MiR-1254 suppresses HO-1 expression through seed region-dependent silencing and non-seed interaction with TFAP2A transcript to attenuate NSCLC growth.
MiR-1254 suppresses HO-1 expression through seed region-dependent silencing and non-seed interaction with TFAP2A transcript to attenuate NSCLC growth.
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DOI：
10.1371/journal.pgen.1006896
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发表时间：
2017-07
期刊：
影响因子：
4.5
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Pu M;Li C;Qi X;Chen J;Wang Y;Gao L;Miao L;Ren J
MicroRNA（miRNAs）是一类小的非编码RNA，其指导转录后基因沉默（PTGS）并在包括癌症发展在内的广泛生物事件中起作用。大多数miRNA通过5'端附近的种子区与靶位点配对，导致mRNA切割和/或翻译抑制。在此，我们证明了miRNA通过种子区和非种子区诱导血红素加氧酶-1（HO-1）的双重调节，从而抑制NSCLC的肿瘤生长。我们鉴定了miR-1254作为抑制HO-1翻译的负调节因子，其通过其种子区直接靶向HO-1 3 'UTR，并通过非种子区依赖性抑制转录因子AP-2 α（TFAP 2A）（HO-1的转录激活因子）来抑制HO-1转录。MiR-1254通过抑制HO-1的表达诱导人非小细胞肺癌（NSCLC）细胞凋亡和细胞周期阻滞，从而抑制NSCLC细胞的生长。与体外研究一致，小鼠异种移植物研究证实miR-1254在体内抑制NSCLC肿瘤生长。此外，我们发现HO-1表达与miR-1254水平在人NSCLC肿瘤样品和细胞系中呈负相关。总之，这些发现将miR-1254对HO-1的双重抑制确定为miRNA的新功能机制，其导致致癌mRNA的更有效抑制，并导致肿瘤抑制作用。一般认为，miRNAs与靶mRNA的3`UTR结合，通过其种子序列介导转录后基因沉默（PTGS）。本文报道了一种新的miRNA双重调控机制。我们描述了miR-1254通过其种子序列直接靶向HO-1的3 'UTR而在转录后水平抑制HO-1，并且还通过其非种子序列抑制转录因子AP-2 α（TFAP 2A）而抑制HO-1转录。MiR-1254通过抑制HO-1的表达诱导人非小细胞肺癌（NSCLC）细胞凋亡和细胞周期阻滞，从而抑制NSCLC细胞的生长。此外，体内小鼠异种移植研究也支持miR-1254对NSCLC生长的抑制作用。这些发现证实了miR-1254对HO-1的双重调控是miRNA的一种新的功能机制，它可以更有效地抑制致癌mRNA，从而抑制NSCLC的生长，从而大大推进了我们对miRNA介导的基因调控的理解。
MicroRNAs (miRNAs) are a class of small non-coding RNAs, which direct post-transcriptional gene silencing (PTGS) and function in a vast range of biological events including cancer development. Most miRNAs pair to the target sites through seed region near the 5’ end, leading to mRNA cleavage and/or translation repression. Here, we demonstrated a miRNA-induced dual regulation of heme oxygenase-1 (HO-1) via seed region and non-seed region, consequently inhibited tumor growth of NSCLC. We identified miR-1254 as a negative regulator inhibiting HO-1 translation by directly targeting HO-1 3’UTR via its seed region, and suppressing HO-1 transcription via non-seed region-dependent inhibition of transcriptional factor AP-2 alpha (TFAP2A), a transcriptional activator of HO-1. MiR-1254 induced cell apoptosis and cell cycle arrest in human non-small cell lung carcinoma (NSCLC) cells by inhibiting the expression of HO-1, consequently suppressed NSCLC cell growth. Consistently with the in vitro studies, mouse xenograft studies validated that miR-1254 suppressed NSCLC tumor growth in vivo. Moreover, we found that HO-1 expression was inversely correlated with miR-1254 level in human NSCLC tumor samples and cell lines. Overall, these findings identify the dual inhibition of HO-1 by miR-1254 as a novel functional mechanism of miRNA, which results in a more effective inhibition of oncogenic mRNA, and leads to a tumor suppressive effect. It is generally accepted that miRNAs bind to 3`UTR of target mRNAs and direct post-transcriptional gene silencing (PTGS) via its seed sequence. Here we report a new dual regulatory mechanism of miRNA. We described that miR-1254 repressed HO-1 at post-transcriptional level by directly targeting HO-1 3’UTR via its seed sequence and also inhibited HO-1 transcription by suppressing the transcriptional factor AP-2 alpha (TFAP2A) via its non-seed sequence. MiR-1254 induced cell apoptosis and cell cycle arrest in human non-small cell lung carcinoma (NSCLC) cells by inhibiting the expression of HO-1, consequently suppressed NSCLC cell growth. Moreover, in vivo mouse xenograft studies also supported the inhibitory effect of miR-1254 on NSCLC growth. These findings identify the dual regulation of miR-1254 on HO-1 as a novel functional mechanism of miRNA, which results in a more effective inhibition on the oncogenic mRNA, and leads to a suppressive effect on NSCLC growth, thus significantly advance our understanding of miRNA-directed gene regulation.
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影响因子：
2.9
作者：
Deininger, MH;Meyermann, R;Schluesener, HJ
通讯作者：
Schluesener, HJ
DOI：
10.1073/pnas.0808830105
发表时间：
2008-10-21
影响因子：
11.1
作者：
Kim, Daniel H.;Saetrom, Pal;Rossi, John J.
通讯作者：
Rossi, John J.
影响因子：
11.5
作者：
Berberat, PO;Dambrauskas, Z;Friess, H
通讯作者：
Friess, H
DOI：
10.1165/rcmb.2006-0340tr
发表时间：
2007-02-01
影响因子：
6.4
作者：
Alam, Jawed;Cook, Julia L.
通讯作者：
Cook, Julia L.
影响因子：
3.7
作者：
Adilakshmi T;Sudol I;Tapinos N
通讯作者：
Tapinos N