DDX6 post-transcriptionally down-regulates miR-143/145 expression through host gene NCR143/145 in cancer cells
DDX6 post-transcriptionally down-regulates miR-143/145 expression through host gene NCR143/145 in cancer cells
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DOI：
10.1016/j.bbagrm.2013.07.010
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发表时间：
2013-10-01
影响因子：
4.7
通讯作者：
Akao, Yukihiro
中科院分区：
文献类型：
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作者：
Iio, Akio;Takagi, Takeshi;Akao, Yukihiro
据报道，在各种人类恶性肿瘤中，发生广泛的microRNA（miRNA）表达失调，并影响各种细胞生长程序。最近的研究表明，作为肿瘤抑制因子的miRNA的表达水平在癌症中经常降低，这是由于染色体缺失、表观遗传变化、异常转录和miRNA加工中的干扰。miR-143和-145是公认的miRNA，在几种组织中高度表达，但在大多数类型的癌症中下调。然而，这种下调的机制尚未被详细研究。在这里，我们发现，DEAD-box RNA解旋酶6，DDX 6（p54/RCK），转录后下调miR-143/145的表达，促进其宿主基因产物，NCR 143/145 RNA的降解在人胃癌细胞系MKN 45中，DDX 6蛋白大量表达和积累在加工体（P-体）。DDX 6优先增加非编码RNA NCR 143/145的不稳定性，其中包括miR-143/145簇，并下调成熟miR-143/145的表达。在人单核细胞系THP-1中，脂多糖处理促进P体的组装，并迅速下调NCR 143/145及其miR-143/145的表达。在这些细胞中，放线菌酮处理导致P体的损失和NCR 143/145 RNA稳定性的增加，从而导致miR-143/145表达的上调。这些数据表明，DDX 6有助于控制P体中的NCR 143/145 RNA稳定性和癌细胞中转录后调节的miR-143/145表达。(C)2013 Elsevier B. V.保留所有权利，
In various human malignancies, widespread dysregulation of microRNA (miRNA) expression is reported to occur and affects various cell growth programs. Recent studies suggest that the expression levels of miRNAs that act as tumor suppressors are frequently reduced in cancers because of chromosome deletions, epigenetical changes, aberrant transcription, and disturbances in miRNA processing. MiR-143 and -145 are well-recognized miRNAs that are highly expressed in several tissues, but down-regulated in most types of cancers. However, the mechanism of this down-regulation has not been investigated in detail. Here, we show that DEAD-box RNA helicase 6, DDX6 (p54/RCK), post-transcriptionally down-regulated miR-143/145 expression by prompting the degradation of its host gene product, NCR143/145 RNA In human gastric cancer cell line MKN45, DDX6 protein was abundantly expressed and accumulated in processing bodies (P-bodies). DDX6 preferentially increased the instability of non-coding RNA, NCR143/145, which encompasses the miR-143/145 cluster, and down-regulated the expression of mature miR-143/145. In human monocytic cell line THP-1, lipopolysaccharide treatment promoted the assembly of P-bodies and down-regulated the expression of NCR143/145 and its miR-143/145 rapidly. In these cells, cycloheximide treatment led to a loss of P-bodies and to an increase in NCR143/145 RNA stability, thus resulting in up-regulation of miR-143/145 expression. These data demonstrate that DDX6 contributed to the control of NCR143/145 RNA stability in P-bodies and post-transcriptionally regulated miR-143/145 expression in cancer cells. (C) 2013 Elsevier B.V. All rights reserved,