Reduced DICER1 elicits an interferon response in endometrial cancer cells.
Reduced DICER1 elicits an interferon response in endometrial cancer cells.
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DOI：
10.1158/1541-7786.mcr-11-0520
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Goodfellow PJ
中科院分区：
文献类型：
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作者：
Chiappinelli KB;Haynes BC;Brent MR;Goodfellow PJ
DICER 1对于成熟microRNA（miRNAs）和其他短的非编码RNA的产生至关重要。一些研究表明DICER 1是一种肿瘤抑制因子。DICER 1水平降低和miRNA丰度变化与侵袭性肿瘤表型相关。减少DICER 1对肿瘤细胞中mRNA转录丰度的总体影响在很大程度上仍然未知。我们使用shRNA稳定敲低子宫内膜癌细胞系中的DICER 1，开始确定DICER 1活性降低如何促成肿瘤表型。DICER 1敲低不影响细胞增殖，但引起增强的细胞迁移和生长在软琼脂。KLE细胞中的miRNA和mRNA分析显示，miRNA水平总体下降，许多mRNA的相对丰度发生变化。mRNA水平最显著的变化之一是干扰素刺激基因（ISG）的上调，其中大多数缺乏已知的miRNA靶序列。在AN 3CA、石川和KLE子宫内膜癌细胞系和正常子宫内膜细胞系EM-E6/E7/TERT中，干扰素应答的关键上游调节因子IFNβ在DICER 1敲减中显著增加。从KLE和EM-E6/E7/TERT shDcr细胞的培养基中分泌的IFNβ足以激活HT 29细胞中的干扰素应答。DICER 1敲除中减少的miRNA加工与细胞质中前体miRNA的增加相关。我们的研究结果表明，前体miRNA水平的升高触发了干扰素对双链RNA的反应。因此，我们报告了癌细胞中DICER 1功能降低的新效应。
DICER1 is essential for the generation of mature microRNAs (miRNAs) and other short noncoding RNAs. Several lines of investigation implicate DICER1 as a tumor suppressor. Reduced DICER1 levels and changes in miRNA abundance have been associated with aggressive tumor phenotypes. The global effects of reduced DICER1 on mRNA transcript abundance in tumor cells remain largely unknown. We used shRNA to stably knock down DICER1 in endometrial cancer cell lines to begin to determine how reduced DICER1 activity contributes to tumor phenotypes. DICER1 knockdown did not affect cell proliferation but caused enhanced cell migration and growth in soft agar. miRNA and mRNA profiling in KLE cells revealed overall decreases in miRNA levels and changes in the relative abundance of many mRNAs. One of the most striking changes in mRNA levels was the upregulation of interferon stimulated genes (ISGs), the majority of which lack known miRNA target sequences. IFNβ, a key upstream regulator of the interferon response, was significantly increased in DICER1 knockdowns in the AN3CA, Ishikawa, and KLE endometrial cancer cell lines and in the normal endometrial cell line EM-E6/E7/TERT. IFNβ secreted in media from KLE and EM-E6/E7/TERT shDcr cells was sufficient to activate an interferon response in HT29 cells. The reduced miRNA processing in DICER1 knockdowns was associated with increases in pre-miRNAs in the cytoplasm. Our findings suggest elevated pre-miRNA levels trigger the interferon response to double-stranded RNA. We thus report a novel effect of reduced DICER1 function in cancer cells.