Molecular pathology parameters in human nasopharyngeal carcinoma

Shi, Wei; Pataki, István; MacMillan, Christine; Pintilie, Melania; Payne, David G.; O'Sullivan, M B Brian; M.B., Bernard J. Cummings; Warde, M B Padraig; Liu, Fei‐Fei

doi:10.1002/cncr.0679

Cited by 69 publications

(52 citation statements)

References 50 publications

(64 reference statements)

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“…Formalin-fixed and paraffin-embedded (FFPE) NPC patient biopsies were randomly selected for immunohistochemical analysis from an archival bank of materials, which have been evaluated previously. [31][32][33] qRT-PCR. Supplementary Table 3 lists all the primer sequences used in this study.…”

Section: Methodsmentioning

confidence: 99%

Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy

et al. 2009

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Overexpression of BMI1 correlates with cancer development, progression, and therapy failure; however, the underlying molecular mechanisms remain to be fully elucidated. Using the C666-1 nasopharyngeal cancer (NPC) model, the role of BMI1 in mediating response of NPC cells to radiation therapy (RT) was investigated. The results showed a novel radioresistance function for BMI1 in NPC, wherein BMI1 depletion sensitized NPC cells to RT. Cell cycle analysis and transmission electron microscopy (TEM) showed apoptosis as the major mode of cell death, and the mitochondria as a primary targeted cellular organelle. Genomewide microarray and pathway analyses revealed that the P53 pathway is a critical mediator of this process. Cotransfection with siP53 rescued C666-1 cells from cytotoxicity upon BMI1 depletion and RT, thereby corroborating the role for P53. Pretreatment with the antioxidant, Trolox, inhibited apoptosis, indicating that production of reactive oxygen species (ROS) is also mediating cytotoxicity. In vivo, BMI1 depletion combined with RT abrogated tumor-forming capacity in SCID mice, showing the relevance of this process in a more complex tumor environment. Hence, we show a novel role for BMI1 in conferring radioresistance in cancer cells through the downregulation of p53-mediated apoptosis. These results suggest a potential strategy of BMI1 depletion combined with RT for tumors wherein BMI1 appears to be driving disease progression.

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Section: Methodsmentioning

confidence: 99%

Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy

et al. 2009

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“…Archival formalin-fixed and paraffin-embedded tumors were obtained from 80 of these patients prior to treatment. The clinical characteristics of this subgroup of patients have been previously published (14,15). As shown in Table 1, the majority of patients were male (60 of 80, or 75%), of Asian/Chinese ethnicity (49 of 80, or 61%), had locally advanced stage III or IV disease (66 of 80, or 83%), and had undifferentiated WHO type 2B NPC (60 of 80, or 75%).…”

Section: Methodsmentioning

confidence: 99%

Prognostic Significance of the Epstein-Barr Virus, p53, Bcl-2, and Survivin in Nasopharyngeal Cancer

Yip

Shi

Pintilie

et al. 2006

Clinical Cancer Research

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Purpose: Nasopharyngeal cancer (NPC) is a malignant epithelial carcinoma which is intimately associated with EBV. The latent presence of EBV affects the function of p53, Bcl-2, and survivin. We thus investigated the relationship between EBV status, p53, Bcl-2, and survivin in biopsy specimens from patients with primary NPC. Experimental Design: Archival formalin-fixed, paraffin-embedded NPC biopsies were evaluated in 80 patients treated with curative radiation from a single institution. The presence of EBV was determined using EBER in situ hybridization, whereas p53, Bcl-2, and survivin were assessed using immunohistochemistry. Results: The majority of NPC specimens in this patient cohort were EBER-positive (64 of 78, or 82%), which in turn, was significantly associated with ethnicity (P = 0.0007), and WHO subtype 2A/2B (P = 0.04). EBER-positive tumors were also associated with p53 (P = 0.002), Bcl-2 (P = 0.04), and nuclear survivin (P = 0.03) expression. Patients with EBER-positive NPC fared better, with a 10-year overall survival of 68% versus 48% for EBER-negative patients (P = 0.03). For nuclear survivin, patients with either low or high nuclear survivin fared worse than patients with intermediate survivin expression (P = 0.05), suggesting that there is an optimal proportion of survivin-expressing cells for best function and clinical outcome. Conclusions: With an extended median follow-up time of 11.4 years, EBV status remains a strong predictor for overall survival in NPC. EBV-positive NPC has strong molecular associations with p53, Bcl-2, and survivin expression. Furthermore, we provide clinical data revealing the potentially dual nature of survivin in predicting clinical outcome.Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck site, with incidences of 20 to 30 per 100,000 people in areas such as Southeast Asia (a region of >100 million people) and the Mediterranean basin (a region of >300 million people) (1). NPC is anatomically located in close proximity to the base of the skull, rendering it a significant challenge for conventional and experimental treatments. In fact, inadequate tumor volume coverage may be partially responsible for the modest 5-year overall survival (OS) rate of f70% when patients are treated with conventional radiotherapy alone (2 -4). Although intensity-modulated radiotherapy does improve local control, the risk of distant metastases remains high at f40% (2). A predilection for developing distant metastases, a young median age of presentation (at f50 years), and the intimate association with EBV are features that render NPC a unique head and neck epithelial malignancy (5).The latent presence of EBV is unique to malignancies such as NPC, Burkitt's lymphoma, Hodgkin's lymphoma, peripheral T cell lymphomas, natural killer cell lymphomas, and gastric carcinomas (1). Approximately 75% to 81% of patients with NPC worldwide harbor the EBV genome, which is present in the type II latency. This form of latency is characterized by the expression ...

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“…The presence of EBV in all 19 NPC samples was confirmed by in situ hybridization using an EBER probe, as previously described. 13 Validation of the microarray data was conducted using an additional 4 independent NPC specimens. All clinical information related to patient characteristics can be found in the Supplemental Section (Supplementary Table I).…”

Section: Clinical Samples and Patients Informationmentioning

confidence: 99%

“…13 The monoclonal mouse antihuman Bcl-2 (DakoCytomation, Denmark), the polyclonal rabbit antihuman survivin (Novus Biologicals, Littleton, CO) and the polyclonal rabbit antihuman integrin a v (Cedarlane Lab Lid, Canada) antibodies were used at dilutions of 1:50; 1:400 and 1:1,000, respectively. Sections of NPC and breast carcinoma, which were previously identified to be positive for Bcl-2 and survivin, served as the respective positive controls.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling

Shi¹,

Bastianutto²,

Li³

et al. 2006

Intl Journal of Cancer

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Gene expression profiling was conducted using primary human nasopharyngeal carcinoma (NPC) biopsy samples to improve the understanding of the molecular pathways defining NPC and to identify novel potential therapeutic targets. RNA samples were extracted from 36 patients suspected to have NPC and hybridized onto the Affymetrix U133A chip. NPC was diagnosed in 19 patients, 11 had lymphoid hyperplasia (LH), and 6 were “normal” biopsies. Clinical stages for these NPC patients ranged from I–IV, including one M1. All NPC patients (except the M1) were treated with curative intent, which included radiotherapy alone (4 patients), or combined with chemotherapy (14 patients). Unsupervised clustering demonstrated a distinct NPC expression pattern, compared to normal biopsies. Subsequent Significance Analysis of Microarrays (SAM) derived from 14 NPC and 6 normal samples discovered 1,089 differentially regulated genes. Pathway analyses revealed novel insights into the mechanisms leading to NPC, whereby upregulation of NFκB2 and survivin play central roles in increasing resistance to apoptosis, and changes in integrin and WNT/β‐catenin signaling leading to uncontrolled proliferation. The role of survivin in resisting apoptosis in NPC was confirmed by RNA interference. Our data provide novel insights into the development and progression of NPC, and suggest survivin as a novel therapeutic target for NPC. © 2006 Wiley‐Liss, Inc.

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Molecular pathology parameters in human nasopharyngeal carcinoma

Cited by 69 publications

References 50 publications

Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy

Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy

Prognostic Significance of the Epstein-Barr Virus, p53, Bcl-2, and Survivin in Nasopharyngeal Cancer

Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling

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