[Show abstract][Hide abstract] ABSTRACT: Overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a DNA/RNA binding protein, is associated with metastasis in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying hnRNP K-mediated metastasis is unclear. The aim of the present study was to determine the role of matrix metalloproteinase (MMP) in hnRNP K-mediated metastasis in NPC.
BMC Cancer 05/2014; 14(1):348. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients.
The Journal of clinical investigation 11/2013; · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypofractionated radiotherapy (RT) has been employed to treat hepatocellular carcinoma (HCC). The present study aimed to report the treatment effects, the dose-response associations and the factors that are associated with radiation-induced liver disease (RILD) in a high-dose hypofractionated RT procedure. A total of 40 patients with non-metastatic HCC who underwent RT for local control of irradiated tumors were studied. The treatment technique was that of three-dimensional conformal or intensity-modulated radiation therapy, with a fraction size of 3 Gy and a total dose of 40-66 Gy in 14-23 fractions. The biologically-effective dose (BED) was 52.0-85.8 Gy10 (median, 74.1 Gy10). Tumor regression was observed in 28 patients (70.0%) with a complete response, partial response, stable disease and progressive disease status in 11 (27.5%), 17 (42.5%), five (12.5%) and seven patients (17.5%), respectively. The one-, two- and five-year overall survival (OS) and in-field control (IFC) rates were 60, 40 and 21% and 73, 62 and 56%, respectively. A positive correlation also emerged between the radiation dose and the IFC (P=0.035). Eight of the 40 patients (20%) developed non-classic RILD. A higher Cancer of the Liver Italian Program score was associated with a higher probability of non-classic RILD (P=0.02). The tumor response and IFC rate of HCC following irradiation were significantly dose-dependent. High-dose hypofractionated X-ray RT is a feasible and effective treatment for HCC in patients with good liver function and for those who meet the criteria for a curative attempt.
[Show abstract][Hide abstract] ABSTRACT: Objective/Hypothesis: The role of tumor volume in T4a laryngeal cancer remains unclear among different treatment modalities. Using tumor volumetry, we investigated the impact of primary tumor volume on this subset of patients. Study Design: Retrospective cohort study of 62 T4a laryngeal cancer patients Methods: From October 2002 to September 2010, 48 patients were treated with definitive chemoradiation therapy (CRT) and 14 patients had undergone total laryngectomy. Tumor volume was calculated and was correlated with the overall survival (OS), progression-free survival (PFS) and local control rate (LCR) data of each treatment group. Results: The 5-year OS, PFS and LCR were significantly lower in the CRT group with tumor volume ≥ 15 cm(3) (22.5% vs. 48.7%, P = 0.009; 32.2% vs. 64.3%, P = 0.003; 45.2% vs. 67.3%, P = 0.039). Multivariate analysis showed that tumor volume was an independent poor prognosticator for OS, PFS and LCR in the CRT group. For tumor volume ≥ 15 cm(3) , total laryngectomy provided a significantly higher 5-year OS and PFS (54.5% vs. 22.5%, P = 0.039; 80.0% vs. 32.2%, P = 0.017) than those treated with definitive CRT. Conclusion: Patients of T4a laryngeal cancer with primary tumor volume ≥ 15 cm(3) had poorer survival outcomes after definitive CRT compared with total laryngectomy. It was also an independent poor prognosticator on LCR, PFS and OS for those receiving definitive CRT. For patients with tumor volume ≥ 15 cm(3) , total laryngectomy provided a better survival outcome than definitive CRT.
[Show abstract][Hide abstract] ABSTRACT: Current standard treatment of nasopharyngeal carcinoma (NPC) is either radiotherapy alone or combined chemoradiotherapy. Surgery in the form of nasopharyngectomy is usually only offered when there is evidence of local recurrence or persistent disease. Recurrent NPC (rNPC) can be detected earlier with the utilization of Epstein-Barr virus molecular diagnosis. This may result in early management with salvage surgery and hence improved survival. The facial translocation approach enhanced our ability to access the nasopharynx. Through a multidisciplinary approach with the collaboration of neurosurgeons, the surgical indication of salvage surgery is extended. This allowed improved respectability in locally advanced disease and involved the skull base and intracranial extension with reasonable morbidity and mortality. Endoscopic nasopharyngectomy is a choice for recurrent NPC with central roof or floor lesions with minimal lateral extension. Multivariate analysis indicated that gender, parapharyngeal space involvement, surgical margin, and the modality of adjuvant therapy impact significantly on local control. The impact on survival is indicated by the dura or brain involvement, local recurrence and modality of adjuvant therapy. It is apparent that recurrent NPC patients who underwent surgery had a significantly better survival rate than the re-radiation therapy group.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: In this study, we investigated the usefulness and limitations of EBV-DNA follow-up in patients who had treated localized nasopharyngeal carcinoma. METHODS: Study subjects comprised 389 patients who had received treatment for localized nasopharyngeal carcinoma in our department. Copy numbers of EBV-DNA in plasma were assessed by real-time quantitative PCR. Patients in whom disease recurrence was suspected underwent image evaluation, esp. PET scan, and tissue proof if it is feasible. Lesions of undermined nature were confirmed by sequential follow-up. RESULTS: Plasma EBV-DNA was detectable in 60 of 63 (95%) patients with metastatic disease and all had positive PET findings. In addition, of the 45 patients with localized recurrent disease, plasma EBV-DNA was detectable in 23 (51%) patients and positive PET scan results were obtained in 40 (89%) of the patients. Of the 284 patients who were disease free, plasma EBV-DNA was detected in 90 (32%) patients. Of the 19 patients in disease free group who were suspected disease recurrence receiving PET scanning, 7 positive PET images were found including 3 second primary malignancy and 4 non-cancer lesions. Two lymphoma cases with positive EBV-DNA value sequentially attacked before or after their NPC were diagnosed. With the cutoff value of 400copies/ml of EBV-DNA, the positive predict value was 73.5% and the negative predict value was 82.1%. The sensitivity was 0.46 and the specificity was 0.94. CONCLUSIONS: EBV-DNA was a good marker for detecting metastatic failure in treated localized NPC. However, careful interpretation with complements from image examination was needed for locoregional failure and other false positive or false negative situations.
[Show abstract][Hide abstract] ABSTRACT: This study is the first to use genome-wide association study (GWAS) data to evaluate the multidimensional genetic architecture underlying nasopharyngeal cancer. Since analysis of data from GWAS confirms a close and consistent association between elevated risk for nasopharyngeal carcinoma (NPC) and major histocompatibility complex class 1 genes, our goal here was to explore lesser effects of gene-gene interactions. We conducted an exhaustive genome-wide analysis of GWAS data of NPC, revealing two-locus interactions occurring between single nucleotide polymorphisms (SNPs), and identified a number of suggestive interaction loci which were missed by traditional GWAS analyses. Although none of the interaction pairs we identified passed the genome-wide Bonferroni-adjusted threshold for significance, using independent GWAS data from the same population (Stage 2), we selected 66 SNP pairs in 39 clusters with P<0.01. We identified that in several chromosome regions, multiple suggestive interactions group to form a block-like signal, effectively reducing the rate of false discovery. The strongest cluster of interactions involved the CREB5 gene and a SNP rs1607979 on chromosome 17q22 (P = 9.86×10(-11)) which also show trans-expression quantitative loci (eQTL) association in Chinese population. We then detected a complicated cis-interaction pattern around the NPC-associated HLA-B locus, which is immediately adjacent to copy-number variations implicated in male susceptibility for NPC. While it remains to be seen exactly how and to what degree SNP-SNP interactions such as these affect susceptibility for nasopharyngeal cancer, future research on these questions holds great promise for increasing our understanding of this disease's genetic etiology, and possibly also that of other gene-related cancers.
PLoS ONE 01/2013; 8(12):e83034. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this cohort study was to examine the role of the chemokine (C-X-C motif) ligand 9 (CXCL9) on nasopharyngeal carcinoma (NPC).
Sera from 205 NPC patients and 231 healthy individuals, and 86 NPC tumor samples were enrolled. CXCL9 expression in tissue samples was analyzed by quantitative real-time PCR and immunohistochemistry. CXCL9 serum concentrations were measured by enzyme-linked immunosorbent assay.
CXCL9 expression was significantly higher in tumors than in normal epithelium. CXCL9 serum concentrations were also significantly higher in NPC patients compared to those in healthy individuals (516.8±617.6 vs. 170.7±375.0 pg/mL, P<0.0001). Serum CXCL9 levels were significantly higher in NPC patients with higher tumor stages, nodal stages, and overall stages (P<0.001, P = 0.001, and P<0.001, respectively). We found a statistically significant correlation between the concentrations of CXCL9 and EBV DNA load in the NPC patients (Spearman's correlation analysis; r = 0.473, P<0.001; 95% confidence interval, 0.346-0.582). Moreover, NPC patients with higher CXCL9 levels (>290 pg/mL, median) before treatment had worse prognoses for overall survival and disease-free survival (P = 0.045 and P = 0.008, respectively). Multivariate logistic regression analyses also indicated that higher CXCL9 serum levels were an independent prognostic factor for disease-free survival (P = 0.015).
Our study demonstrated that CXCL9 is associated with tumor burden and aggressiveness of NPC tumors and the serum level of this ligand may be useful as a prognostic indicator.
PLoS ONE 01/2013; 8(11):e80052. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammasomes are cytoplasmic receptors that can recognize intracellular pathogens or danger signals and are critical for IL-1β production. Although several key components of inflammasome activation have been identified, there has not been a systematic analysis of the protein components found in the stimulated complex. In this study, we used the isobaric tags for relative and absolute quantification (iTRAQ) approach to systemically analyze the interactomes of the NLRP3, AIM2, and RIG-I inflammasomes in NPC cells treated with specific stimuli of these interactomes (H2O2, poly (dA:dT) and EBER, respectively). We identified a number of proteins that appeared to be involved in the interactomes and also could be precipitated with anti-ASC antibodies after stimulation. Among them, EB1 was an interacting component in all three interactomes. Silencing of EB1 expression by small interfering RNA inhibited the activation of the three inflammasomes, as indicated by reduced levels of IL-1β secretion. We confirmed that EB1 directly interacted with AIM2 and ASC in vitro and in vivo. Most importantly, fluorescence confocal microscopy showed that EB1 was required for formation of the speck-like particles that represent activation of the AIM2 inflammasome. In NPC tissues, IHC staining showed that EB1 expression was elevated and significantly correlated with AIM2 and ASC expression in NPC tumor cells. In sum, we profiled the interactome components of three inflammasomes and show for the first time that EB1 is crucial for the speck-like particle formation that represents activated inflammasomes.
[Show abstract][Hide abstract] ABSTRACT: Introduction. The purpose of this study was to determine the influence of Chinese medicine in a Chinese medicine ward (CMW) on weight loss and quality of life in patients with head and neck (HN) cancers during radiotherapy (RT). METHODS: From 2006 to 2010, patients with HN cancers hospitalized in the CMW for ≥10 days during RT were included. Outpatients with HN cancers from the Department of Radio-oncology were also enrolled. Body weight was evaluated near the beginning and the end of RT. Quality of life was assessed near the end of RT. RESULTS: Sixty-nine inpatients and 74 outpatients with radiation doses ≥60 Gy were included. Inpatients had significantly lesser weight loss than outpatients (P = .016) during RT or chemoradiation. Patients hospitalized for ≥40 days had lesser weight reduction than those hospitalized for a shorter period (P = .025). In the quality-of-life assessment, inpatients had significantly lower score for the item "lack of appetite" on the M.D. Anderson Symptom Inventory than outpatients (P = .002). CONCLUSIONS: Patients with HN cancers receiving hospitalization and Chinese medicine in the CMW had lesser weight loss than outpatients. By monitoring the patient's condition to adjust the prescription of Chinese medicine, this treatment minimized the weight loss resulting from RT or chemoradiation potentially because of a better functioning of appetite. Patients receiving integrated medicine early showed better results than those starting this treatment later.
Integrative Cancer Therapies 05/2012; · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim was to study the expression of Secretory Leukocyte Protease Inhibitor (SLPI) and to explore its correlation with the presence of Epstein-Barr Virus (EBV) among patients with nasopharyngeal carcinoma.
The expression levels of SLPI mRNA in NPC cell lines and in ten matched-pairs of NPC and adjacent normal tissue were examined by quantitative real-time Polymerase Chain Reaction (PCR). Furthermore, protein expression of SLPI in 71 paraffin-embedded NPC biopsies was assessed by immunohistochemistry. Finally, the serum level of SLPI in 177 NPC patients and 103 healthy controls was evaluated by enzyme-linked immunosorbent assay (ELISA).
The expression of SLPI mRNA in NPC cells was significantly lower than in the adjacent normal epithelium (p<0.001). When the expression of SLPI in EBV-positive and -negative NPC cell lines was compared, we found that both mRNA and protein expressions of SLPI were significantly higher in EBV-negative cells. Furthermore, the results of immunohistochemical analysis demonstrated that the frequency of reduced SLPI expression in EBV-positive biopsies was significantly higher than that in EBV-negative biopsies.
In this study, we have confirmed that SLPI is significantly down-regulated in NPC tissues. In addition, based on our preliminary results, we propose that the reduction of SLPI in NPC cells is associated with the presence of the EBV genome and/or the expression of EBV-encoded genes. SLPI may play an important role in EBV-mediated NPC tumorigenesis.
Anticancer research 04/2012; 32(4):1299-307. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the association of pretreatment body mass index (preT BMI) with outcomes of head-and-neck cancer in patients treated with radiotherapy (RT).
All 1,562 patients diagnosed with head-and-neck cancer and treated with curative-intent RT to a dose of 60 Gy or higher were retrospectively studied. Body weight was measured both at entry and at the end of RT. Cancer-specific survival (CSS), overall survival (OS), locoregional control (LRC), and distant metastasis (DM) were analyzed by preT BMI (<25 kg/m(2) vs. ≥25 kg/m(2)). The median follow-up was 8.6 years.
Patients with lower preT BMI were statistically significantly associated with poorer CSS and OS than those with higher preT BMI. There was no significant difference between preT BMI groups in terms of LRC and DM. Body weight loss (BWL) during radiation did not influence survival outcomes. However, in the group with higher preT BMI, CSS, OS, and DM-free survival of patients with less BWL during radiation were statistically longer when compared with greater BWL.
This study demonstrates that higher preT BMI positively influenced survival outcomes for patients with head-and-neck cancer. Patients with higher preT BMI who were able to maintain their weight during radiation had significantly better survival than patients with greater BWL.
International journal of radiation oncology, biology, physics 02/2012; 83(1):e93-e100. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The plasma concentration of Epstein-Barr virus (EBV) DNA is associated with tumor burden and prognosis in patients with nasopharyngeal carcinoma (NPC), but data on the relationship between viral load and (18)F-FDG PET functional parameters are lacking. We examined the association of (18)F-FDG PET functional parameters and EBV DNA load with the clinicopathologic characteristics and clinical outcomes of patients with NPC.
One hundred eight patients with NPC who underwent (18)F-FDG PET before treatment were included in this study. We determined total lesion glycolysis (TLG) of the primary tumor, the cervical nodes, and their combination and the maximal standardized uptake value of the primary tumor and cervical lymph nodes. EBV DNA was measured by real-time polymerase chain reaction.
EBV DNA was significantly associated with total TLG (R(2) = 0.589). Total TLG values had the highest correlation with EBV DNA load and were significantly associated with tumor, nodal, and overall stages. However, tumor TLG greater than the median (>65 g) was the only parameter significantly associated with overall, local recurrence-free, disease-free, and distant metastasis-free survivals (P = 0.033, 0.014, <0.001, and 0.023, respectively). After allowance for potential confounders, tumor TLG retained its independent significance for overall and disease-free survival rates (P = 0.045 and 0.006, respectively).
Total TLG values are primarily associated with tumor burden and clinical stage, whereas tumor TLG is the best predictor of patient survival after treatment.
Journal of Nuclear Medicine 01/2012; 53(1):21-8. · 5.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The association between human leukocyte antigen (HLA) genes (located in the Major Histocompatibility Complex [MHC] region of chromosome 6p21) and NPC has been known for some time. Recently, two genome-wide association studies (GWAS) conducted in Taiwan and China confirmed that the strongest evidence for NPC association was mapped to the MHC region. It is still unclear, however, whether these findings reflect direct associations with Human Leukocyte Antigen (HLA) genes and/or to other genes in this gene-rich region.
To better understand genetic associations for NPC within the MHC region of chromosome 6, we conducted an evaluation that pooled two previously conducted NPC case-control studies in Taiwan (N = 591 cases and N = 521 controls). PCR-based genotyping was performed for 12 significant SNPs identified within 6p21 in the Taiwan NPC GWAS and for the HLA-A gene (exons 2 and 3).
After confirming homogeneity between the two studies, pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. We found that HLA-A (p-trend = 0.0006) and rs29232 (within the GABBR1 gene; p-trend = 0.005) were independent risk factors for NPC after adjustment for age, gender, study and each other. NPC risk was highest among individuals who were homozygous for the HLA-A*0207 risk allele and carriers of the rs29232 risk allele (A).
Our study suggests that most of the SNPs significantly associated with NPC from GWAS reflect previously identified HLA-A associations. An independent effect of rs29232 (GABBR1), however, remained, suggesting that additional genes within this region might be associated with NPC risk.
PLoS ONE 01/2012; 7(8):e42767. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the pretreatment copy number and the clearance rate of plasma Epstein-Barr virus (EBV) DNA as novel prognostic outcome markers for metastatic nasopharyngeal carcinoma (NPC).
Seventy-three patients with metastatic NPC were treated at outpatient department. Plasma EBV DNA concentrations and half-life values of plasma viral clearance rates, were determined by real-time quantitative polymerase chain reaction.
Treatment response evaluated after 3 to 6 months of treatment showed that the overall response rate was 53.5%. The pretreatment plasma EBV DNA concentrations and the half-life of plasma EBV DNA clearance rates had significant effects on treatment response and overall survival prediction. In the chemotherapy regimen, gemcitabine plus cisplatin had a better treatment outcome than the cisplatin plus oral UFT and calcium folinate-based regimens.
The pretreatment plasma EBV DNA copy number and their clearance rates are significant predictors for NPC treatment outcome.
Head & Neck 11/2011; 34(8):1064-70. · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Copy number variations (CNVs), a major source of human genetic polymorphism, have been suggested to have an important role in genetic susceptibility to common diseases such as cancer, immune diseases and neurological disorders. Nasopharyngeal carcinoma (NPC) is a multifactorial tumor closely associated with genetic background and with a male preponderance over female (3:1). Previous genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that are associated with NPC susceptibility. Here, we sought to explore the possible association of CNVs with NPC predisposition. Utilizing genome-wide SNP-based arrays and five CNV-prediction algorithms, we identified eight regions with CNV that were significantly overrepresented in NPC patients compared with healthy controls. These CNVs included six deletions (on chromosomes 3, 6, 7, 8 and 19), and two duplications (on chromosomes 7 and 12). Among them, the CNV located at chromosome 6p21.3, with single-copy deletion of the MICA and HCP5 genes, showed the highest association with NPC. Interestingly, it was more specifically associated with an increased NPC risk among males. This gender-specific association was replicated in an independent case-control sample using a self-established deletion-specific polymerase chain reaction strategy. To the best of our knowledge, this is the first study to explore the role of constitutional CNVs in NPC, using a genome-wide platform. Moreover, we identified eight novel candidate regions with CNV that merit future investigation, and our results suggest that similar to neuroblastoma and prostate cancer, genetic structural variations might contribute to NPC predisposition.
Human Molecular Genetics 07/2011; 20(14):2889-96. · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to determine the therapeutic outcome of papillary thyroid cancer (PTC) patients in different risk groups in one institute.
A total of 1,759 PTC patients were categorized into low- (n = 1,123), intermediate- (n = 75), and high-risk (n = 561) groups according to tumor-node-metastasis (TNM) stage.
Of the patients, 15.1% presented with lymph node metastases, and 4.6% presented with distant metastases at the time of thyroid operation. After 8.0 ± 0.1 years of follow-up, 73 (4.2%) patients died of thyroid cancer. Tumor size, local invasion, and lymph node metastases adversely influenced recurrence and survival. Of the patients in the 3 groups, 9 (0.8%), 8 (10.7%), and 56 (10.0%) died of thyroid cancer, respectively. In addition, 88 (7.8%), 14 (18.7%), and 144 (25.8%) patients showed recurrence during the follow-up period. Patients with highly aggressive histological patterns showed increased recurrence and cancer mortality compared with the low-risk group; otherwise, values were not higher than those of the high-risk group.
The cancer-related mortality was nearly 10% in the intermediate- and high-risk groups, and the patients in these groups required aggressive surgical and postoperative adjuvant therapies.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to examine cytokine profiles of peripheral blood for nasopharyngeal carcinoma (NPC).
A total of 132 patients with untreated NPC, 169 healthy individuals, and 32 patients with chronic rhinosinusitis (CRS) were enrolled in this study. The plasma levels of 13 cytokines were measured by the multiplexed immunobead-based method.
The levels of interleukin (IL)-6, IL-8, interferon-inducible protein 10 (IP-10), tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and macrophage inflammatory protein (MIP)-3α were significantly elevated in patients with NPC; but the stem cell factor (SCF) levels were significantly lower. The levels of IL-6, IL-8, IP-10, and MIP-3α were significantly elevated in patients with advanced stages disease and correlated with Epstein-Barr virus (EBV) DNA. A 2-marker panel consisting of MIP-3α and SCF increased the screening efficacy of EBV-specific viral capsid antigen (VCA) IgA or EBV DNA, although the addition of MIP-3α and SCF to the combined set of currently available markers (EBV VCA IgA and EBV DNA) did not improve the accuracy of the diagnostic panel. The patients with NPC with higher levels of IL-8, VEGF, MIP-3α, and EBV DNA had worse prognoses for overall survival (p = .008, .035, .005, and .007, respectively).
Simultaneous, large-scale measurement of multiple cytokines may improve NPC detection and prognostic prediction.
Head & Neck 06/2011; 33(6):886-97. · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumor necrosis factor alpha (TNFα) is an inflammatory cytokine that is present in the microenvironment of many tumors and is known to promote tumor progression. To examine how TNFα modulates the progression and metastasis of nasopharyngeal carcinoma, we used Affymetrix chips to identify TNFα-inducible genes that are dysregulated in this tumor. Elevated expression of TNFAIP2, which encodes TNFα-inducible protein 2 and not previously known to be associated with cancer, was found and confirmed by quantitative RT-PCR of TNFAIP2 expression in nasopharyngeal carcinoma and adjacent normal tissues. Immunohistochemical analysis showed that the TNFAIP2 protein was highly expressed in tumor cells. Analysis of 95 nasopharyngeal carcinoma biopsy specimens revealed that high TNFAIP2 expression was significantly correlated with high-level intratumoral microvessel density (P=0.005) and low distant metastasis-free survival (P=0.001). A multivariate analysis further confirmed that TNFAIP2 was an independent prognostic factor for nasopharyngeal carcinoma (P=0.002). In vitro, TNFα treatment of nasopharyngeal carcinoma HK1 cells was found to induce TNFAIP2 expression, and siRNA-based knockdown of TNFAIP2 dramatically reduced the migration and invasion of nasopharyngeal carcinoma HK1 cells. These results collectively suggest for the first time that TNFAIP2 is a cell migration-promoting protein and its expression predicts distant metastasis. Our data suggest that TNFAIP2 may serve as an independent prognostic indicator for nasopharyngeal carcinoma.
Modern Pathology 11/2010; 24(2):175-84. · 5.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nasopharyngeal carcinoma (NPC) is usually diagnosed at advanced clinical stages, resulting in poor outcomes. To discover serum biomarkers for improved NPC diagnosis and/or management, we simultaneously analyzed the NPC cell secretome and tissue transcriptome to identify candidate genes/proteins that are highly upregulated in NPC tissues and also secreted/released from NPC cells. Among the 30 candidates identified, 11 proteins were chosen for further validation using the serum samples from NPC patients and healthy controls, including cystatin A, cathepsin B, manganese superoxide dismutase and matrix metalloproteinase 2. The results showed that serum levels of all the four proteins were indeed higher in NPC patients versus healthy controls and that the use of a three-marker panel (cystatin A, manganese superoxide dismutase and matrix metalloproteinase 2) can contribute to a better NPC detection than each marker alone. In addition, a higher pretreated serum level of cystatin A was found to be associated with a higher nodal stage and poorer prognosis of NPC patients and cystatin A could modulate the migration and invasion of NPC cells in vitro. Altogether, our results indicate that analysis of both the cancer cell secretome and tissue transcriptome is a feasible strategy for efficient identification of novel NPC serum marker panel.