Journal
CANCER SCIENCE
Volume 113, Issue 8, Pages 2862-2877Publisher
WILEY
DOI: 10.1111/cas.15440
Keywords
BZLF1; estrogen; lytic infection; nasopharyngeal carcinoma; ZEBRA
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology [16H05480, 17H01590]
- Grants-in-Aid for Scientific Research [16H05480, 17H01590] Funding Source: KAKEN
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This study suggests that the expression of ZEBRA protein is associated with a worse prognosis in patients with nasopharyngeal carcinoma (NPC). The expression of ZEBRA is regulated by estrogen receptor alpha, and estrogen promotes ZEBRA transcription and reactivation of Epstein-Barr virus (EBV), contributing to the progression of NPC.
Several epidemiological studies have suggested that Epstein-Barr virus (EBV) lytic infection is essential for the development of nasopharyngeal carcinoma (NPC), as the elevation of antibody titers against EBV lytic proteins is a common feature of NPC. Although ZEBRA protein is a key trigger for the initiation of lytic infection, whether its expression affects the prognosis and pathogenesis of NPC remains unclear. In this study, 64 NPC biopsy specimens were analyzed using immunohistochemistry. We found that ZEBRA was significantly associated with a worsening of progression-free survival in NPC (adjusted hazard ratio, 3.58; 95% confidence interval, 1.08-11.87; p = 0.037). Moreover, ZEBRA expression positively correlated with key endocrinological proteins, estrogen receptor alpha, and aromatase. The transcriptional level of ZEBRA is activated by estrogen in an estrogen receptor alpha-dependent manner, resulting in an increase in structural gene expression levels and extracellular virus DNA copy number in NPC cell lines, reminiscent of lytic infection. Interestingly, it did not suppress cellular proliferation or increase apoptosis, in contrast with cells treated with 12-O-tetradecanoylphorbol-13-acetate and sodium butyrate, indicating that viral production induced by estrogen is not a cell lytic phenomenon. Our results suggest that intratumoral estrogen overproduced by aromatase could induce ZEBRA expression and EBV reactivation, contributing to the progression of NPC.
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