Esophageal cancer (EC) is among the severest cancers causing most fatalities around the world with an increasing incidence. Oleuropein exhibits anti-tumor properties in several human cancers. We aimed to investigate the effect of oleuropein in human EC, and to reveal the molecular target involved in EC tumorigenesis. Cell proliferation, migration and invasion assays were performed to assess the effect of oleuropein on EC cells. A xenograft tumor mouse model was utilized to assess the in vivo effect of oleuropein. Hypoxia-inducible factor-1α (HIF1α) and B-cell translocation gene 3 (BTG3) expressions were examined in oleuropein-treated EC cells. The regulatory effect of HIF1α on BTG3 mRNA was evaluated by chromatin immunoprecipitation and luciferase reporter assays. Oleuropein inhibited the growth of EC cells and xenograft EC tumor, as well as inhibiting HIF1α and upregulating BTG3 expressions. BTG3 mRNA expression was under hypoxia inhibition through the HRE in its promoter region. BTG3 knockdown abolished the inhibitory effect of oleuropein on EC cells in vitro, as well as on EC xenograft tumor in vivo. Oleuropein inhibits EC tumorigenesis through hypoxic suppression of BTG3 mRNA, supporting the clinical application of oleuropein, and HIF1α and BTG3 mRNA as potential molecular targets in treatment against EC.

中文翻译：

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橄榄苦苷通过低氧抑制BTG3 mRNA抑制食道癌

食道癌（EC）是导致世界上大多数死亡的最严重的癌症之一，发病率也在不断上升。橄榄苦苷在几种人类癌症中表现出抗肿瘤特性。我们旨在调查橄榄苦苷在人类EC中的作用，并揭示参与EC肿瘤发生的分子靶标。进行细胞增殖，迁移和侵袭测定以评估橄榄苦苷对EC细胞的作用。使用异种移植肿瘤小鼠模型评估体内橄榄苦苷的作用。缺氧诱导因子-1α（HIF1α）和B细胞易位基因3（BTG3）表达在橄榄苦苷处理的EC细胞中进行了检查。通过染色质免疫沉淀和荧光素酶报告基因分析评估了HIF1α对BTG3 mRNA的调节作用。橄榄苦苷可抑制EC细胞和异种移植EC肿瘤的生长，并抑制HIF1α和上调BTG3的表达。通过其启动子区域中的HRE，BTG3 mRNA表达受到缺氧抑制。BTG3敲除取消了橄榄苦苷对体外EC细胞的抑制作用以及对体内EC异种移植瘤的抑制作用。。橄榄苦苷通过低氧抑制BTG3 mRNA抑制EC的肿瘤发生，支持橄榄苦苷的临床应用以及HIF1α和BTG3 mRNA作为治疗EC的潜在分子靶标。