Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: Association with p53 expression

Sheu, Lai-Fa; Chen, Ann; Meng, Ching Liang; Ho, Keang-Po; Lin, Fei-Jan; Lee, Wei Hwa

doi:10.1016/s0046-8177(97)90078-2

Cited by 59 publications

(53 citation statements)

References 23 publications

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“…We did not identify any evidence of lytic activity in the adjacent tumour or lymphoid stroma of NPC biopsies. To an extent, these results are not unexpected since both post-transplant lymphoproliferative disorders as well as NPC contain high expression of Bcl-2 within tumour cells [Sheu et al, 1997] and we found that all cases of NPC that we studied were positive for Bcl-2. Many studies have shown an interaction between EBV and Bcl-2.…”

Section: Discussionsupporting

confidence: 71%

Comparative analysis of the expression of the epstein‐barr virus (EBV) anti‐apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV‐related lymphoid diseases

Nicholls

Kremmer

Meseda

et al. 2001

Journal of Medical Virology

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Epstein-Barr virus (EBV) has been identified in a wide range of neoplastic and non-neoplastic disorders. The EBV open reading frame BHRF1 encodes a protein with partial sequence and functional homology to the anti-apoptotic onco-protein Bcl-2 and may therefore have a role in the proliferation of EBV positive cells. We have developed a rat monoclonal antibody against pBHRF1, which can detect BHRF1 in paraffin sections. While a number of mutant versions of BHRF1 were recognised, the monoclonal did not detect the BHRF1 homologue encoded by Herpesvirus papio or two mutants with deletions in the BH2 region. This novel rat monoclonal antibody (6A9) was used to examine tissue sections from 39 cases of non-keratinising undifferentiated nasopharyngeal carcinoma (NPC), 6 cases of metastatic NPC, 7 cases of EBV-positive NPC with squamous differentiation from Chinese patients, 15 cases of EBV-positive post-transplant lymphoproliferative disorder (PTLD), 6 EBV-containing lymphoblastoid cell lines, and 2 cases of oral hairy leukoplakia (OHL). In 11 cases of undifferentiated NPC, RT-PCR data were available for comparison with the immunohistochemistry. Both cases of OHL and two cases of LCL were positive for BHRF1 but none of the PTLD showed positive staining. All cases of undifferentiated NPC were positive for Bcl-2 but only one BHRF1 positive cell was identified in 1 of 39 cases of primary undifferentiated NPC. The 6A9 antibody produced less background staining and no nuclear positivity compared with the commercially available mouse monoclonal 5B11. It is concluded that BHRF1 can not be detected by immunohistochemistry in NPC and therefore it appears not to play a significant anti-apoptotic role in the progression of this EBV-associated tumour. The 6A9 monoclonal appears to be superior to 5B11 for the detection of pBHRF1 in tissue sections.

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Section: Discussionsupporting

confidence: 71%

Comparative analysis of the expression of the epstein‐barr virus (EBV) anti‐apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV‐related lymphoid diseases

Nicholls

Kremmer

Meseda

et al. 2001

Journal of Medical Virology

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“…2). Other groups have also reported a significant association between p53 and Bcl-2 expression in NPC (20,21), along with an association between EBV with both p53 and Bcl-2 overexpression in adult (22) and pediatric (23) NPC. Thus, one would surmise that the optimal treatment modalities or regimens for EBV-negative and EBVpositive NPC should be different, although we might require additional insights from future gene expression microarray studies to fully elucidate the distinct molecular profiles between EBV-positive and EBV-negative NPC.…”

Section: Fig 3 Kaplan-meier Plots For Os (A) and Dfs (B) As A Functmentioning

confidence: 82%

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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“…However, Bcl-2 is overexpressed in the majority of NPC tumors (61-89%), even in the absence of detectable LMP1 expression, and it is postulated that Bcl-2 may play a critical role in promoting cell survival and mediating resistance to chemotherapeutic agents in NPC. [6][7][8][9][10][11][12] Thus, Bcl-2 represents a rational therapeutic target in NPC.…”

Section: Discussionmentioning

confidence: 99%

“…5 Although a direct link between LMP-1 expression, Bcl-2 upregulation and cell survival in NPC is unclear, the majority of NPC tumors overexpress Bcl-2, even in the absence of LMP-1 expression. [6][7][8][9][10][11][12] Given the antiapoptotic function of Bcl-2 and its role in conferring resistance to chemotherapy, it represents a rational target for modulation using antisense strategies in NPC.…”

Section: Epstein-barr Virus (Ebv) Is Causally Linked To Undifferentiamentioning

confidence: 99%

“…Animals were injected with 5 million C666-1 and randomized to CDDP (diamonds), CDDP 1 2 base mismatch control oligo MM (triangles) or CDDP 1 G3139 (squares) (n 5 5-6 per arm). Treatment with oligo was initiated on day 7 at a dose of 25 mg/kg every 3 days 3 5 doses (days [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. CDDP was administered on day 14 (8 mg/kg 3 1).…”

Section: G3139 Inhibits C666-1 Growth and Enhances Sensitivity To Cddmentioning

confidence: 99%

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Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice

Lacy

Loomis

Grill

et al. 2006

Intl Journal of Cancer

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Nasopharyngeal carcinoma (NPC) is causally linked to Epstein‐Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP‐1), is expressed in the majority of NPCs. LMP‐1 upregulates antiapoptotic genes, including bcl‐2, and Bcl‐2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl‐2, it represents a rational therapeutic target in NPC. We have investigated the antitumor and chemosensitizing effects of the Bcl‐2 antisense oligodeoxynucleotide G3139 (oblimersen, Genasense) in NPC. For these studies, we used the C666‐1 line, a stably infected NPC‐derived line that co‐expresses LMP‐1 and Bcl‐2. We have shown that G3139 treatment of C666‐1 in vitro caused sequence‐dependent suppression of Bcl‐2 protein, inhibition of cell growth and enhanced sensitivity to cisplatin (CDDP), as measured by increased antiproliferative and apoptotic effects. In vivo, G3139 treatment (25 mg/kg every 3 days × 5 doses) delayed engraftment and significantly inhibited growth of established C666‐1 xenografts in SCID mice compared to control oligo‐treated animals. However, G3139 alone did not prevent engraftment or cure established tumors in any animals. In contrast, G3139 treatment (25 mg/kg every 3 days × 5 starting on day 7) in combination with CDDP (8 mg/kg on day 14) completely abrogated tumor engraftment in 80% of animals compared to CDDP (0%) or CDDP + control oligo (0%). When treatment was delayed until tumor was established, G3139 in combination with CDDP significantly inhibited tumor growth compared to CDDP or CDDP + control oligo, and cured 69% animals with established tumors. No animals treated with G3139, CDDP or CDDP + control oligo were cured. Tumor burden and response to treatment correlated with EBV DNA load in serum, measured by real‐time PCR. Western blots of tumor extracts obtained during oligo treatment showed that Bcl‐2 levels were significantly decreased in G3139‐treated animals. Our studies have demonstrated that the Bcl‐2 antisense oligodeoxynucleotide, G3139, has proapoptotic effects in C666‐1, and in combination with CDDP, is curative in C666‐1 NPC xenograft tumors in vivo. The sequence‐dependency of these effects is consistent with an antisense mechanism. These studies suggest that Bcl‐2 may represent a biologically relevant target for the development of novel combinatorial therapies for NPC. © 2006 Wiley‐Liss, Inc.

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Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: Association with p53 expression

Cited by 59 publications

References 23 publications

Comparative analysis of the expression of the epstein‐barr virus (EBV) anti‐apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV‐related lymphoid diseases

Comparative analysis of the expression of the epstein‐barr virus (EBV) anti‐apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV‐related lymphoid diseases

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

Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice

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Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: Association with p53 expression

Cited by 59 publications

References 23 publications

Comparative analysis of the expression of the epstein‐barr virus (EBV) anti‐apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV‐related lymphoid diseases

Comparative analysis of the expression of the epstein‐barr virus (EBV) anti‐apoptotic gene BHRF1 in nasopharyngeal carcinoma and EBV‐related lymphoid diseases

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

Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice

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Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice