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Can Res文章:DNA超甲基化引起miR-886-3p低表达预示小细胞肺癌不良预后

日期:2019/02/17  来源:新葡萄京娱乐场官方网站

  

  很多miRNA在肿瘤转移机制中发挥重要作用,本项研究对来42名小细胞肺癌患者的福尔马林固定石蜡包埋组织样本(FFPE)中进行miRNA进行了表达谱分析,发现miR-886-3p表达下调与小细胞肺癌生存期降低密切相关。在另一组40个病例的独立样本集中验证了这一发现。在培养的小细胞肺癌细胞系和临床肿瘤样本中的检测确认, miR-886-3的低表达是由于该基因启动子区DNA高甲基化导致的。在进一步的研究表明miR-886-3p通过通过抑制靶基因PLK1和TGF-β1转录后环节,抑制NCI-H446细胞的增殖、迁移和侵袭。活体实验证实上调miR-886-3p可以抑制NCI-H446细胞生长,骨、肌肉侵袭以及肺转移能力。这项研究发现了一个新的miR-886-3p-PLK1 / TGF-β1信号关联机制调控了小细胞肺癌的进程,miR-886基因启动子区超甲基化造成表明miR-886-3p表达降低,这可以作为小细胞肺癌不良预后预测指标,并有潜力成为新型的治疗靶点。本研究由中国医学科学院詹启敏院士领导的研究团队完成,相关研究论文发表在4月的Cancer Research杂志上。本研究中miRNA芯片检测和miRNA定量PCR验证工作北京新葡萄京娱乐场官方网站生物技术有限企业完成


原文摘要:

      DNA Methylation-Mediated Repression of miR-886-3p Predicts Poor Outcome of Human Small Cell Lung Cancer

  Small cell lung cancer (SCLC) is one of the most aggressive types of cancer, yet the pathologic mechanisms underlying its devastating clinical outcome remain elusive. In this report, we surveyed 924 miRNA (miR) for their expressions in the formalin-fixed paraffin-embedded specimens from 42 patients with SCLC, and found that the downregulated miR-886-3p is closely correlated with the shorter survival of SCLC. This correlation was validated with another 40 cases. It was further discovered that loss of miR-886-3p expression was mediated by DNA hypermethylation of its promoter in both cultured SCLC cells and tumor samples. Moreover, miR-886-3p potently repressed cell proliferation, migration, and invasion of NCI-H446 cell in cell culture via suppression of the expression of its target genes: PLK1 and TGF-β1 at posttranscription levels. Forced upregulation of miR-886-3p greatly inhibited in vivo tumor growth, bone/muscle invasion, and lung metastasis of NCI-H446 cells. This newly identified miR-886-3p-PLK1/TGF-β1 nexus that modulates SCLC aggression suggests that both loss of miR-886-3p expression and hypermethylation of the miR-886 promoter are the promising indicators for poor outcome of as well as new therapeutic targets for SCLC.

原文出处http://cancerres.aacrjournals.org/content/73/11/3326.abstract

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