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The role of DOT1L in the proliferation and prognosis of gastric cancer.

DOT1L 在胃癌增殖和预后中的作用

  • 影响因子:2.87
  • DOI:10.1042/BSR20193515
  • 作者列表:"Song Z","Wei Z","Wang Q","Zhang X","Tao X","Wu N","Liu X","Qian J
  • 发表时间:2020-01-31
Abstract

BACKGROUND:Disruptor of telomeric silencing-1-like (DOT1L), a methyltransferase of H3K79, was observed to be amplified and overexpressed in certain malignancies. This work was aimed at investigating the differences in DOT1L expression and its regulatory mechanism in gastric cancer (GC) and healthy samples. METHODS:Immunohistochemistry was used to detect DOT1L levels in 101 cases of GC and marching adjacent normal tissues. DOT1L was inhibited by small interfering RNA (siRNA) and EPZ5676; a targeting drug. The ability of cells to proliferate were checked by cell counting kit-8 (CCK-8) and clone formation assays, with flow cytometry for observing the cell cycle. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot revealed the gene and protein profiles. Finally, the outcome of EPZ5676 administration was checked on a murine model. RESULTS:The expression of DOT1L is significantly increased in gastric malignant tumors that is related to the degree of differentiation, lymph node metastasis and TNM staging. DOT1L serves as an independent marker for the prognosis of overall survival (OS) with high levels implying worse prognosis. In addition, DOT1L regulates cyclin-dependent kinase (CDK) 4 (CDK4) and CDK6 through H3K79me2, which leads to a change in the cell cycle at G1, thereby affecting the proliferation of tumors in vitro and in vivo. CONCLUSIONS:This is a first clinical demonstration of the applicability of DOT1L overexpression in gastric tumors. The work is suggestive of altered proliferation of cells by DOT1L via regulating cyclins and H3K79 methylation. This indicates the role of DOT1L in the prognosis and possible medical intervention of GC.

摘要

背景: 端粒沉默-1 样 (DOT1L) 的干扰物,H3K79 的甲基转移酶,在某些恶性肿瘤中观察到扩增和过表达。这项工作旨在研究胃癌 (GC) 和健康样本中 DOT1L 表达的差异及其调控机制。 方法: 采用免疫组织化学方法检测 101 例胃癌及癌旁正常组织中 DOT1L 水平。DOT1L 被小干扰 RNA (siRNA) 和靶向药物 EPZ5676 抑制。通过细胞计数试剂盒-8 (CCK-8) 和克隆形成试验检测细胞增殖能力,用流式细胞术观察细胞周期。定量逆转录聚合酶链反应 (qRT-PCR) 和 Western blot 揭示了基因和蛋白谱。最后,在小鼠模型上检查 EPZ5676 给药的结果。 结果: DOT1L 在胃恶性肿瘤中表达明显增高,且与分化程度、淋巴结转移及 TNM 分期有关。DOT1L 作为总生存期 (OS) 预后的独立标志物,高水平提示预后更差。此外,DOT1L 通过 H3K79me2 调控细胞周期蛋白依赖性激酶 (CDK) 4 (CDK4) 和 CDK6,导致细胞周期在 G1, 从而影响肿瘤在体外和体内的增殖。 结论: 这是 DOT1L 过表达在胃肿瘤中适用性的首次临床证明。这项工作提示 DOT1L 通过调节细胞周期蛋白和 H3K79 甲基化改变细胞增殖。这表明 DOT1L 在 GC 的预后和可能的医疗干预中的作用。

关键词: DOT1L EPZ5676 胃癌 预后
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