Open AccessEstrogen induces the expression of EBV lytic protein ZEBRA , a marker of poor prognosis in nasopharyngeal carcinoma
Author(s) -
Dochi Hirotomo,
Kondo Satoru,
Murata Takayuki,
Fukuyo Masaki,
Nanbo Asuka,
Wakae Kousho,
Jiang WenPing,
HamabeHoriike Toshihide,
Tanaka Mariko,
Nishiuchi Takumi,
Mizokami Harue,
MoriyamaKita Makiko,
Kobayashi Eiji,
Hirai Nobuyuki,
Komori Takeshi,
Ueno Takayoshi,
Nakanishi Yosuke,
Hatano Miyako,
Endo Kazuhira,
Sugimoto Hisashi,
Wakisaka Naohiro,
Juang ShinHun,
Muramatsu Masamichi,
Kaneda Atsushi,
Yoshizaki Tomokazu
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15440
Subject(s) - lytic cycle , biology , nasopharyngeal carcinoma , cancer research , estrogen , estrogen receptor , epstein–barr virus , virus , immunology , medicine , cancer , endocrinology , breast cancer , genetics , radiation therapy
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.