- Open Access
Nasopharyngeal carcinoma: molecular biomarker discovery and progress
Molecular Cancervolume 6, Article number: 1 (2007)
Nasopharyngeal carcinoma (NPC) is a rare malignancy in most part of the world and it is one of the most confusing, commonly misdiagnosed and poorly understood diseases. The cancer is an Epstein-Barr virus-associated malignancy with a remarkable racial and geographical distribution. It is highly prevalent in southern Asia where the disease occurs at a prevalence about a 100-fold higher compared with other populations not at risk. The etiology of NPC is thought to be associated with a complex interaction of genetic, viral, environmental and dietary factors. Thanks to the advancements in genomics, proteomics and bioinformatics in recent decades, more understanding of the disease etiology, carcinogenesis and progression has been gained. Research into these components may unravel the pathways in NPC development and potentially decipher the molecular characteristics of the malignancy. In the era of molecular medicine, specific treatment to the potential target using technologies such as immunotherapy and RNAi becomes formulating from bench to bedside application and thus makes molecular biomarker discovery more meaningful for NPC management. In this article, the latest molecular biomarker discovery and progress in NPC is reviewed with respect to the diagnosis, monitoring, treatment and prognostication of the disease.
Nasopharyngeal carcinoma (NPC) is a disease in which malignant cells form in the tissues of the nasopharynx. As one of the most common cancers among Chinese or Asian ancestry, it poses one of the serious health problems in southern China where an annual incidence of more than 20 cases per 100,000 is reported. Men are twice as likely to develop NPC as women. The rate of incidence generally increases from ages 20 to around 50. Signs and symptoms at presentation include painless, enlarged cervical lymph nodes, nasal obstruction, epistaxis, diminished hearing, tinnitus, recurrent otitis media, cranial nerve dysfunction, sore throat and headache. According to the tumour-node-metastasis staging system promulgated by the American Joint Committee on Cancer, patients are designated into stages 0, I, IIA, IIB, III, IVA, IVB and IVC.
Molecular biomarkers in etiology
Factors thought to predispose to NPC include ethnic background, Epstein-Barr virus (EBV) exposure and consumption of food with volatile nitrosamines . It was found that the polymorphism of a nitrosamine metabolizing gene, CYP2A6, might play a crucial role in NPC susceptibility and it might be used as a risk marker for NPC .
In the most prevalent area, a lot of genetic polymorphism of CYP2F1 gene is found in Guangdong population of China. When the genetic polymorphism of CYP2F1 was investigated, the cooperated operations with multiple genetic polymorphisms of one or more genes were found to be potential critical factors contributing to the development and progression of NPC . On the other hand, the XRCC1 gene is important in DNA base excision repair. It was hypothesized that two common single nucleotide polymorphisms of XRCC1 (codons 194 Arg → Trp and 399 Arg → Gln) were related to the risk of NPC and interacted with tobacco smoking. The XRCC1 Trp194Trp variant genotype was found to be associated with a reduced risk of developing NPC in Guangdong population, particularly in males and smokers . On the other hand, Cyclin D1 (a key regulator of the cell cycle) and its altered activity associated with the development of cancer has been studied in a low-risk country. The proportion of NPC cases attributable to the GG Cyclin D1 genotype was 15% in Portuguese patients with NPC. This result might be important in the definition of a biologic predictive profile for the development of NPC within the Portugal population .
Molecular biomarkers of carcinogenesis
NPC is a complex disease caused by an interaction of EBV chronic infection, environment and host genes, in a multi-step process of carcinogenesis. Genomic instability can be an early event marker in carcinogenesis of NPC. Aggravation of genomic alterations is also a poor prognosis for cancer recovery . For understanding the putative order of genetic alteration in NPC carcinogenesis, evolutionary tree models (branching and distance-based tree models) were used to analyze comparative genomic hybridization data of NPC cases. Chromosome 12 gain and consistent loss of 3p for both tree models were important early events in NPC progression. The tree models suggested two subclasses of 3p-derived NPC, one marked by 1q+, 9p- and 13q-, and the other marked by 14q-, 16q-, 9q- and 1p- .
Using bioinformatics to analyze the expression and location of UBAP1 protein, it was found that EGFP/UBAP1 was expressed and existed mainly in the nuclear, especially accumulated on the nuclear envelope. The expression difference in NPC cells might be related to the carcinogenesis of NPC . Moreover, a locus on 3p21 was identified to link to NPC in a linkage analysis . RASSF1A is a tumour suppressor gene on 3p21.3 frequently inactivated by promoter hypermethylation in NPC. Investigated by high-density oligonucleotide array, the expressions of activin βE and Id2 in NPC were tightly regulated by RASSF1A. RASSF1A-induced repression of Id2 was mediated by the overexpression of activin βE. The results suggested a novel RASSF1A pathway in which both activin βE and Id2 were involved .
A new carcinoma-related gene named KIAA1173 locating at 3p22.1 was also characterized. It was strongly expressed in normal nasopharyngeal mucosa epithelia, but downregulated in NPC. KIAA1173 might be associated with the carcinogenesis of NPC . In a study using microdissection and cDNA microarray, gene expression patterns suggested the dysregulation of the GTP/GDP-bound Ras cycle and an abnormal hyperactivity of cell cycle in NPC. Alterations in the Wingless-type (Wnt) pathway suggested that this pathway might be activated in NPC . On the other hand, elevation of plasma osteopontin level was found in patients with undifferentiated NPC. The finding indicated a potential role of osteopontin in the pathogenesis and nodal metastasis of undifferentiated NPC .
Molecular diagnostic biomarkers
Diagnosis is made 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 . Elevated RNase activity has previously been described in the circulation of cancer patients, and NPC was found to be associated with disturbances in the integrity of cell-free circulating RNA. Measurement of plasma RNA integrity might serve as a useful marker for the diagnosis and monitoring of NPC .
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 H-cadherin) from nasopharyngeal swabs suggested it could be utilized as a tool for early diagnosis . Systematically identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and further confirmed by Western blot analysis in the NPC cell-lines, fibronectin, Mac-2 binding protein and plasminogen activator inhibitor 1 were found to be potential markers for diagnosis of NPC  (Table 1).
Molecular biomarkers of targeted therapies
High-dose radiotherapy with adjunctive chemotherapy is the primary treatment of NPC . Surgery, when feasible, is usually reserved for nodes that fail to regress after radiotherapy and chemotherapy, or for nodes that recurrent following clinical complete response. Radiotherapy dose and field margins are individually tailored to the location and size of the primary tumour and lymph nodes [20, 21]. New types of treatment are being tested in clinical trials, which include biological therapy and intensity-modulated radiation therapy. Advances in immunologic research and combined chemotherapy offer hope for better control of the disease .
Using oligonucleotide microarray analysis mapping close to a previously defined 11q22-23 NPC critical region, THY1 showed consistent downregulated expression in the tumour segregants. THY1 was identified to be a candidate tumour suppressor gene significantly associated with lymph node metastatic NPC . Employing the monochromosome transfer approach, it was shown that chromosome 3p could suppress tumour growth in vivo. By quantitative reverse transcription polymerase chain reaction (PCR), a candidate tumour suppressor gene BLU/ZMYND10 mapping in the 3p21.3 critical region, was frequently downregulated in NPC cell lines and NPC biopsies . Another tumour suppressor gene DLC-1, locating at the human chromosome region 8p22, is frequently deleted in NPC. The mRNA level of DLC-1 was found to be downregulated in NPC. To identify the mechanism of DLC-1 downregulation, the methylation status of DLC-1 was investigated using methylation-specific PCR. Results showed that DLC-1 might be a NPC-related tumour suppressor gene affected by aberrant promoter methylation and gene deletion .
Stress-responsive gene GADD45G was found to be a functional new-age tumour suppressor, with its response to environmental stresses frequently disrupted epigenetically in NPC . Another study suggested that a novel bromodomain gene, BRD7, was identified to be associated with NPC. Overexpression of BRD7 could inhibit NPC cell growth and arrest cells in cell cycle by transcriptionally regulating some important molecules involved in ras/MEK/ERK and Rb/E2F pathway, and downregulate the promoter activity of E2F3. The nuclear localization of BRD7 was critical for the expression of cell cycle related molecules and cell biological function . Using colony formation assay, Cheung et al found a suppression of human MAD2B conferred hypersensitivity to a range of DNA-damaging agents, especially DNA cross-linkers, such as cisplatin and gamma-irradiation. The result indicated that cancer cells were sensitized to DNA-damaging anticancer drugs through inactivation of MAD2B in NPC .
Constitutive activation of Wnt signaling and WIF-1 silencing was found in NPC cell lines. Utilizing methylation-specific PCR and sequence analysis, frequent hypermethylation of the WIF-1 promoter correlated with WIF-1 silencing was demonstrated in NPC cell lines. These results indicated that aberrant Wnt signaling was a common event in NPC carcinogenesis linked with WIF-1 silencing in cell lines. Strategies targeting these molecules might be potentially promising in treating NPC . The 14-3-3σ gene product, up-regulated by p53 in response to DNA damage, is involved in cell-cycle checkpoint control and is a human cancer epithelial marker downregulated in various tumours. It was reported that overexpression of 14-3-3σ in NPC cell lines reduced the tumour volume in nude mice. This finding provided an insight into the role of 14-3-3σ in NPC and suggested that modulating 14-3-3σ activity might be useful in the treatment of NPC .
Using immunohistochemical streptomycin-avidin peroxidase staining and terminal deoxynucleotidyl transferase mediate dUTP nick and labeling technique, He and Kong demonstrated that the expression of effector cell protease receptor-1 played a role in increase the apoptosis and decrease the proliferation of cell in NPC. This suggested that effector cell protease receptor-1 might be a potential therapy for NPC . Death-associated protein kinase (DAPK) is a Ca/calmodulin-regulated serine/threonine kinase and a positive mediator of apoptosis. Loss of DAPK expression was shown to be associated with promoter region methylation in NPC. A demethylating agent, 5-Aza-2'-deoxycytidine, might slow the growth of NPC cells in vitro and in vivo by reactivating the DAPK gene silenced by de novo methylation . The antiapoptotic gene bcl-2 antisense 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 .
The discovery of RNA interference (RNAi) gene silencing by double-stranded RNA earned the Nobel Prize in Physiology or Medicine in 2006 and led the treatment of disease to a new horizon. The transient transfected bcl-xL siRNA4 could effectively inhibit the growth of the cancer cells and induce their apoptosis. Knockdown of bcl-xL expression with RNAi induced NPC cells apoptosis, suggesting that the siRNA technique could provide a new method for anti-NPC gene therapy . Epidermal growth factor receptor silencing by RNAi could reduce the proliferation of NPC cells and induce cell cycle arrest at G1 phase, which shed light on the possible use of RNAi for further investigation of the pathogenesis and gene therapy of NPC . Pathway analyses by microarrays revealed that upregulation of NF-κB2 and survivin played central roles in increasing resistance to apoptosis, as well as changes in integrin and Wnt/β-catenin signaling leading to uncontrolled proliferation. The role of survivin in resisting apoptosis in NPC was confirmed by RNAi, which suggested survivin as a novel therapeutic target for NPC .
Molecular biomarkers for treatment response monitoring
Major factors adversely influencing outcome of treatment include large size of the tumour, advanced tumour stage and the presence of involved cervical lymph nodes [37, 38]. The DNA anueploid content in NPC was found to be positively related to the S phase cells by flow cytometric analysis. Patients having a low expression of Ki67 or DNA aneuploid in tumour cells were not sensitive to chemotherapy, liable to metastasis to distant organs and had a poor prognosis. It was suggested that DNA ploidy and Ki67 could be used as an independent and objective marker to evaluate the radiosensitivity and prognosis of NPC . The changes of serum vascular endothelial growth factor (VEGF) before and after radiotherapy in NPC patients were studied. Zhao et al reported that patients with high serum VEGF level were found to have a poor prognosis . Endothelin-1 is a potent vasoactive peptide and a hypoxia-inducible angiogenic growth factor associated with the development and spread of solid tumours. Pretreatment plasma big endothelin-1 levels might be useful in predicting posttreatment distant failure in patients with advanced-stage NPC .
Ceruloplasmin (CPL) was identified as a potential serum biomarker by mass spectrometric analysis and MASCOT database search. The enhanced expression of CPL in the NPC patients' sera was confirmed by competitive enzyme-linked immunosorbent assay (ELISA). When follow-up two-dimensional electrophoresis and ELISA studies were performed on the NPC patients who responded positively to treatment, the difference in CPL expression was no longer significant  (Table 1).
Using proteinchip profiling analysis, two isoforms of serum amyloid A (SAA) protein were identified as useful biomarkers to monitor relapse of NPC. Monitoring the patients longitudinally for SAA level by proteinchip and validated by immunoassay showed a dramatic SAA increase, which correlated with relapse and a drastic fall correlated with response to salvage chemotherapy . Further examination was conducted to found other serum biomarkers that were associated with active disease or chemotherapy response in NPC patients treated by two different drug combinations. Using tandem MS sequencing and immunoaffinity capture assay, two potential biomarkers were identified as a fragment of inter-α-trypsin inhibitor precursor and platelet factor-4. These disease and treatment associated serum biomarkers might serve to diagnose and triage NPC patients for appropriate chemotherapy treatment respectively  (Table 1).
Molecular biomarkers for prognosis and progression of cancer
Small cancers of the nasopharynx are highly curable by radiotherapy with chemotherapy and have shown survival rates of 80% to 90% . Moderately advanced lesions without clinical evidence of spread to cervical lymph nodes are often curable and have shown survival rates of 50% to 70%. Patients with advanced lesions, especially those associated with clinically positive cervical lymph nodes, cranial nerve involvement and bone destruction, are poorly controlled locally by radiotherapy with or without surgery and often develop distant metastases despite local control [46, 47]. Although most recurrences occur within five years of diagnosis, relapse can be seen at longer intervals .
It has been reported that average expression of Tiam1 in NPC tissue was higher than in normal nasopharyngeal tissue. This data suggested that the overexpression of the Tiam1 correlated invasion and metastasis of NPC . Interleukin IL-8 receptor A was demonstrated to be overexpressed in tumour cells and correlated significantly with angiogenesis in NPC. The result suggested that the expression of IL-8 receptor A in tumour cells might be an important indicator of poor prognosis in NPC . The positive gradual expression of estrogen and progestogen receptors in NPC was well correlated with distant metastasis. Strong positive expression pointed out bad prognosis and endocrine treatment might reduce and postpone distant metastasis . Adopting immunohistochemistry labeled streptavidin biotin method, overexpression of epidermal growth factor receptor and phosphorylated extracellular signal-regulated kinase was detected in NPC. The abnormally high expression signified poor prognosis in NPC patients .
VEGF expression was assessed in NPC and benign adenoid lesions by immunohistochemistry and EBV presence by PCR using primers directed against EBV nuclear antigen EBNA-1. The results pointed towards the potential of the expression pattern of VEGF as a tumour marker for the early diagnosis of metastatic NPC and also showed that presence of EBV was related to up regulation of VEGF . An immunohistochemistry study found that VEGF and its receptors fms-like tyrosine kinase-1 and kinase insert domain containing receptor were widely expressed in NPC tissues. Their expressions were positively related to clinical features and prognosis of NPC patients . 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 .
NPC samples expressed high levels of survivin and livin, which might play an important role in the oncogenesis and tumour development. Overexpression of survivin was related with poor prognosis, suggesting that the determination of survivin expression might provide predictive information on NPC patients . It has been reported that high Bmi-1 oncoprotein expression was found to be positively correlated with poor prognosis of NPC patients. This finding suggested that Bmi-1 played an important role in the development and progression of NPC, and that it was a valuable marker for assessing the prognosis of NPC patients . Immunohistochemistry was performed on formalin-fixed paraffin-embedded sections of patients with NPC. Bar-Sela et al found that heparanase expression was inversely correlated with survival of NPC patients, clearly indicating that heparanase was a reliable prognostic factor for this malignancy .
Molecular biomarkers of Epstein-Barr virus-associated nasopharyngeal carcinoma
EBV is an oncogenic human gamma-herpesvirus that persistently infects more than 90% of the human population. There are compelling evidences suggesting that EBV is a causal agent of NPC and is most likely to be involved in the multi-step and multi-factorial development of the cancer. EBV encoded genes have been shown to be involved in immune evasion and in the regulation of various cellular signaling cascades. The fact that EBV genome is present in almost all NPC tissues renders it an ideal tumour marker for NPC. Quantitative analyses of EBV antibodies and EBV DNA have been shown to be clinically useful for the early detection, monitoring and prognostication of NPC.
Assessment of immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies responses to various EBV antigen complexes, usually involving multiple serological assays, is important for the early diagnosis of NPC. EBNA-1, the viral protein uniformly expressed in NPC, represents a prime target for T-cell based immunotherapy . Through combination of two synthetic peptides representing immunodominant epitopes of EBNA-1 and viral capsid antigen VCA-p18, a one-step sandwich ELISA for the specific detection of EBV reactive IgA and IgG antibodies in NPC patients was developed . Comparing the antibody levels to VCA of EBV as potential diagnostic markers of NPC, VCA-IgA had an advantage over VCA-IgG despite the slightly lower sensitivity due to its consistently more distinct fluorescence reaction . In a combination of the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry serum protein profiles with EBNA-1 IgA test, the diagnostic sensitivity and specificity were increased to 99% and 96% respectively . The results of immunoprecipitation suggested a direct interaction between EBNA-5 and p63 protein in NPC, and this binding would increase the stability of p63. It was suggested that p63 might be used as an adjunct diagnostic marker of NPC and contributed a new way to understand the contribution of the EBV in the pathogenesis of NPC . Dynamic detection of serum sialic acid and VCA-IgA might be a valuable technique for diagnosis and monitoring radiotherapy effectiveness in NPC patients. The combined determination of the two indexes could raise the positive rate of patients with NPC . Poorly differentiated squamous cancer was found to be associated with EBV antibodies . 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 .
The molecular nature of circulating EBV DNA has been identified as free DNA fragments, and it was not contained inside intact virions. By quantitative size analysis, Chan and Lo demonstrated that more than 80% of these DNA fragments were less than 180 bp in size . In the comparison of EBV DNA levels in plasma and peripheral blood cell in NPC patients, plasma EBV DNA derived from the cancer cells was more sensitive and reliable than peripheral blood cell EBV DNA from circulating mononuclear cells for diagnosis, staging and therapeutic effect evaluation at a molecular level in NPC clinical practice . The detection of plasma EBV DNA could reflect the tumours growth and decline. It was an important and sensitive index in diagnosing the residual and relapse of NPC . Plasma EBV DNA concentration could be used to predict distant metastasis in NPC. The detecting rates of both pre-treatment and post-treatment EBV DNA concentrations in patients with distant metastasis were significantly higher than those with continuous remission and those with local relapse . The plasma EBV DNA load was shown to be proportionately related to the presence of NPC. This finding underscored the prognostic value of cell-free EBV DNA quantification .
There was a study showing that consecutive patients with metastatic or recurrent NPC receiving combination chemotherapy were monitored for EBV DNA in their serum. Profile of EBV encoded RNA (EBER-1) DNA showed concordance with clinical course of either continuous remission or later progression. EBER-1 DNA in serum could become a useful adjunctive surrogate marker to monitor chemotherapeutic response in NPC patients with distant metastasis or advanced local recurrence . Differential expression of EBER and several tumour-related genes were found in NPC using tissue microarray analysis. EBV infection, together with overexpression of p53, and loss expressions of p16 and p27 proteins were involved in the multistep process of human nasopharyngeal epithelial carcinogenesis .
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. It was most closely related to CD80 or B7-1, a co-stimulatory molecule present on antigen presenting cells, from which BARF1 was derived during evolution . Measurement of EBV DNA load combined with BARF1 mRNA detection in simple nasopharyngeal brushings allowed non-invasive NPC diagnosis. It reflected carcinoma-specific EBV involvement at the anatomical site of tumour development and reduced the need for invasive biopsies. This procedure might be useful for confirmatory diagnosis in large serological NPC screening program .
In vitro EBV infection resulted in the activation of STAT3 and NF-κB signal cascades in nasopharyngeal epithelial cells. Increased expression of their downstream targets (c-Myc, bcl-xL, IL-6, LIF, SOCS-1, SOCS-3, VEGF and COX-2) was also observed. EBV latent infection induced the suppression of p38-MAPK activities, but did not activate PKR cascade. These findings suggested that EBV latent infection was able to manipulate multiple cellular signal cascades to protect infected cells from immunologic attack and to facilitate cancer development . Measuring the expression of latent EBV genes in NPC and normal nasopharyngeal tissue samples, it was shown that deregulation of key proteins involving in apoptosis (bcl-2 related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1 and NIN) and metastasis (matrix metalloproteinase 1) were closely correlated with the levels of EBV gene expression in NPC .
Of the EBV-encoded product, latent membrane protein LMP-1 is considered to be an oncogene playing an essential role in cell transformation and metastasis. It is necessary for EBV-induced transformation of B lymphocytes and is able to transform Rat-1 fibroblasts. LMP-1 can activate a wide array of signaling pathways, including phosphatidylinositol 3-kinase-Akt and NF-κB. It was found that the signature amino acid changes of the LMP-1 variants did not hinder or enhance their in vitro transforming potentials or affect their signaling properties . Combing the novel strategy of phosphoprotein enrichment with proteomics technology to elucidate the signaling cascade activated by LMP-1, annexin A2, heat shock protein 27, stathmin, annexin I, basic transcription factor 3 and porin were identified to be novel signaling molecules or targets with no previously known function in LMP-1 signal transduction  (Table 1). Pilot study of LMP-1 and CD99 expressions in NPC suggested that the LMP-1 induced down-regulation of the CD99 pathway was important in nasopharyngeal carcinogenesis, and that the expression of CD99 in lymphoid stroma might regulate immune response to 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 .
It was suggested that nasopharyngeal swab could be effective method for gene detection. As a parameter in diagnosis of NPC, LMP-1 might be superior to VCA-IgA. Thirty-bp deletion of LMP-1 was widespread in NPC patients . The nasopharyngeal swab coupled with PCR based EBV LMP-1 and EBNA detection could serve as a good supplement to pathological diagnosis of NPC .
EBV-encoded LMP-1 was vulnerable to RNAi and selective inhibition of LMP-1 had anti-proliferation effect on NPC cell. RNAi could be a powerful tool in further investigations of LMP-1 and a novel therapeutic strategy for EBV-associated NPC patients . A recombinant adeno-associated virus type 2 vector was used to deliver shRNA targeting EBV LMP-1 into the EBV-positive human NPC C666-1 cells. Results demonstrated that long-term suppression of EBV-encoded LMP-1 in vivo is an effective means for preventing NPC metastasis .
Contemporary NPC research has distincted itself from the traditional one with the unprecedented large amount of data and tremendous diagnostic and therapeutic innovations. Data are currently generated in high-throughput fashions with the integration and application of systems biology. Genomics, proteomics, metabolomics and bioinformatics each plays a more and more important role for molecular biomarker discovery . We now have a better understanding of the disease, including its diagnosis, monitoring, treatment and prognostication. In the era of molecular targeted therapy, specific treatment to the potential target using technologies such as immunotherapy and RNAi becomes formulating from bench to bedside application and thus makes molecular biomarker discovery more meaningful for NPC management.
Chien YC, Chen JY, Liu MY, Yang HI, Hsu MM, Chen CJ, Yang CS: Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med. 2001, 345: 1877-1882. 10.1056/NEJMoa011610
Tiwawech D, Srivatanakul P, Karalak A, Ishida T: Cytochrome P450 2A6 polymorphism in nasopharyngeal carcinoma. Cancer Lett. 2005, 241: 135-141. 10.1016/j.canlet.2005.10.026
Jiang J, Li Z, Su G, Jia W, Zhang R, Yu X, Zhang M, Wen J, Zeng Y: Study on genetic polymorphisms of CYP2F1 gene in Guangdong population of China. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006, 23: 383-387.
Cao Y, Miao XP, Huang MY, Deng L, Hu LF, Ernberg I, Zeng YX, Lin DX, Shao JY: Polymorphisms of XRCC1 genes and risk of nasopharyngeal carcinoma in the Cantonese population. BMC Cancer. 2006, 6: 167- 10.1186/1471-2407-6-167
Catarino RJ, Breda E, Coelho V, Pinto D, Sousa H, Lopes C, Medeiros R: Association of the A870G cyclin D1 gene polymorphism with genetic susceptibility to nasopharyngeal carcinoma. Head Neck. 2006, 28: 603-608. 10.1002/hed.20377
Brennan BM: Nasopharyngeal carcinoma. Orphanet J Rare Dis. 2006, 1: 23- 10.1186/1750-1172-1-23
Shih-Hsin Wu L: Construction of evolutionary tree models for nasopharyngeal carcinoma using comparative genomic hybridization data. Cancer Genet Cytogenet. 2006, 168: 105-108. 10.1016/j.cancergencyto.2006.02.017
Zeng ZY, Qian J, Xiong W, Zhou YH, Zhang WL, Li XL, Tang K, Li WF, Li GY: Expression and location of UBAP1 protein associated with nasopharyngeal carcinoma. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005, 30: 621-624.
Zeng Z, Zhou Y, Zhang W, Li X, Xiong W, Liu H, Fan S, Qian J, Wang L, Li Z, Shen S, Li G: Family-based association analysis validates chromosome 3p21 as a putative nasopharyngeal carcinoma susceptibility locus. Genet Med. 2006, 8: 156-160.
Chow LS, Lam CW, Chan SY, Tsao SW, To KF, Tong SF, Hung WK, Dammann R, Huang DP, Lo KW: Identification of RASSF1A modulated genes in nasopharyngeal carcinoma. Oncogene. 2006, 25: 310-316.
Zhang SQ, Peng H, Song LY, Li XM, Jiang HY, Yao KT, Zhao T: Detection of KIAA1173 gene expression in nasopharyngeal carcinoma tissues and cell lines on tissue microarray. Ai Zheng. 2005, 24: 1322-1326.
Zeng Z, Zhou Y, Xiong W, Luo X, Zhang W, Li X, Fan S, Cao L, Tang K, Wu M, Li G: Analysis of gene expression identifies candidate molecular markers in nasopharyngeal carcinoma using microdissection and cDNA microarray. J Cancer Res Clin Oncol. 2007, 133: 71-81. 10.1007/s00432-006-0136-2
Wong TS, Kwong DL, Sham J, Wei WI, Kwong YL, Yuen AP: Elevation of plasma osteopontin level in patients with undifferentiated nasopharyngeal carcinoma. Eur J Surg Oncol. 2005, 31: 555-558. 10.1016/j.ejso.2005.01.005
Chen YK, Su CT, Ding HJ, Chi KH, Liang JA, Shen YY, Chen LK, Yeh CL, Liao AC, Kao CH: Clinical usefulness of fused PET/CT compared with PET alone or CT alone in nasopharyngeal carcinoma patients. Anticancer Res. 2006, 26: 1471-1477.
Abou-Elhamd KE, Habib TN: The flow cytometric analysis of premalignant and malignant lesions in head and neck squamous cell carcinoma. Oral Oncol. 2006,http://dx.doi.org/doi:10.1016/j.oraloncology.2006.01.007,
Wong BC, Chan KC, Chan AT, Leung SF, Chan LY, Chow KC, Lo YM: Reduced plasma RNA integrity in nasopharyngeal carcinoma patients. Clin Cancer Res. 2006, 12: 2512-2516. 10.1158/1078-0432.CCR-05-2572
Sun D, Zhang Z, Van DN, Huang G, Ernberg I, Hu L: Aberrant methylation of CDH13 gene in nasopharyngeal carcinoma could serve as a potential diagnostic biomarker. Oral Oncol. 2006,http://dx.doi.org/doi:10.1016/j.oraloncology.2006.01.007,
Wu CC, Chien KY, Tsang NM, Chang KP, Hao SP, Tsao CH, Chang YS, Yu JS: Cancer cell-secreted proteomes as a basis for searching potential tumour markers: nasopharyngeal carcinoma as a model. Proteomics. 2005, 5: 3173-3182. 10.1002/pmic.200401133
Baujat B, Audry H, Bourhis J, Chan AT, Onat H, Chua DT, Kwong DL, Al-Sarraf M, Chi KH, Hareyama M, Leung SF, Thephamongkhol K, Pignon JP, : Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys. 2006, 64: 47-56. 10.1016/j.ijrobp.2005.06.037
Lee AW, Law SC, Foo W, Poon YF, Chan DK, O SK, Tung SY, Cheung FK, Thaw M, Ho JH: Nasopharyngeal carcinoma: local control by megavoltage irradiation. Br J Radiol. 1993, 66: 528-536.
Sanguineti G, Geara FB, Garden AS, Tucker SL, Ang KK, Morrison WH, Peters LJ: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys. 1997, 37: 985-996. 10.1016/S0360-3016(97)00104-1
Jeyakumar A, Brickman TM, Jeyakumar A, Doerr T: Review of nasopharyngeal carcinoma. Ear Nose Throat J. 2006, 85: 168-170.
Lung HL, Bangarusamy DK, Xie D, Cheung AK, Cheng Y, Kumaran MK, Miller L, Liu ET, Guan XY, Sham JS, Fang Y, Li L, Wang N, Protopopov AI, Zabarovsky ER, Tsao SW, Stanbridge EJ, Lung ML: THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma. Oncogene. 2005, 24: 6525-6532.
Yau WL, Lung HL, Zabarovsky ER, Lerman MI, Sham JS, Chua DT, Tsao SW, Stanbridge EJ, Lung ML: Functional studies of the chromosome 3p21.3 candidate tumor suppressor gene BLU/ZMYND10 in nasopharyngeal carcinoma. Int J Cancer. 2006, 119: 2821-2826. 10.1002/ijc.22232
Peng D, Ren CP, Yi HM, Zhou L, Yang XY, Li H, Yao KT: Genetic and epigenetic alterations of DLC-1, a candidate tumor suppressor gene, in nasopharyngeal carcinoma. Acta Biochim Biophys Sin (Shanghai). 2006, 38: 349-355. 10.1111/j.1745-7270.2006.00164.x
Ying J, Srivastava G, Hsieh WS, Gao Z, Murray P, Liao SK, Ambinder R, Tao Q: The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clin Cancer Res. 2005, 11: 6442-6449. 10.1158/1078-0432.CCR-05-0267
Zhou M, Liu H, Xu X, Zhou H, Li X, Peng C, Shen S, Xiong W, Ma J, Zeng Z, Fang S, Nie X, Yang Y, Zhou J, Xiang J, Cao L, Peng S, Li S, Li G: Identification of nuclear localization signal that governs nuclear import of BRD7 and its essential roles in inhibiting cell cycle progression. J Cell Biochem. 2006, 98: 920-930. 10.1002/jcb.20788
Cheung HW, Chun AC, Wang Q, Deng W, Hu L, Guan XY, Nicholls JM, Ling MT, Chuan Wong Y, Tsao SW, Jin DY, Wang X: Inactivation of human MAD2B in nasopharyngeal carcinoma cells leads to chemosensitization to DNA-damaging agents. Cancer Res. 2006, 66: 4357-4367. 10.1158/0008-5472.CAN-05-3602
Lin YC, You L, Xu Z, He B, Mikami I, Thung E, Chou J, Kuchenbecker K, Kim J, Raz D, Yang CT, Chen JK, Jablons DM: Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines. Biochem Biophys Res Commun. 2006, 341: 635-640. 10.1016/j.bbrc.2005.12.220
Yang H, Zhao R, Lee MH: 14-3-3sigma, a p53 regulator, suppresses tumor growth of nasopharyngeal carcinoma. Mol Cancer Ther. 2006, 5: 253-260. 10.1158/1535-7163.MCT-05-0395
He N, Kong W: The role of EPR-1 in proliferation and apoptosis in nasopharyngeal carcinoma. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005, 19: 782-784.
Kong WJ, Zhang S, Guo CK, Wang YJ, Chen X, Zhang SL, Zhang D, Liu Z, Kong W: Effect of methylation-associated silencing of the death-associated protein kinase gene on nasopharyngeal carcinoma. Anticancer Drugs. 2006, 17: 251-259. 10.1097/00001813-200603000-00003
Lacy J, Loomis R, Grill S, Srimatkandada P, Carbone R, Cheng YC: Systemic bcl-2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice. Int J Cancer. 2006, 119: 309-316. 10.1002/ijc.21804
Li JX, Zhou KY, Cai KR, Liang T, Tang XD, Zhang YF: Knockdown of bcl-xL expression with RNA interference induces nasopharyngeal carcinoma cells apoptosis. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2005, 40: 347-351.
Weng DS, Wu ZR, Wang S, Ding YQ: Effect of silencing epidermal growth factor receptor expression by RNA interference on the growth of nasopharyngeal carcinoma cell 5-8F. Nan Fang Yi Ke Da Xue Xue Bao. 2006, 26: 71-74.
Shi W, Bastianutto C, Li A, Perez-Ordonez B, Ng R, Chow KY, Zhang W, Jurisica I, Lo KW, Bayley A, Kim J, O'sullivan B, Siu L, Chen E, Liu FF: Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling. Int J Cancer. 2006, 119: 2467-2675. 10.1002/ijc.22107
Perez CA, Devineni VR, Marcial-Vega V, Marks JE, Simpson JR, Kucik N: Carcinoma of the nasopharynx: factors affecting prognosis. Int J Radiat Oncol Biol Phys. 1992, 23: 271-280.
Geara FB, Sanguineti G, Tucker SL, Garden AS, Ang KK, Morrison WH, Peters LJ: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of distant metastasis and survival. Radiother Oncol. 1997, 43: 53-61. 10.1016/S0167-8140(97)01914-2
Shi X, Yuan X, Tao D, Gong J, Hu G: Analysis of DNA ploidy, cell cycle and Ki67 antigen in nasopharyngeal carcinoma by flow cytometry. J Huazhong Univ Sci Technolog Med Sci. 2005, 25: 198-201.
Zhao GQ, Xu Y, Wang Q: Significance of serum vascular endothelial growth factor test before radiotherapy in patients with nasopharyngeal carcinoma. Zhong Xi Yi Jie He Xue Bao. 2005, 3: 274-277.
Mai HQ, Zeng ZY, Zhang CQ, Feng KT, Guo X, Mo HY, Deng MQ, Min HQ, Hong MH: Elevated plasma big ET-1 is associated with distant failure in patients with advanced-stage nasopharyngeal carcinoma. Cancer. 2006, 106: 1548-1553. 10.1002/cncr.21790
Doustjalali SR, Yusof R, Govindasamy GK, Bustam AZ, Pillay B, Hashim OH: Patients with nasopharyngeal carcinoma demonstrate enhanced serum and tissue ceruloplasmin expression. J Med Invest. 2006, 53: 20-28. 10.2152/jmi.53.20
Cho WC, Yip TT, Yip C, Yip V, Thulasiraman V, Ngan RK, Yip TT, Lau WH, Au JS, Law SC, Cheng WW, Ma VW, Lim CK: Identification of serum amyloid A protein as a potentially useful biomarker to monitor relapse of nasopharyngeal cancer by serum proteomic profiling. Clin Cancer Res. 2004, 10: 43-52. 10.1158/1078-0432.CCR-0413-3
Cho WC, Yip TT, Ngan RK, Yip TT, Podust VN, Yip C, Yiu HH, Yip V, Cheng WW, Ma VW, Law SC: ProteinChip array profiling for identification of disease- and chemotherapy-associated biomarkers of nasopharyngeal carcinoma. Clin Chem. 2007,http://dx.doi.org/doi:10.1373/clinchem.2005.065805,
Bailet JW, Mark RJ, Abemayor E, Lee SP, Tran LM, Juillard G, Ward PH: Nasopharyngeal carcinoma: treatment results with primary radiation therapy. Laryngoscope. 1992, 102: 965-972.
Fandi A, Altun M, Azli N, Armand JP, Cvitkovic E: Nasopharyngeal cancer: epidemiology, staging, and treatment. Semin Oncol. 1994, 21: 382-397.
Teo PM, Chan AT, Lee WY, Leung TW, Johnson PJ: Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys. 1999, 43: 261-271. 10.1016/S0360-3016(98)00383-6
Cooper JS, Scott C, Marcial V, Griffin T, Fazekas J, Laramore G, Hoffman A: The relationship of nasopharyngeal carcinomas and second independent malignancies based on the radiation therapy oncology group experience. Cancer. 1991, 67: 1673-1677. 10.1002/1097-0142(19910315)67:6<1673::AID-CNCR2820670632>3.0.CO;2-1
Mo L, Wang H, Huang G, Zhao H, Kuang G: Correlation between expression of the Tiam1 gene and the invasion and metastasis in nasopharyngeal carcinoma. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005, 19: 785-787.
Horikawa T, Kaizaki Y, Kato H, Furukawa M, Yoshizaki T: Expression of interleukin-8 receptor A predicts poor outcome in patients with nasopharyngeal carcinoma. Laryngoscope. 2005, 115: 62-67.
Mo L, Kuang G, Luo Y, Yang R: Relationship between the expression of estrogen and progestrogen receptors in distant metastasis of nasopharyngeal carcinoma. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2006, 20: 494-495.
Wang SS, Guan ZZ, Xiang YQ, Wang B, Lin TY, Jiang WQ, Zhang L, Zhang HZ, Hou JH: Significance of EGFR and p-ERK expression in nasopharyngeal carcinoma. Zhonghua Zhong Liu Za Zhi. 2006, 28: 28-31.
Krishna SM, James S, Balaram P: Expression of VEGF as prognosticator in primary nasopharyngeal cancer and its relation to EBV status. Virus Res. 2006, 115: 85-90. 10.1016/j.virusres.2005.07.010
Sha D, He YJ: Expression and clinical significance of VEGF and its receptors Flt-1 and KDR in nasopharyngeal carcinoma. Ai Zheng. 2006, 25: 229-234.
Jiang WZ, Liao YP, Zhao YP, Zhao SP: Expression clinical significance of nm23-H1 and vessel endothelium growth factor protein in nasopharyngeal carcinoma. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2006, 41: 200-204.
Xiang Y, Yao H, Wang S, Hong M, He J, Cao S, Min H, Song E, Guo X: Prognostic value of survivin and livin in nasopharyngeal carcinoma. Laryngoscope. 2006, 116: 126-130. 10.1097/01.mlg.0000187392.87904.35
Song LB, Zeng MS, Liao WT, Zhang L, Mo HY, Liu WL, Shao JY, Wu QL, Li MZ, Xia YF, Fu LW, Huang WL, Dimri GP, Band V, Zeng YX: Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. Cancer Res. 2006, 66: 6225-6232. 10.1158/0008-5472.CAN-06-0094
Bar-Sela G, Kaplan-Cohen V, Ilan N, Vlodavsky I, Ben-Izhak O: Heparanase expression in nasopharyngeal carcinoma inversely correlates with patient survival. Histopathology. 2006, 49: 188-193. 10.1111/j.1365-2559.2006.02469.x
Tsang CW, Lin X, Gudgeon NH, Taylor GS, Jia H, Hui EP, Chan AT, Lin CK, Rickinson AB: CD4+ T-cell responses to Epstein-Barr virus nuclear antigen EBNA-1 in Chinese populations are highly focused on novel C-terminal domain-derived epitopes. J Virol. 2006, 80: 8263-8266. 10.1128/JVI.00400-06
Fachiroh J, Paramita DK, Hariwiyanto B, Harijadi A, Dahlia HL, Indrasari SR, Kusumo H, Zeng YS, Schouten T, Mubarika S, Middeldorp JM: Single-assay combination of Epstein-Barr virus (EBV) EBNA-1 and viral capsid antigen-p18-derived synthetic peptides for measuring anti-EBV immunoglobulin G (IgG) and IgA antibody levels in sera from nasopharyngeal carcinoma patients: options for field screening. J Clin Microbiol. 2006, 44: 1459-1467. 10.1128/JCM.44.4.1459-1467.2006
Wong MM, Lye MS, Cheng HM, Sam CK: Epstein-Barr virus serology in the diagnosis of nasopharyngeal carcinoma. Asian Pac J Allergy Immunol. 2005, 23: 65-67.
Ho DW, Yang ZF, Wong BY, Kwong DL, Sham JS, Wei WI, Yuen AP: Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry serum protein profiling to identify nasopharyngeal carcinoma. Cancer. 2006, 107: 99-107. 10.1002/cncr.21970
Guo C, Pan ZG, Li DJ, Yun JP, Zheng MZ, Hu ZY, Cheng LZ, Zeng YX: The expression of p63 is associated with the differential stage in nasopharyngeal carcinoma and EBV infection. J Transl Med. 2006, 4: 23- 10.1186/1479-5876-4-23
Jiang LN, Dai LC, He JF, Chen YW, Ma ZH: [Significance of detection of serum sialic acid and Epstein-Barr virus VCA-IgA in diagnosis and monitoring radiotherapy effectiveness in nasopharyngeal carcinoma patients]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2006, 20 (2): 30-32.
Neel HB, Pearson GR, Taylor WF: Antibodies to Epstein-Barr virus in patients with nasopharyngeal carcinoma and in comparison groups. Ann Otol Rhinol Laryngol. 1984, 93: 477-482.
Lin JC, Chen KY, Wang WY, Jan JS, Liang WM, Tsai CS, Wei YH: Detection of Epstein-Barr virus DNA the peripheral-blood cells of patients with nasopharyngeal carcinoma: relationship to distant metastasis and survival. J Clin Oncol. 2001, 19: 2607-2615.
Chan KC, Lo YM: Clinical applications of plasma Epstein-Barr virus DNA analysis and protocols for the quantitative analysis of the size of circulating Epstein-Barr virus DNA. Methods Mol Biol. 2006, 336: 111-121.
Shao JY, Zhang Y, Li YH, Gao HY, Feng HX, Wu QL, Cui NJ, Cheng G, Hu B, Hu LF, Ernberg I, Zeng YX: Comparison of Epstein-Barr virus DNA level in plasma, peripheral blood cell and tumor tissue in nasopharyngeal carcinoma. Anticancer Res. 2004, 24: 4059-4066.
Jiang W, Liao Y: The dynamic study between EBV DNA with nasopharyngeal carcinoma. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005, 19: 920-922.
Hou X, Zhang L, Zhao C, Li S, Lu LX, Han F, Shao JY, Huang PY: Prognostic impact of plasma Epstein-Barr virus DNA concentration on distant metastasis in nasopharyngeal carcinoma. Ai Zheng. 2006, 25: 785-792.
Tan EL, Looi LM, Sam CK: Evaluation of plasma Epstein-Barr virus DNA load as a prognostic marker for nasopharyngeal carcinoma. Singapore Med J. 2006, 47: 803-807.
Ngan RK, Lau WH, Yip TT, Cho WC, Cheng WW, Lim CK, Wan KK, Chu E, Joab I, Grunewald V, Poon YF, Ho JH: Remarkable application of serum EBV EBER-1 in monitoring response of nasopharyngeal cancer patients to salvage chemotherapy. Ann N Y Acad Sci. 2001, 945: 73-79.
Fan SQ, Ma J, Zhou J, Xiong W, Xiao BY, Zhang WL, Tan C, Li XL, Shen SR, Zhou M, Zhang QH, Ou YJ, Zhuo HD, Fan S, Zhou YH, Li GY: Differential expression of Epstein-Barr virus-encoded RNA and several tumor-related genes in various types of nasopharyngeal epithelial lesions and nasopharyngeal carcinoma using tissue microarray analysis. Hum Pathol. 2006, 37: 593-605. 10.1016/j.humpath.2006.01.010
Tarbouriech N, Ruggiero F, de Turenne-Tessier M, Ooka T, Burmeister WP: Structure of the Epstein-Barr virus oncogene BARF1. J Mol Biol. 2006, 359: 667-678. 10.1016/j.jmb.2006.03.056
Stevens SJ, Verkuijlen SA, Hariwiyanto B, Harijadi , Paramita DK, Fachiroh J, Adham M, Tan IB, Haryana SM, Middeldorp JM: Noninvasive diagnosis of nasopharyngeal carcinoma: nasopharyngeal brushings reveal high Epstein-Barr virus DNA load and carcinoma-specific viral BARF1 mRNA. Int J Cancer. 2006, 119: 608-614. 10.1002/ijc.21914
Lo AK, Lo KW, Tsao SW, Wong HL, Hui JW, To KF, Hayward DS, Chui YL, Lau YL, Takada K, Huang DP: Epstein-Barr virus infection alters cellular signal cascades in human nasopharyngeal epithelial cells. Neoplasia. 2006, 8: 173-180. 10.1593/neo.05625
Sengupta S, den Boon JA, Chen IH, Newton MA, Dahl DB, Chen M, Cheng YJ, Westra WH, Chen CJ, Hildesheim A, Sugden B, Ahlquist P: Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma. Cancer Res. 2006, 66: 7999-8006. 10.1158/0008-5472.CAN-05-4399
Mainou BA, Raab-Traub N: LMP-1 strain variants: biological and molecular properties. J Virol. 2006, 80: 6458-6468. 10.1128/JVI.00135-06
Yan G, Li L, Tao Y, Liu S, Liu Y, Luo W, Wu Y, Tang M, Dong Z, Cao Y: Identification of novel phosphoproteins in signaling pathways triggered by latent membrane protein-1 using functional proteomics technology. Proteomics. 2006, 6: 1810-1821. 10.1002/pmic.200500156
Kim HS, Kim JS, Kim JS, Park JT, Lee MC, Juhng SW, Cho JH, Park CS: The association between CD99 and LMP-1 expression in nasopharyngeal carcinoma. Exp Oncol. 2006, 28: 40-43.
Du CW, Wen BG, Li DR, Lin YC, Zheng YW, Chen L, Chen JY, Lin W, Wu MY: Latent membrane protein-1 of Epstein-Barr virus increases sensitivity to arsenic trioxide-induced apoptosis in nasopharyngeal carcinoma cell. Exp Oncol. 2005, 27: 267-272.
Du C, Wen B, Li D, Lin Y, Zheng Y, Peng X, Hong C, Chen J, Lin W, Hong X, Xie L, Wu M: Downregulation of Epstein-Barr virus-encoded latent membrane protein-1 by arsenic trioxide in nasopharyngeal carcinoma cells. Tumori. 2006, 92: 140-148.
Du CW, Wen BG, Li DR, Peng X, Hong CQ, Chen JY, Lin ZZ, Hong X, Lin YC, Xie LX, Wu MY, Zhang H: Arsenic trioxide reduces the invasive and metastatic properties of nasopharyngeal carcinoma cells in vitro. Braz J Med Biol Res. 2006, 39: 677-685. 10.1590/S0100-879X2006000500015
Xie Y, Huang G, Zhang Z, Wen W, Wu Y, Wei Z: Application of EB virus latent membrane protein-1 in nasopharyngeal swab in diagnosis of nasopharyngeal carcinoma. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2006, 20: 499-501.
Hao SP, Tsang NM, Chang KP, Ueng SH: Molecular diagnosis of nasopharyngeal carcinoma: detecting LMP-1 and EBNA by nasopharyngeal swab. Otolaryngol Head Neck Surg. 2004, 131: 651-654. 10.1016/j.otohns.2004.04.013
Li G, Li XP, Peng Y, Liu X, Li XH: Effective inhibition of EB virus-encoded latent membrane protein-1 by siRNA in EB virus (+) nasopharyngeal carcinoma cell. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2005, 40: 406-410.
Li X, Liu X, Li CY, Ding Y, Chau D, Li G, Kung HF, Lin MC, Peng Y: Recombinant adeno-associated virus mediated RNA interference inhibits metastasis of nasopharyngeal cancer cells in vivo and in vitro by suppression of Epstein-Barr virus encoded LMP-1. Int J Oncol. 2006, 29: 595-603.
Cho WC: Research progress in SELDI-TOF MS and its clinical applications. Sheng Wu Gong Cheng Xue Bao. 2006, 22: 871-876.