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Molecular mechanisms of associations between abnormal differentiation and altered regulations of gene expressions.

异常分化与基因表达调节改变之间关联的分子机制。

基本信息

批准号：
18590308
负责人：
OSADA Hirotaka
金额：
$ 2.44万
依托单位：
Aichi Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590308/
关键词：
lung cancer neuroendocrine epigenetic miRNA histone modification chromatin 肺癌 microRNA

项目摘要

The proneural basic-helix-loop-helix protein achaete-scute homologue 1(ASH1) is expressed in a very limited spectrum in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features. In the present study, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/β-catenin signaling, E-cadherin, and integrinβ1 through ASH 1-mediated deacetylation and repressive trimethylation of lysine 27(H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process … More of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions.We previously reported the amplification and overexpression of the miR-17-92 microRNAs(miRNA) cluster at 13q31.3 in lung cancers. In the present study, we show that inhibition of miR-17-5p and miR-20a with antisense oligonucleotides can induce apoptosis selectively in lung cancer cells overexpressing miR-17-92, suggesting the possibility of 'OncomiR addiction' to expression of these miRNAs in a subset of lung cancers. During the course of this study, we also found that enforced expression of a genomic region, termed C2, residing 3' to miR-17-92 in the intron 3 of C13orf25 led to marked growth inhibition in association with double stranded RNA-dependent protein kinase activation. Taken together, the present findings contribute towards better understanding of the oncogenic roles of miR-17-92, which might ultimately lead to the future translation into clinical applications. Less

前神经碱性螺旋环螺旋蛋白无毛鳞片同源物1（ASH 1）以谱系特异性方式在非常有限的谱中表达，包括正常肺神经内分泌细胞和具有神经内分泌特征的肺癌细胞。我们以前的研究结果表明，ASH 1可能在具有神经内分泌特征的肺癌的生长和生存中起着至关重要的作用。在本研究中，我们首次报道了ASH 1作为一种双重转录因子，通过激活神经内分泌分化标志物和抑制假定的肿瘤抑制因子发挥作用。发现该蛋白通过ASH 1介导的DKK 1和E-cadherin启动子区域中组蛋白H3的赖氨酸27（H3 K27 me 3）的脱乙酰化和抑制性三甲基化来抑制Wnt/β-catenin信号传导、E-cadherin和整合素β1的负调节因子DKK 1和DKK 3。我们的研究结果为更好地理解ASH 1在此过程中的分子和细胞生物学作用提供了重要线索 ...更多信息我们先前报道了在肺癌中13q31.3的miR-17-92 microRNA（miRNA）簇的扩增和过表达。在本研究中，我们发现，用反义寡核苷酸抑制miR-17- 5 p和miR-20 a可以选择性地诱导过表达miR-17-92的肺癌细胞凋亡，这表明在肺癌的一个子集中，这些miRNA的表达可能存在“OncomiR成瘾”。在本研究过程中，我们还发现，位于C13 orf 25内含子3中miR-17-92 3'端的基因组区域（称为C2）的强制表达导致与双链RNA依赖性蛋白激酶激活相关的显著生长抑制。总之，目前的研究结果有助于更好地理解miR-17-92的致癌作用，这可能最终导致未来转化为临床应用。少