Department of General Surgery, The First People Hospital of Zhangjiagang City, Soochow University, Suzhou, China.
Center of Translational Medicine, The First People Hospital of Zhangjiagang City, Soochow University, Suzhou, China.
Cancer Lett. 2019 Feb 28;443:13-24. doi: 10.1016/j.canlet.2018.11.028. Epub 2018 Nov 29.
Advanced stage nasopharyngeal carcinoma (NPC) has a poor prognosis. Triptonide ("TN") is a small molecule monomer extract from the ancient Chinese herb Tripterygium wilfordii Hook. We show that TN, at nanomolar concentrations, potently inhibited survival and proliferation of multiple established and primary human NPC cells. TN induced NPC cell cycle arrest and apoptosis activation. NPC cell migration and invasion were also inhibited by TN. Importantly, TN was non-cytotoxic to nasopharyngeal epithelial cells. TN treatment in NPC cells disrupted LncRNA THOR ("Lnc-THOR")-IGF2BP1 association, causing depletion of Lnc-THOR and downregulation of IGF2BP1 mRNA targets (Myc, IGF2 and Gli1). Lnc-THOR or IGF2BP1 knockout by CRISPR/Cas9 gene-editing methods mimicked and abolished TN's actions in NPC cells. Conversely, ectopic Lnc-THOR overexpression inhibited TN-induced cytotoxicity in NPC cells. Significantly, Lnc-THOR, IGF2BP1 and its mRNA targets are elevated in human NPC tissues and cells, but almost undetectable in nasopharyngeal epithelial tissues and cells. In vivo, intraperitoneal TN administration significantly inhibited subcutaneous NPC xenograft growth in mice. Similarly, Lnc-THOR-knockout HONE-1 xenografts grew significantly slower than control tumors. Thus, TN inhibits human NPC cell growth in vitro and in vivo via disrupting Lnc-THOR-IGF2BP1 signaling.
晚期鼻咽癌（NPC）预后不良。雷公藤内酯醇（“TN”）是从中国古代草药雷公藤中提取的一种小分子单体。我们表明，TN 在纳摩尔浓度下，能强烈抑制多种已建立和原发性人 NPC 细胞的存活和增殖。TN 诱导 NPC 细胞周期停滞和凋亡激活。TN 还抑制 NPC 细胞迁移和侵袭。重要的是，TN 对鼻咽上皮细胞无细胞毒性。TN 处理 NPC 细胞会破坏 LncRNA THOR（“Lnc-THOR”）-IGF2BP1 复合物，导致 Lnc-THOR 耗竭和 IGF2BP1 mRNA 靶标（Myc、IGF2 和 Gli1）下调。通过 CRISPR/Cas9 基因编辑方法敲除 Lnc-THOR 或 IGF2BP1 可模拟并消除 TN 在 NPC 细胞中的作用。相反，外源性 Lnc-THOR 过表达抑制了 TN 诱导的 NPC 细胞毒性。重要的是，Lnc-THOR、IGF2BP1 及其 mRNA 靶标在人 NPC 组织和细胞中升高，但在鼻咽上皮组织和细胞中几乎检测不到。在体内，腹腔内 TN 给药显著抑制了小鼠皮下 NPC 异种移植的生长。同样，Lnc-THOR 敲除的 HONE-1 异种移植的生长速度明显慢于对照肿瘤。因此，TN 通过破坏 Lnc-THOR-IGF2BP1 信号通路抑制人 NPC 细胞在体外和体内的生长。
