Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China.
Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China.
Toxicology. 2019 Jun 1;421:1-8. doi: 10.1016/j.tox.2019.03.017. Epub 2019 Apr 3.
Identification of new molecular targets for the treatment of endometrial cancer (EC) is an important clinical goal, especially for the patients which were resistant to conventional therapies. The aryl hydrocarbon receptor (AhR) is a ligand- activated transcription factor known primarily as the mediator of dioxin toxicity. However, the AhR can also inhibit cellular proliferation in a ligand-dependent manner and act as a tumor suppressor in mice, thus may be a potential anticancer target. In this study, we investigated if the endogenous AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) regulated proliferation and migration of EC cells via AhR.
We used quantitative real-time PCR and western blot to assess the expression of AhR in EC tissues and paired adjacent normal tissues. In addition, we conducted transwell assay to test whether the treatment of ITE altered the locomotive potential and proliferation of EC cells. Next, we conducted mouse xenograft models to further explore the in vivo effect of ITE.
We found that the AhR protein and RNA levels were increased mildly in EC tissues relative to the para-tumor normal endometrial tissues. Besides, ITE suppressed EC cells proliferation and migration in vitro, and also suppressed EC cells xenograft growth in mice.
Our results strongly supported the possibility of using the ITE as a small molecular compound for the treatment of EC.
鉴定子宫内膜癌（EC）治疗的新分子靶点是一个重要的临床目标，特别是对于那些对传统疗法有抗药性的患者。芳香烃受体（AhR）是一种配体激活的转录因子，主要作为二恶英毒性的介质。然而，AhR 也可以以配体依赖的方式抑制细胞增殖，并在小鼠中充当肿瘤抑制因子，因此可能是一种潜在的抗癌靶点。在这项研究中，我们研究了内源性 AhR 配体 2-(1'H-吲哚-3'-羰基)-噻唑-4-羧酸甲酯（ITE）是否通过 AhR 调节 EC 细胞的增殖和迁移。
我们使用定量实时 PCR 和 Western blot 来评估 AhR 在 EC 组织和配对的相邻正常组织中的表达。此外，我们进行了 Transwell 测定，以测试 ITE 是否改变了 EC 细胞的游动潜能和增殖。接下来，我们进行了小鼠异种移植模型，以进一步探索 ITE 的体内作用。
我们发现，相对于肿瘤旁正常子宫内膜组织，AhR 蛋白和 RNA 水平在 EC 组织中略有增加。此外，ITE 抑制了 EC 细胞在体外的增殖和迁移，也抑制了 EC 细胞异种移植在小鼠中的生长。
我们的结果强烈支持使用 ITE 作为治疗 EC 的小分子化合物的可能性。
