A novel 3′-tRNAGIu-derived fragment acts as a tumor suppressor in breast cancer by targeting nucleolin
A novel 3′-tRNAGIu-derived fragment acts as a tumor suppressor in breast cancer by targeting nucleolin
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DOI：
10.1096/fj.201900382rr
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发表时间：
2019-12-01
期刊：
影响因子：
4.8
通讯作者：
Amici, Augusto
中科院分区：
文献类型：
--
作者：
Falconi, Maurizio;Giangrossi, Mara;Amici, Augusto
tRNA衍生片段（tRFs）是一类新的非编码小RNA。据报道，tRF在癌症中被解除调节，但其生物学功能仍有待充分了解。我们已经确定了一个新的tRF（命名为tRF 3E），来自成熟的tRNA（G1 u），这是专门表达在健康的乳腺，但不是在乳腺癌（BC）。一致地，在具有表皮生长因子受体2（HER 2）阳性BC的患者的血液中tRF 3E水平显著降低，反映肿瘤状态（对照>早期癌症>转移性癌症）。在Delta 16 HER 2转基因小鼠中重现了tRF 3E下调，代表了BC临床前模型。用于寻找能够选择性结合tRF 3E的蛋白质的下拉测定已经表明，该tRF与核仁素（NCL）特异性相互作用，核仁素是在BC中过表达的RNA结合蛋白，并且能够抑制p53 mRNA的翻译。通过计算机模拟预测和EMSA分析，NCL-tRF 3E复合物的结合特性与tRF 3E对p53 mRNA的竞争性置换一致，导致p53表达增加，从而调节癌细胞生长。在这里，我们提供的证据表明，tRF 3E发挥了重要作用的发病机制，通过NCL介导的机制显示肿瘤抑制功能的BC。
tRNA-derived fragments (tRFs) have been defined as a novel class of small noncoding RNAs. tRFs have been reported to be deregulated in cancer, but their biologic function remains to be fully understood. We have identified a new tRF (named tRF3E), derived from mature tRNA(G1u), that is specifically expressed in healthy mammary glands but not in breast cancer (BC). Consistently, tRF3E levels significantly decrease in the blood of patients with epidermal growth factor receptor 2 (HER2)-positive BC reflecting tumor status (control > early cancer > metastatic cancer). tRF3E down-regulation was recapitulated in Delta 16HER2 transgenic mice, representing a BC preclinical model. Pulldown assays, used to search for proteins capable to selectively bind tRF3E, have shown that this tRF specifically interacts with nucleolin (NCL), an RNA-binding protein overexpressed in BC and able to repress the translation of p53 mRNA. The binding properties of NCL-tRF3E complex, predicted in silico and analyzed by EMSA assays, are congruent with a competitive displacement of p53 mRNA by tRF3E, leading to an increased p53 expression and consequently to a modulation of cancer cell growth. Here, we provide evidence that tRF3E plays an important role in the pathogenesis of BC displaying tumor-suppressor functions through a NCL-mediated mechanism.