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首页> 外文期刊>PLoS Genetics >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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MiR-1254 suppresses HO-1 expression through seed region-dependent silencing and non-seed interaction with TFAP2A transcript to attenuate NSCLC growth

机译：MiR-1254通过依赖种子区域的沉默以及与TFAP2A转录本的非种子相互作用来减弱NSCLC的生长来抑制HO-1表达

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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.
机译：微小RNA（miRNA）是一类小的非编码RNA，可指导转录后基因沉默（PTGS），并在包括癌症发生在内的各种生物学事件中发挥作用。大多数miRNA通过5'端附近的种子区与靶位点配对，从而导致mRNA裂解和/或翻译抑制。在这里，我们证明了miRNA通过种子区和非种子区对血红素加氧酶-1（HO-1）的双重调节，从而抑制了NSCLC的肿瘤生长。我们将miR-1254确定为通过直接通过其种子区靶向HO-1 3'UTR并通过非种子区依赖性转录因子AP-2α抑制来抑制HO-1转录的负调控因子，从而抑制HO-1翻译。 TFAP2A），HO-1的转录激活因子。 MiR-1254通过抑制HO-1的表达诱导人非小细胞肺癌（NSCLC）细胞的细胞凋亡和细胞周期停滞，因此抑制了NSCLC细胞的生长。与体外研究一致，小鼠异种移植研究证实了miR-1254在体内抑制了NSCLC肿瘤的生长。此外，我们发现HO-1表达与人类NSCLC肿瘤样品和细胞系中的miR-1254水平呈负相关。总体而言，这些发现确定了miR-1254对HO-1的双重抑制是miRNA的新功能机制，从而导致对致癌mRNA的更有效抑制，并导致了肿瘤抑制作用。

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