Luteolin suppresses gastric cancer progression by reversing epithelial-mesenchymal transition via suppression of the Notch signaling pathway.
Luteolin suppresses gastric cancer progression by reversing epithelial-mesenchymal transition via suppression of the Notch signaling pathway.
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DOI：
10.1186/s12967-017-1151-6
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发表时间：
2017-02-27
影响因子：
7.4
通讯作者：
Liu BY
中科院分区：
文献类型：
--
作者：
Zang MD;Hu L;Fan ZY;Wang HX;Zhu ZL;Cao S;Wu XY;Li JF;Su LP;Li C;Zhu ZG;Yan M;Liu BY
胃癌（Gastric cancer，GC）是世界上最严重的恶性肿瘤之一，也是世界上第二大恶性肿瘤死亡原因。木犀草素，一种存在于许多水果和绿色植物中的类黄酮，抑制癌症进展。毛地黄黄酮对胃癌细胞的作用及其机制尚不清楚。分别采用CCK-8、transwell法和流式细胞仪检测毛地黄黄酮对体外和体内细胞增殖、迁移、侵袭和凋亡的影响。实时逆转录聚合酶链反应（RT-PCR）和蛋白质印迹进行评估Notch 1信号和激活的上皮间质转化（EMT）在GC细胞处理或没有毛地黄黄酮。进行免疫组织化学以检查异种移植肿瘤中的增殖和Notch 1表达。木犀草素以剂量依赖和时间依赖的方式显著抑制细胞增殖、侵袭和迁移，并促进细胞凋亡。木犀草素通过收缩细胞骨架和诱导上皮生物标志物E-钙粘蛋白的表达以及下调间充质生物标志物N-钙粘蛋白、波形蛋白和Snail来逆转EMT。此外，Notch 1信号被木樨草素抑制，并且Notch 1的下调对细胞增殖、迁移和凋亡具有与木樨草素处理相似的作用。此外，毛地黄黄酮抑制体内肿瘤生长。Notch 1的高表达与较差的总生存期和较差的首次进展时间相关。此外，免疫共沉淀分析显示，活化的Notch 1和β-catenin形成复合物，并调节细胞增殖、迁移和侵袭。本研究发现，毛地黄黄酮通过抑制Notch 1信号通路和逆转EMT抑制胃癌的进展，提示毛地黄黄酮可能是一种有效的抗肿瘤药物。
Gastric cancer (GC) is one of the most malignant tumors and the second leading cause of cancer-related deaths in the world. Luteolin, a flavonoid present in many fruits and green plants, suppresses cancer progression. The effects of luteolin on GC cells and their underlying mechanisms remain unclear. Effects of luteolin on cell proliferation, migration, invasion, and apoptosis were examined in vitro and in vivo by cell counting kit-8 (CCK-8), transwell assays, and flow cytometry, respectively. Real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blots were performed to evaluate Notch1 signaling and activation of epithelial-mesenchymal transition (EMT) in GC cells treated with or without luteolin. Immunohistochemistry was performed to examine proliferation and Notch1 expression in xenograft tumors. Luteolin significantly inhibited cell proliferation, invasion, and migration in a dose-dependent and time-dependent manner and promoted cell apoptosis. Luteolin reversed EMT by shrinking the cytoskeleton and by inducing the expression of epithelial biomarker E-cadherin and downregulating the mesenchymal biomarkers N-cadherin, vimentin and Snail. Furthermore, Notch1 signaling was inhibited by luteolin, and downregulation of Notch1 had similar effects as luteolin treatment on cell proliferation, migration, and apoptosis. In addition, luteolin suppressed tumor growth in vivo. A higher expression of Notch1 correlated with a poor overall survival and a poor time to first progression. Furthermore, co-immunoprecipitation analysis revealed that activated Notch1 and β-catenin formed a complex and regulated cell proliferation, migration, and invasion. In this study, GC progression was inhibited by luteolin through suppressing Notch1 signaling and reversing EMT, suggesting that luteolin may serve as an effective anti-tumor drug in GC treatment.