Estrogen induces the expression of EBV lytic protein ZEBRA, a marker of poor prognosis in nasopharyngeal carcinoma. Issue 8 (27th June 2022)

• Record Type: Journal Article
• Authors: Dochi, Hirotomo; Kondo, Satoru; Murata, Takayuki; Fukuyo, Masaki; Nanbo, Asuka; Wakae, Kousho; Jiang, Wen‐Ping; Hamabe‐Horiike, Toshihide; Tanaka, Mariko; Nishiuchi, Takumi; Mizokami, Harue; Moriyama‐Kita, Makiko; Kobayashi, Eiji; Hirai, Nobuyuki; Komori, Takeshi; Ueno, Takayoshi; Nakanishi, Yosuke; Hatano, Miyako; Endo, Kazuhira; Sugimoto, Hisashi; Wakisaka, Naohiro; Juang, Shin‐Hun; Muramatsu, Masamichi; Kaneda, Atsushi; Yoshizaki, Tomokazu
• Is Part Of: Cancer science. Volume 113:Issue 8(2022)
• Page Start: 2862
• Page End: 2877
• Publication Date: 2022-06-27
• Subjects: BZLF1 -- estrogen -- lytic infection -- nasopharyngeal carcinoma -- ZEBRA; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15440
• Languages: English
• ISSNs: 1347-9032

Abstract

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. Abstract : We have revealed that EBV lytic protein ZEBRA is significantly associated with poor prognosis of nasopharyngeal carcinoma. Moreover, our study suggests that locally expressed intratumoral estrogen induces EBV lytic protein ZEBRA expression from the gene expression level. We expect of the development of novel treatment modalities such as anti‐hormonal treatment.