Hypoxia represses microRNA biogenesis proteins in breast cancer cells.
Hypoxia represses microRNA biogenesis proteins in breast cancer cells.
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DOI：
10.1186/1471-2407-14-533
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发表时间：
2014-07-22
期刊：
影响因子：
3.8
通讯作者：
Gleadle JM
中科院分区：
文献类型：
--
作者：
Bandara V;Michael MZ;Gleadle JM
癌症通常以缺氧为特征，也以成熟microRNAs水平的全球性降低为特征。我们检验了这样的假设，即低氧可能通过抑制microRNA生物发生蛋白的作用来介导这种减少。将乳腺癌细胞系暴露于低氧和低氧诱导因子(HIF)及HIF羟基酶活性的调控下。用RT-PCR和免疫印迹法检测低氧对microRNA生物合成相关酶(DICER、DROSHA、TARPB2、DCGR8、XPO5)的mRNA和蛋白水平的影响。采用基因芯片研究、RT-PCR和报告分析等方法检测缺氧对microRNAs的影响。在乳腺癌细胞系中，暴露在低氧环境中的细胞中DICER的mRNA和蛋白水平显着降低。这种作用不依赖于HIF，但依赖于HIF羟基酶PHD2，并且部分由microRNAs的反馈效应所介导。此外，在microRNA生物发生中起关键作用的其他几种蛋白质(DROSHA、TARBP2和DCGR8)在低氧条件下也显示出显著的协同抑制作用。尽管有这些实质性的变化，但在成熟的microRNA生产中没有观察到或轻微的变化。这些观察结果进一步提供了氧气可获得性和基因表达之间的重要接口，并为在某些癌症中观察到的microRNAs水平降低提供了潜在的机制解释。它们进一步支持了microRNA生物发生途径调控中反馈机制的存在和microRNAs的相对稳定性。
Cancers are commonly characterised by hypoxia and also by global reductions in the levels of mature microRNAs. We have examined the hypothesis that hypoxia might mediate this reduction through repressive effects on microRNA biogenesis proteins. Breast cancer cell lines were exposed to hypoxia and manipulations of hypoxia inducible factor (HIF) and HIF hydroxylase activity. The effects of hypoxia on the mRNA and protein levels of enzymes involved in microRNA biogenesis (Dicer, Drosha, TARPB2, DCGR8, XPO5) was determined by RT PCR and immunoblotting. The effect of hypoxia on microRNAs was determined with microarray studies, RT PCR and reporter assays. In breast cancer lines there was significant reduction of Dicer mRNA and protein levels in cells exposed to hypoxia. This effect was independent of HIF but dependent on the HIF hydroxylase PHD2 and was partly mediated by feedback effects via microRNAs. Furthermore, several other proteins with critical roles in microRNA biogenesis (Drosha, TARBP2 and DCGR8) also showed significant and co-ordinated repression under hypoxic conditions. Despite these substantial alterations no, or modest, changes were observed in mature microRNA production. These observations provide further and important interfaces between oxygen availability and gene expression and a potential mechanistic explanation for the reduced levels of microRNAs observed in some cancers. They provide further support for the existence of feedback mechanisms in the regulation of the microRNA biogenesis pathway and the relative stability of microRNAs.
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影响因子：
64.8
作者：
Chendrimada, TP;Gregory, RI;Shiekhattar, R
通讯作者：
Shiekhattar, R
影响因子：
4.8
作者：
Ho, J. J. David;Metcalf, Julie L.;Marsden, Philip A.
通讯作者：
Marsden, Philip A.
DOI：
10.1126/science.1190809
发表时间：
2010-06-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cifuentes D;Xue H;Taylor DW;Patnode H;Mishima Y;Cheloufi S;Ma E;Mane S;Hannon GJ;Lawson ND;Wolfe SA;Giraldez AJ
通讯作者：
Giraldez AJ
影响因子：
11.2
作者：
Iorio, MV;Ferracin, M;Croce, CM
通讯作者：
Croce, CM
影响因子：
10.5
作者：
Han, JJ;Lee, Y;Kim, VN
通讯作者：
Kim, VN