Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells
Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells
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DOI：
10.1016/j.ydbio.2007.08.007
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发表时间：
2007-10-15
影响因子：
2.7
通讯作者：
Hogan, Brigid L. M.
中科院分区：
文献类型：
--
作者：
Lu, Yun;Thomson, J. Michael;Hogan, Brigid L. M.
miR-17-92基因座编码一簇7个microRNA，转录为单个初级转录物。它可以加速c-Myc诱导的B细胞淋巴瘤的发展，并在许多肿瘤中高度表达，包括肺肿瘤。然而，miR-17-92在发育中的作用尚未得到充分研究。从肺发育过程中microRNA的分析来看，miR-17-92簇的表达在早期阶段很高，但随着发育的进行而下降。我们使用小鼠表面活性蛋白C（Sftpc）启动子在胚胎肺上皮中过表达该簇。转基因肺具有非常异常的致死表型。它们含有大量增殖的上皮细胞，这些细胞保留高水平的Sox 9，这是远端祖细胞的标志物。近端上皮细胞的分化也受到抑制。此外，在死亡的转基因幼崽的肺中观察到神经内分泌细胞簇的数量显著增加。我们确定了一个肿瘤抑制因子，Rb家族的Rbl 2，作为miR-17- 5 p的新靶点。总之，这些研究表明，mir-17-92通常促进肺上皮祖细胞的高增殖和未分化表型。(C)2007年爱思唯尔公司All rights reserved.
The miR-17-92 locus encodes a cluster of 7 microRNAs transcribed as a single primary transcript. It can accelerate c-Myc induced B cell lymphoma development and is highly expressed in many tumors, including lung tumors. However, the role of miR-17-92 in development has not been well studied. From analysis of microRNAs during lung development, expression of the miR-17-92 cluster is high at early stages, but declines as development proceeds. We used the mouse surfactant protein C (Sftpc) promoter to over-express the cluster in embryonic lung epithelium. Transgenic lungs have a very abnormal lethal phenotype. They contain numerous proliferative epithelial cells that retain high levels of Sox9, a marker of distal progenitors. The differentiation of proximal epithelial cells was also inhibited. Furthermore, a significant increase in the number of neuroendocrine cell clusters was observed in the lungs of dead transgenic pups. We identify a tumor suppressor, Rbl2 which belongs to the Rb family, as a new target for miR-17-5p. Together, these studies suggest that mir-17-92 normally promotes the high proliferation and undifferentiated phenotype of lung epithelial progenitor cells. (C) 2007 Elsevier Inc. All rights reserved.