缺氧介导的微小RNA生物合成下调促进肿瘤进展。
Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression.
作者信息
Rupaimoole Rajesha, Wu Sherry Y, Pradeep Sunila, Ivan Cristina, Pecot Chad V, Gharpure Kshipra M, Nagaraja Archana S, Armaiz-Pena Guillermo N, McGuire Michael, Zand Behrouz, Dalton Heather J, Filant Justyna, Miller Justin Bottsford, Lu Chunhua, Sadaoui Nouara C, Mangala Lingegowda S, Taylor Morgan, van den Beucken Twan, Koch Elizabeth, Rodriguez-Aguayo Cristian, Huang Li, Bar-Eli Menashe, Wouters Bradly G, Radovich Milan, Ivan Mircea, Calin George A, Zhang Wei, Lopez-Berestein Gabriel, Sood Anil K
机构信息
1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
出版信息
Nat Commun. 2014 Oct 29;5:5202. doi: 10.1038/ncomms6202.
Cancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumour progression. We show that hypoxia-mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumours. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumour regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumour microenvironment.
已有研究表明癌症相关的微小RNA（miRNA）生物合成失调，但其潜在机制仍不清楚。在此，我们报告了缺氧对癌细胞中Drosha和Dicer下调的一种先前未被认识的作用，这种作用导致miRNA生物合成失调并促进肿瘤进展。我们发现缺氧介导的Drosha下调依赖于ETS1/ELK1转录因子。此外，成熟miRNA芯片和深度测序研究揭示了缺氧条件下细胞中miRNA成熟的改变。在功能水平上，这种现象导致体外和体内癌症进展增加，来自患者样本的数据表明缺氧肿瘤中miRNA生物合成下调。在体内通过靶向ETS1/ELK1的小干扰RNA（siRNA）挽救Drosha可导致肿瘤显著消退。这些发现为深入理解肿瘤微环境中整体miRNA下调的机制提供了新的线索。
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