Estrogen induces the expression of EBV lytic protein ZEBRA, a marker of poor prognosis in nasopharyngeal carcinoma

Hirotomo Dochi, Satoru Kondo, Takayuki Murata, Masaki Fukuyo, Asuka Nanbo, Kousho Wakae, Wen Ping Jiang, Toshihide Hamabe-Horiike, Mariko Tanaka, Takumi Nishiuchi, Harue Mizokami, Makiko Moriyama-Kita, Eiji Kobayashi, Nobuyuki Hirai, Takeshi Komori, Takayoshi Ueno, Yosuke Nakanishi, Miyako Hatano, Kazuhira Endo, Hisashi SugimotoNaohiro Wakisaka, Shin Hun Juang, Masamichi Muramatsu, Atsushi Kaneda, Tomokazu Yoshizaki

Research output: Contribution to journalArticlepeer-review

Abstract

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 α, and aromatase. The transcriptional level of ZEBRA is activated by estrogen in an estrogen receptor α-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.

Original languageEnglish
Pages (from-to)2862-2877
Number of pages16
JournalCancer science
Volume113
Issue number8
DOIs
Publication statusPublished - 08-2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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