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

原神经性碱性螺旋环状螺旋蛋白Achaete-Scute Homologue 1(ASH1)以谱系特异性的方式在一个非常有限的谱带中表达，包括正常肺神经内分泌细胞和具有神经内分泌功能的肺癌细胞。我们以前的结果表明，ASH1可能在具有神经内分泌特征的肺癌的生长和生存中发挥关键作用。在本研究中，我们首次报道ASH1通过激活神经内分泌分化标记物和抑制可能的肿瘤抑制因子而发挥双重转录因子的功能。该蛋白通过ASH1介导的脱乙酰化和组蛋白H3赖氨酸27(H3K27me3)在Dkk1和E-钙粘素启动子区域的三甲基化抑制Wnt/β-连环蛋白信号负调控因子Dkk1和Dkk3、E-钙粘素和整合素β1的失活。我们的结果为更好地理解ash1在…过程中的分子和细胞生物学作用提供了重要线索。更多具有神经内分泌特征的肺癌的致癌作用值得进一步研究，以揭示这种具有双重功能的转录因子的谱系特异性依赖性。我们先前报道了miR-17-92microRNAs(MiRNA)簇在肺癌中的扩增和过表达。在本研究中，我们发现，用反义寡核苷酸抑制miR-17-5p和miR-20a可以选择性地诱导过表达miR-17-92的肺癌细胞凋亡，这表明在一组肺癌中可能对这些miRNAs的表达上瘾。在本研究过程中，我们还发现，在C13orf25的内含子3中，位于3‘到miR-17-92的基因组区域C2的强制表达导致显著的生长抑制，并与双链RNA依赖的蛋白激酶激活有关。综上所述，本研究结果有助于更好地理解miR-17-92的致癌作用，最终可能导致未来将其转化为临床应用。较少

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