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1.  Pretreatment platelet count as a predictor for survival and distant metastasis in nasopharyngeal carcinoma patients 
Oncology Letters  2015;9(3):1458-1466.
The aim of the present study was to investigate the prognostic value of different pretreatment platelet (PLT) counts on the treatment outcome in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone. A total of 1,501 NPC patients, including 412 receiving CCRT and 1,089 receiving RT, were enrolled in the present study. The PLT count cut-off points for the CCRT and RT groups were 150 and 300×109/l, respectively, and the PLT counts were categorized it into three groups: Low (PLT≤150×109/l), moderate (150×109/l300×109/l). To identify independent predictors of overall survival (OS), the Cox proportional hazards model was used to determine local-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) rates in the CCRT and RT patients. Furthermore, univariate and multivariate analysis indicated that compared with a moderate PLT count, a low PLT count was an independent unfavorable prognostic factor for OS rate in CCRT patients [hazard ratio (HR), 2.024; 95% confidence interval (CI), 1.165–3.516], and a high PLT count was an independent unfavorable prognostic factor for OS and DMFS rates in CCRT (OS: HR, 1.742; 95% CI, 1.090–2.786; DFMS: HR, 2.110; 95%CI, 1.084–4.108) and RT (OS: HR, 1.740; 95%CI, 1.283–2.362; DMFS: HR, 2.819; 95% CI, 1.766–4.497) patients. Compared with a low PLT count, a high PLT count was significantly and independently associated with a poor DMFS rate in the RT patients (P=0.025; HR, 2.454; 95% CI, 1.121–5.372). Therefore, the present study indicates that low and high PLT counts may be useful indicators of survival and distant metastasis in NPC patients who have undergone radiation treatment.
doi:10.3892/ol.2015.2872
PMCID: PMC4314978  PMID: 25663931
platelet count; nasopharyngeal carcinoma; radiotherapy; concurrent chemoradiotherapy; predictor; prognosis
2.  Familial nasopharyngeal carcinomas possess distinguished clinical characteristics in southern China 
Objective
To compare clinical characteristics between familial nasopharyngeal carcinomas (NPCs) and sporadic NPCs in Guangdong province, China, a high-risk area.
Methods
Between 1991 and 2001, 993 NPC patients treated at the Cancer Center of Sun Yat-Sen University in Guangdong were randomly selected as probands. Information about NPC among the probands’ relatives and other information were obtained from a retrospective review of the patients’ medical records. The patients were divided into sporadic NPC, low-frequency familial NPC (one NPC patient in addition to the proband in three generations), and high-frequency familial NPC (2 or more additional NPC patients in three generations) groups. Pathological and clinical characteristics were compared among these groups.
Results
Of the 993 patients, 131 (13.2%) had a familial history of NPC. The average age at diagnosis was the lowest in the high-frequency familial NPC group (39 years; P=0.048). Although the overall survival (OS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) rates did not differ between familial and sporadic NPCs, the locoregional recurrence-free survival (LRFS) rate increased in the order sporadic NPCs, low-frequency familial NPCs, and high-frequency familial NPCs (P=0.009), with 5-year rates of 70%, 83%, and 87%, respectively. Multivariate analysis showed that family history of NPC was an independent favorable prognostic factor for LRFS, with adjusted hazard ratio (aHR) of 0.548, 95% CI (0.342-0.878). The high LRFS for familial NPCs was mainly noted among young, advanced-stage patients who received continuous radiation treatment.
Conclusions
Genetic factors may play an important role in the etiology of high-frequency familial NPC and underlie the early age of onset and sensitivity to radiotherapy.
doi:10.3978/j.issn.1000-9604.2014.10.03
PMCID: PMC4220253  PMID: 25400419
Nasopharyngeal carcinoma (NPC); familial; clinical behavior
3.  Alternative endpoints to the 5-year overall survival and locoregional control for nasopharyngeal carcinoma: A retrospective analysis of 2,450 patients 
Molecular and Clinical Oncology  2014;2(3):385-392.
The purpose of the present study was to investigate alternative endpoints to the 5-year overall survival (OS) and locoregional control (LRC) for nasopharyngeal carcinoma (NPC). A total of 2,450 NPC patients were enrolled in this study, including 1,842 patients treated with two-dimensional (2D) radiotherapy (RT), 451 treated with 3D conformal RT (CRT) and 157 treated with intensity-modulated RT (IMRT). We sequentially calculated the 1-, 2-, 3- and 4-year survival rates using a life table and compared these with the 5-year survival rate using the McNemar method, with the survival rate of the last indifferent comparison being considered as the alternative endpoint. For 2D RT, stage I patients exhibited similar survival rates at 1 and 5 years (98.9 vs. 94.4%, respectively; P=0.125 for both OS and LRC); stage N3 patients exhibited similar 4-year OS (55.2 vs. 53.5%; P=1.000) and 2-year LRC (78.3 vs. 71.2%; P=0.125) to the 5-year OS and LRC. For IMRT, the 1-, 2-, 3-, 4- and 5-year OS and LRC rates in stage I/II NPC patients were 100, 98, 96, 94 and 94% for OS and 100, 98, 96, 96 and 96% for LRC, respectively. No significant differences were observed for all the comparisons. For stage III/IV NPC patients treated with IMRT, the 1-, 2-, 3-, 4- and 5-year rates were 99.1, 96.3, 92.5, 88.8 and 85.0% for OS and 98.1, 97.2, 95.3, 90.7 and 89.7% for LRC, respectively. Only the 4-year OS and LRC rates were indifferent from those at 5 years (P=0.125 for OS and P=1.00 for LRC). In conclusion, the 1-year OS and LRC for stage I NPC patients treated with 2D RT or stage I/II NPC patients treated with IMRT, the 4-year OS and 2-year LRC for stage N3 NPC patients treated with 2D RT and the 4-year OS and LRC for stage III/IV NPC patients treated with IMRT were determined as the alternative endpoints to the 5-year OS and LRC for NPC patients.
doi:10.3892/mco.2014.262
PMCID: PMC3999144  PMID: 24772305
alternative endpoints; 5-year; locoregional control; nasopharyngeal carcinoma; overall survival
4.  Increased pretreatment levels of serum LDH and ALP as poor prognostic factors for nasopharyngeal carcinoma 
Chinese Journal of Cancer  2012;31(4):197-206.
Serum enzymes that play potential roles in tumor growth have recently been reported to have prognostic relevance in a diverse array of tumors. However, prognosis-related serum enzymes are rarely reported for nasopharyngeal carcinoma (NPC). To clarify whether the level of serum enzymes is linked to the prognosis of NPC, we reviewed the pretreatment data of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and glutamyl transferase (GGT) in 533 newly diagnosed NPC patients who underwent radical radiotherapy between May 2002 and October 2003 at Sun Yat-sen University Cancer Center. Patients were grouped according to the upper limit of normal values of LDH, ALP, and GGT. The Kaplan-Meier method and log-rank test were used for selecting prognostic factors from clinical characteristics and serum enzymes, and the Chi-square test was applied to analyze the relationships of clinical characteristics and serum enzymes. Finally, a Cox proportional hazards model was used to identify the independent prognostic factors. We found that increased levels of LDH had poor effects on both overall survival and distant metastasis-free survival (P = 0.009 and 0.035, respectively), and increased pretreatment level of serum ALP had poor effects on both overall survival and local recurrence-free survival (P = 0.037 and 0.039, respectively). In multivariate analysis, increased LDH level was identified as an independent prognostic factor for overall survival. Therefore, we conclude that increased pretreatment serum LDH and ALP levels are poor prognostic factors for NPC.
doi:10.5732/cjc.011.10283
PMCID: PMC3777475  PMID: 22237040
Nasopharyngeal carcinoma; LDH; ALP; GGT; prognosis
5.  Aurora-A is an efficient marker for predicting poor prognosis in human nasopharyngeal carcinoma with aggressive local invasion: 208 cases with a 10-year follow-up from a single institution 
Oncology Letters  2012;3(6):1237-1244.
Aurora-A kinase (Aur-A), a member of a family of mitotic serine/threonine kinases, is known to be amplified in epithelial malignancies. In this study, we focused our investigation on Aur-A expression and its prognostic significance in nasopharyngeal carcinoma (NPC). Immunohistochemical staining for Aur-A was performed on the paraffin sections of 208 patients with NPC. Data were subjected to statistical analysis with respect to clinicopathological variables, overall survival and disease-free survival. An immunohistochemical analysis showed that Aur-A was highly expressed in 132 (63.5%) of the 208 NPC tissues examined. Aur-A expression was significantly correlated with T classification (P=0.012), clinical stage (P=0.003) and skull base invasion (P=0.003). Statistical analysis showed that Aur-A expression was inversely correlated with the 10-year overall and disease-free survival rates of NPC patients. Results of the multivariate analysis revealed that Aur-A expression was an independent prognostic indicator for patient survival. More significantly, Aur-A was found to be a marker for poor survival, which was mainly attributed to its high expression in the subgroup of T4 tumor classification with aggressive local invasion. These results indicated that Aur-A expression is inversely correlated with survival and directly correlated with the malignant status of NPC. Therefore, Aur-A may serve as a potential biological marker for poor prognosis in the T4 subgroup of patients.
doi:10.3892/ol.2012.660
PMCID: PMC3392567  PMID: 22783425
nasopharyngeal carcinoma; Aurora-A; prognosis; T4 subgroup patients
6.  Bmi-1 induces radioresistance in MCF-7 mammary carcinoma cells 
Oncology Reports  2011;27(4):1116-1122.
Bmi-1, a member of the polycomb family, it is involved in self renewal of stem cells and functions as an oncogene in many malignant human cancer types. Recent studies have demonstrated that Bmi-1 is a predictive factor for poor patient prognosis. However, the underlying mechanisms of radioresistance mediated by Bmi-1 are poorly understood. In this study, the dose-survival relationship was analyzed using a clonogenic survival assay and combined radiation treatment with Bmi-1 overexpression or silencing. DNA double-strand break (DSB) and repair was assessed by immunofluorescence staining of γH2AX foci. In addition, mitochondrial membrane potential was detected between Bmi-1 knockdown and control MCF-7 cells after irradiation. Apoptosis and cell cycle were evaluated by flow cytometry. We found that exposure of MCF-7 cells overexpressing Bmi-1 to ionizing radiation resulted in dramatically enhanced survival relative to control cells, whereas cells with silenced Bmi-1 showed markedly reduced survival. Bmi-1 inhibition significantly increased DSBs and decreased DSB repair. Furthermore, Bmi-1 knockdown induced loss of mitochondrial membrane potential and enhanced apoptosis by up-regulating p53, p21, Bax expression and down-regulating p-AKT and Bcl-2 expression. These results indicate that Bmi-1 may play an important role in radiosensitivity, and the suppression of its expression might be a potential therapeutic target for breast cancer.
doi:10.3892/or.2011.1615
PMCID: PMC3583403  PMID: 22209830
Bmi-1; radioresistance; mammary carcinoma cells
7.  The clinical characteristics and treatment outcome of 57 children and adolescents with primary central nervous system germ cell tumors 
Chinese Journal of Cancer  2014;33(8):395-401.
Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.
doi:10.5732/cjc.013.10112
PMCID: PMC4135369  PMID: 25011460
Primary central nervous system germ cell tumors; chemotherapy; radiotherapy; survival rate; children
8.  Correction: High Weight Loss during Radiation Treatment Changes the Prognosis in Under-/Normal Weight Nasopharyngeal Carcinoma Patients for the Worse: A Retrospective Analysis of 2433 Cases 
PLoS ONE  2013;8(12):10.1371/annotation/3dc37158-1f60-436e-9bd5-2a822aa2c9cb.
doi:10.1371/annotation/3dc37158-1f60-436e-9bd5-2a822aa2c9cb
PMCID: PMC3865324
9.  High Weight Loss during Radiation Treatment Changes the Prognosis in Under-/Normal Weight Nasopharyngeal Carcinoma Patients for the Worse: A Retrospective Analysis of 2433 Cases 
PLoS ONE  2013;8(7):e68660.
Background
Although weight loss is common in nasopharyngeal carcinoma (NPC) patients receiving radiotherapy, the prognostic influence of weight loss and its impact modified by body mass index (BMI) are still unclear.
Methods
2433 NPC patients receiving radical radiotherapy at Sun Yat-sen University Cancer Center from November, 2000 to December, 2004 were enrolled. Weight change during radiation treatment was categorized into high weight loss (HWL) and low weight loss (LWL). The associations of HWL with overall survival (OS) and disease-specific survival (DSS) were analyzed by Cox regression.
Results
Among underweight patients, HWL was independently associated with poor OS (hazard ratio [HR], 2.06; 95% CI 1.36–3.11) and DSS (HR, 2.27; 95% CI 1.38–3.73), as compared with LWL, after adjusting for covariates. In normal weight patients, the impact of HWL on OS (HR, 1.47; 95% CI 1.19–1.80) and DSS (HR, 1.59; 95% CI 1.24–2.03) was moderate. Among overweight/obese patients, no significant association between HWL and OS (HR, 1.22; 95% CI 0.95–1.55), or DSS (HR, 1.23; 95% CI 0.93–1.64) was found.
Conclusion
Except for overweight/obese patients, high weight loss during radiation treatment was independently associated with poor survival in NPC. This impact was more prominent in the underweight patient group.
doi:10.1371/journal.pone.0068660
PMCID: PMC3711826  PMID: 23869226
10.  Challenges in the modification of the M1 stage of the TNM staging system for nasopharyngeal carcinoma: A study of 1027 cases and review of the literature 
A series of modifications have been introduced to the TNM staging system over time for nasopharyngeal carcinoma (NPC), mainly focused on the T (primary tumor) and N (local node) components of the system. The M1 stage is a ‘catch all’ classification, covering a group of patients whose outlook ranges from potentially curable to incurable. Since the current M1 stage does not allow clinicians to stratify patients according to prognosis or guide therapeutic decision-making and allow comparison of results of radical and non-radical treatments, we aimed to subdivide the M1 stage according to a retrospective study of 1027 metastatic NPC patients and to review the relevant literature. Between 1995 and 2007, 1027 inpatients with distant metastasis from NPC were retrospectively analyzed. Various possible subdivisions of the M1 stage were considered, looking at different metastatic sites, the number of metastatic organs and the number of metastases. Survival rates were calculated using the Kaplan-Meier method and compared using the log-rank test. The most frequently involved metastatic sites were the bone, lung and liver. The incidence rates of solitary metastatic lesions and pulmonary metastasis were 16.2 and 41.3%. Despite the poor survival of these patients with a median survival of 30.8 months, patients in the metachronous metastatic group with metastases to the lung and/or solitary lesions, were defined as M1a, and were significantly associated with favorable median survival of 41.5 and 49.1 months in the univariate and multivariate analysis, respectively. Patients in the metachronous metastatic group with metastasis to the lung and/or solitary lesions (M1a) have a more favorable prognosis compared with those patients with multiple metastases located in other anatomic sites (M1b). These data, in one of the largest reported metastatic NPC cohorts, are the first to show the prognostic impact of metastatic status in NPC. As a powerful predictor, the potential clinical value of a modified M1 of the TNM system for NPC will facilitate patient counseling and individualize management.
doi:10.3892/etm.2012.584
PMCID: PMC3460246  PMID: 23139721
distant metastasis; M1 stage; nasopharyngeal carcinoma; metastatic survival; prognostic factors
11.  Long-term molecular changes in WHO grade II astrocytomas following radiotherapy 
Chinese Journal of Cancer  2012;31(3):159-165.
Monitoring the long-term radiotherapy-associated molecular changes in low-grade gliomas (LGGs) facilitates the understanding of LGG response to radiotherapy. In this study, we used immunohistochemistry to analyze the expression of Ki-67, tumor protein P53 (TP53), P21, and P27 in 8 paired WHO grade II astrocytoma samples. The interval between radiotherapy (RT) and the second surgery was more than 3 months in all cases. The average Ki-67 labeling index (LI) was 5.3% in pre-RT samples and 11.54% in post-RT samples. Ki-67 LI was higher in the primary tumors that underwent malignant transformation observed at the second surgery after radiation. Post-RT Ki-67 LI decreased in 2 cases with an interval of less than 12 months between RT and the second surgery. TP53 expression was found in 3 out of 4 pre-RT samples with malignant transformation and in 1 out of 4 pre-RT samples without malignant transformation. Post-RT TP53 increased in 2 cases in which increased expression of P21 or P27 was also observed. Our study suggests that radiotherapy can inhibit WHO grade II astrocytoma proliferation as reflected by Ki-67 LI, but the effect attenuates with time. In addition, there is a tendency of malignant transformation for WHO grade II astrocytomas with a high Ki-67 level or TP53 expression in initial samples.
doi:10.5732/cjc.011.10149
PMCID: PMC3777483  PMID: 22313596
Radiotherapy; WHO grade II astrocytoma; malignant transformation; Ki-67; TP53
12.  Establishment and characterization of a novel nasopharyngeal carcinoma cell line (SUNE2) from a Cantonese patient 
Chinese Journal of Cancer  2012;31(1):36-44.
The undifferentiated form of nasopharyngeal carcinoma (NPC) is the most common malignant head and neck cancer in South China, especially in Cantonese populations. However, few NPC cell lines have been established from the patients in this region. In this study, we established a new NPC cell line, termed SUNE2, from a Cantonese patient with undifferentiated NPC. This cell line had extremely low concentrations of Epstein-Barr virus (EBV) DNA in long-term culture and expressed low levels of latent membrane protein 1 (LMP1), latent membrane protein 2A (LMP2A), BamH1-A right frame 1 (BARF1), EBV-encoded RNA-1 (EBER1), and EBV-encoded RNA-2 (EBER2) in early passages. SUNE2 cells also showed much stronger transforming ability than 5-8F cells in colony formation assays and anchorage-independent growth assays in soft agar, and they only need 2 weeks to form tumors in nude mice. In summary, the SUNE2 cell line is a new in vitro model that can be used for further research on the mechanisms underlying the occurrence and development of NPC.
doi:10.5732/cjc.011.10317
PMCID: PMC3777465  PMID: 22176775
Nasopharyngeal carcinoma; Epstein-Barr virus; SUNE2 cell line
13.  Prognostic significance and therapeutic implications of centromere protein F expression in human nasopharyngeal carcinoma 
Molecular Cancer  2010;9:237.
Background
Our recent cDNA microarray data showed that centromere protein F (CENP-F) is significantly upregulated in primary cultured nasopharyngeal carcinoma (NPC) tumor cells compared with normal nasopharyngeal epithelial cells. The goal of this study was to further investigate the levels of CENP-F expression in NPC cell lines and tissues to clarify the clinical significance of CENP-F expression in NPC as well as the potential therapeutic implications of CENP-F expression.
Methods
Real-time RT-PCR and western blotting were used to examine CENP-F expression levels in normal primary nasopharyngeal epithelial cells (NPEC), immortalized nasopharyngeal epithelial cells and NPC cell lines. Levels of CENP-F mRNA were determined by real-time RT-PCR in 23 freshly frozen nasopharyngeal biopsy tissues, and CENP-F protein levels were detected by immunohistochemistry in paraffin sections of 202 archival NPC tissues. Statistical analyses were applied to test for prognostic associations. The cytotoxicities of CENP-F potential target chemicals, zoledronic acid (ZOL) and FTI-277 alone, or in combination with cisplatin, in NPC cells were determined by the MTT assay.
Results
The levels of CENP-F mRNA and protein were higher in NPC cell lines than in normal and immortalized NPECs. CENP-F mRNA level was upregulated in nasopharyngeal carcinoma biopsy tissues compared with noncancerous tissues. By immunohistochemical analysis, CENP-F was highly expressed in 98 (48.5%) of 202 NPC tissues. Statistical analysis showed that high expression of CENP-F was positively correlated with T classification (P < 0.001), clinical stage (P < 0.001), skull-base invasion (P < 0.001) and distant metastasis (P = 0.012) inversely correlated with the overall survival time in NPC patients. Multivariate analysis showed that CENP-F expression was an independent prognostic indicator for the survival of the patient. Moreover, we found that ZOL or FTI-277 could significantly enhance the chemotherapeutic sensitivity of NPC cell lines (HONE1 and 6-10B) with high CENP-F expression to cisplatin, although ZOL or FTI-277 alone only exhibited a minor inhibitory effect to NPC cells.
Conclusion
Our data suggest that CENP-F protein is a valuable marker of NPC progression, and CENP-F expression is associated with poor overall survival of patients. In addition, our data indicate a potential benefit of combining ZOL or FTI-277 with cisplatin in NPC suggesting that CENP-F expression may have therapeutic implications.
doi:10.1186/1476-4598-9-237
PMCID: PMC2944187  PMID: 20828406
14.  Epstein-Barr Virus-Encoded LMP2A Induces an Epithelial–Mesenchymal Transition and Increases the Number of Side Population Stem-like Cancer Cells in Nasopharyngeal Carcinoma 
PLoS Pathogens  2010;6(6):e1000940.
It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tumor virus to be associated with various malignancies, most notably NPC. LMP2A, the Epstein-Barr virus encoded latent protein, has been reported to play roles in oncogenic processes. We report by immunostaining in our current study that LMP2A is overexpressed in 57.6% of the nasopharyngeal carcinoma tumors sampled and is mainly localized at the tumor invasive front. We found also in NPC cells that the exogenous expression of LMP2A greatly increases their invasive/migratory ability, induces epithelial–mesenchymal transition (EMT)-like cellular marker alterations, and stimulates stem cell side populations and the expression of stem cell markers. In addition, LMP2A enhances the transforming ability of cancer cells in both colony formation and soft agar assays, as well as the self-renewal ability of stem-like cancer cells in a spherical culture assay. Additionally, LMP2A increases the number of cancer initiating cells in a xenograft tumor formation assay. More importantly, the endogenous expression of LMP2A positively correlates with the expression of ABCG2 in NPC samples. Finally, we demonstrate that Akt inhibitor (V) greatly decreases the size of the stem cell side populations in LMP2A-expressing cells. Taken together, our data indicate that LMP2A induces EMT and stem-like cell self-renewal in NPC, suggesting a novel mechanism by which Epstein-Barr virus induces the initiation, metastasis and recurrence of NPC.
Author Summary
Epstein-Barr virus (EBV) infects about 90% of people worldwide and persists benignly as a latent infection. However, EBV is associated with different types of human cancer. Nasopharyngeal carcinoma (NPC) is the most commonly known EBV associated cancer and expresses a well defined set of latent viral genes, including LMP2A, which has been detected in the majority of NPC samples. Several studies indicated this latent viral protein drove cellular invasion and metastasis. For this study, enforced LMP2A expressing NPC cell lines were generated. We show here that LMP2A induces an Epithelial–Mesenchymal Transition and increases the Stem-like Cancer Cells in NPC. Our results suggest that LMP2A supports tumor initiation and recurrence of the infected nasopharyngeal epithelial cells. For the first time we report a virus protein that functions in the initiation and progression of cancer by inducing the cancer stem-like cells. These findings permit a more detailed understanding of function and contribution to viral pathogenesis and provide a novel therapeutic target for NPC therapy.
doi:10.1371/journal.ppat.1000940
PMCID: PMC2880580  PMID: 20532215
15.  The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells 
The Journal of Clinical Investigation  2009;119(12):3626-3636.
The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1–mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3β signaling. Chromatin immunoprecipitation assays revealed that Bmi-1 transcriptionally downregulated expression of the tumor suppressor PTEN in tumor cells through direct association with the PTEN locus. This in vitro analysis was consistent with the statistical inverse correlation detected between Bmi-1 and PTEN expression in a cohort of human nasopharyngeal carcinoma biopsies. Moreover, ablation of PTEN expression partially rescued the migratory/invasive phenotype of Bmi-1–silenced cells, indicating that PTEN might be a major mediator of Bmi-1–induced EMT. Our results provide functional and mechanistic links between the oncoprotein Bmi-1 and the tumor suppressor PTEN in the development and progression of cancer.
doi:10.1172/JCI39374
PMCID: PMC2786794  PMID: 19884659

Results 1-15 (15)