) by MAP kinase-interacting kinases (Mnk) on Ser-209
promotes cellular proliferation, survival, malignant transformation and
metastasis. The results showed that the positive percentage of p-Mnk1 and
p-eIF4E proteins expression in NPC (83.5% and 75.4%, respectively) was
significantly higher than that in non-cancerous nasopharyngeal epithelium
(40.0% and 32.9%, respectively). Increase of p-eIF4E and p-Mnk1 expression was
significantly correlated inversely with overall survival.in summery,high
expression of p-Mnk1 and p-eIF4E might be novel valuable biomarkers to predict
poor prognosis of NPC.
a stroma-associated protein, statistical analysis showed over-expression of
periostin was significantly associated with advanced clinical stage (P <
0.001) and lymph node metastasis (P < 0.001) and decreased overall survival
(P < 0.001) in NPC. The result showed that periostin was able to promote
invasiveness of NPC cell. Cox regression analysis indicated over-expression of
periostin was an independent prognostic factor. Periostin is a potential
biomarker for the differentiation and prognosis of NPC, and it might play an
important role in the progression of NPC. A correlation analysis
demonstrated that high expression of H3K27me3 was positively associated with
tumor later T classification, tumor metastasis, advanced clinical stage and
chemoradioresistance (P < 0.05). These findings provide evidence that
H3K27me3 expression, as examined by IHC, has the potential to be used as an
immunomarker to predict NPC chemoradiotherapy response and patient prognosis.
Secretory cells and tissue proteome transcriptome analysis of serum
marker screening nasopharyngeal carcinoma, serum cystatin A levels found in
patients with nasopharyngeal carcinoma was significantly higher than that in
healthy controls . Pre-treatment
of nasopharyngeal carcinoma patients with high levels of cystatin A N the
higher stages, the prognosis is poor. Tip cystatin A may be a potential
prognostic marker of nasopharyngeal carcinoma.
these markers used existing in tumors that also existing in the normal
population and non-cancer patient's blood and body fluids. In the diagnosis of
malignancy, the sensitivity and specificity is not high, it is currently only used for secondary tumors
diagnosis, these markers cannot be solely over the reference range for
diagnosis. Therefore, these markers in the early diagnosis of NPC need requires
a lot of research, but it makes sense in the monitoring of prognosis and
treatment of NPC. With the development of molecular biology, there have appeared
new detection methods, Genomics, proteomics, metabolomics and bioinformatics
each plays a more and more important role for molecular biomarker discovery.
Make the specificity and sensitivity improved in the related markers of NPC,
but still not ideal. We now have a better understanding of this disease,
including its diagnosis, monitoring, treatment and prognosis. In the era of
molecular targeted therapy, explore the best combined detection of new markers is still the direction of research.
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