YBX1-interacting small RNAs and RUNX2 can be blocked in primary bone cancer using CADD522.
YBX1-interacting small RNAs and RUNX2 can be blocked in primary bone cancer using CADD522.
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使用 CADD522 可以在原发性骨癌中阻断 YBX1 相互作用的小 RNA 和 RUNX2。
DOI：
10.1016/j.jbo.2023.100474
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发表时间：
2023-04
影响因子：
3.4
通讯作者：
Fraser, William D.
中科院分区：
文献类型：
--
作者：
Green, Darrell;Singh, Archana;Tippett, Victoria L.;Tattersall, Luke;Shah, Karan M.;Siachisumo, Chileleko;Ward, Nicole J.;Thomas, Paul;Carter, Simon;Jeys, Lee;Sumathi, Vaiyapuri;McNamara, Iain;Elliott, David J.;Gartland, Alison;Dalmay, Tamas;Fraser, William D.
原发性骨癌（PBC）包括几种亚型，每种亚型都由独特的遗传驱动因素支持。这种驱动因素的多样性产生了新的形态学特征和临床行为，偶然使PBC成为一种极好的转移模型。在这里，我们报告说，一些转移RNA衍生的小RNA称为tRNA片段（tRFs）作为一个组成型肿瘤抑制机制，通过钝化一个潜在的促转移蛋白-RNA相互作用。当比较低级别、中等级别和高级别患者肿瘤时，这种机制在PBC进展中降低，tRNAGlyTCC裂解为5′端tRF-GlyTCC的逐渐丧失。我们检测到miR-140的反复激活导致高级别患者肿瘤中RUNX 2表达上调。tRF-GlyTCC和RUNX 2在其3′端共有一个序列基序，该基序与已知稳定促转移mRNA的YBX 1识别位点相匹配。研究这种相互作用网络的某些方面，分别使用小RNA模拟物和反义LNA的功能获得和丧失实验表明，异位tRF-GlyTCC降低了RUNX 2表达并分散了体外3D微团结构。iCLIP测序显示YBX 1与RUNX 2的3′ UTR物理结合。YBX 1，tRF-GlyTCC和RUNX 2之间的相互作用导致RUNX 2抑制剂CADD 522作为PBC治疗的开发。体外CADD 522评估显示对PBC细胞行为的显著影响。在异种移植小鼠模型中，CADD 522作为单一药物而不进行手术，可显著减少肿瘤体积，增加总体和无转移生存期，并减少癌症诱导的骨疾病。我们的研究结果提供了对PBC分子异常的深入了解，这些分子异常导致了新靶点和新治疗方法的鉴定。
Primary bone cancer (PBC) comprises several subtypes each underpinned by distinctive genetic drivers. This driver diversity produces novel morphological features and clinical behaviour that serendipitously makes PBC an excellent metastasis model. Here, we report that some transfer RNA-derived small RNAs termed tRNA fragments (tRFs) perform as a constitutive tumour suppressor mechanism by blunting a potential pro-metastatic protein-RNA interaction. This mechanism is reduced in PBC progression with a gradual loss of tRNAGlyTCC cleavage into 5′ end tRF-GlyTCC when comparing low-grade, intermediate-grade and high-grade patient tumours. We detected recurrent activation of miR-140 leading to upregulated RUNX2 expression in high-grade patient tumours. Both tRF-GlyTCC and RUNX2 share a sequence motif in their 3′ ends that matches the YBX1 recognition site known to stabilise pro-metastatic mRNAs. Investigating some aspects of this interaction network, gain- and loss-of-function experiments using small RNA mimics and antisense LNAs, respectively, showed that ectopic tRF-GlyTCC reduced RUNX2 expression and dispersed 3D micromass architecture in vitro. iCLIP sequencing revealed YBX1 physical binding to the 3′ UTR of RUNX2. The interaction between YBX1, tRF-GlyTCC and RUNX2 led to the development of the RUNX2 inhibitor CADD522 as a PBC treatment. CADD522 assessment in vitro revealed significant effects on PBC cell behaviour. In xenograft mouse models, CADD522 as a single agent without surgery significantly reduced tumour volume, increased overall and metastasis-free survival and reduced cancer-induced bone disease. Our results provide insight into PBC molecular abnormalities that have led to the identification of new targets and a new therapeutic.
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影响因子：
3.3
作者：
Fricke C;Green D;Smith D;Dalmay T;Chapman T
通讯作者：
Chapman T
影响因子：
14.9
作者：
Chan PP;Lowe TM
通讯作者：
Lowe TM
DOI：
10.1038/nrc.2017.99
发表时间：
2018-01
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Anastasiadou E;Jacob LS;Slack FJ
通讯作者：
Slack FJ
影响因子：
4.1
作者：
Billmeier M;Green D;Hall AE;Turnbull C;Singh A;Xu P;Moxon S;Dalmay T
通讯作者：
Dalmay T
影响因子：
64.5
作者：
Goodarzi H;Liu X;Nguyen HC;Zhang S;Fish L;Tavazoie SF
通讯作者：
Tavazoie SF