A 5'-tRNA halve, tiRNA-Gly promotes cell proliferation and migration via binding to RBM17 and inducing alternative splicing in papillary thyroid cancer.
A 5'-tRNA halve, tiRNA-Gly promotes cell proliferation and migration via binding to RBM17 and inducing alternative splicing in papillary thyroid cancer.
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在甲状腺乳头状癌中，tiRNA-Gly是一种5'-tRNA半体，通过与RBM17结合并诱导选择性剪接促进细胞增殖和迁移。
DOI：
10.1186/s13046-021-02024-3
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发表时间：
2021-07-05
期刊：
影响因子：
--
通讯作者：
Liao T
中科院分区：
文献类型：
--
作者：
Han L;Lai H;Yang Y;Hu J;Li Z;Ma B;Xu W;Liu W;Wei W;Li D;Wang Y;Zhai Q;Ji Q;Liao T
tRNA衍生的小非编码RNA（sncRNA）主要分为tRNA半体（tiRNA）和片段（tRFs）。tiRNA在人类实体瘤中的生物学功能受到越来越多的关注，但关于tiRNA介导的肿瘤发生机制的研究却很少。tiRNAs和剪接相关蛋白之间的直接调控关系仍然难以捉摸。通过tRNA片段深度测序筛选甲状腺乳头状癌（PTC）相关的tRNA片段，并通过PTC组织中的qRT-PCR和北方印迹进行验证。采用细胞计数试剂盒、transwells法和裸鼠皮下移植瘤法评价tRNA片段的生物学功能。采用tRNA片段下拉法、RNA免疫沉淀法、Western Blot法、免疫荧光法、免疫组化法等方法研究其作用机制。在此，我们已经基于tRFs和tiRNAs测序鉴定了33 nt tiRNA-Gly在乳头状甲状腺癌（PTC）中显著增加。tiRNA-Gly的异位表达促进细胞增殖和迁移，而下调tiRNA-Gly则表现出相反的作用。机制研究表明tiRNA-Gly直接结合剪接相关RNA结合蛋白RBM 17的UHM结构域。与tiRNA-Gly的相互作用可使RBM 17从细胞质转位到细胞核中。此外，tiRNA-Gly通过泛素/蛋白酶体依赖性方式抑制RBM 17的降解而增加RBM 17蛋白的表达。此外，在tiRNA-Gly高表达的人PTC组织中RBM 17水平上调。体内小鼠模型显示，抑制tiRNA-Gly降低RBM 17表达。重要的是，tiRNA-Gly可以诱导MAP 4K 4 mRNA的外显子16剪接，导致下游信号通路的磷酸化，这是RBM 17依赖性的。我们的研究首次证实了tiRNA-Gly可以直接与RBM 17结合，并通过RBM 17介导的选择性剪接发挥致癌作用。这一全新的模型拓宽了我们对肿瘤细胞中tRNA片段直接结合RNA结合蛋白并在选择性剪接中发挥作用的分子机制的理解。在线版本包含补充材料，可通过10.1186/s13046-021-02024-3获得。
tRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Biological functions of tiRNAs in human solid tumor are attracting more and more attention, but researches concerning the mechanisms in tiRNAs-mediated tumorigenesis are rarely. The direct regulatory relationship between tiRNAs and splicing-related proteins remain elusive. Papillary thyroid carcinoma (PTC) associated tRNA fragments were screened by tRNA fragments deep sequencing and validated by qRT-PCR and Northern Blot in PTC tissues. The biological function of tRNA fragments were assessed by cell counting kit, transwells and subcutaneous transplantation tumor of nude mice. For mechanistic study, tRNA fragments pull-down, RNA immunoprecipitation, Western Blot, Immunofluorescence, Immunohistochemical staining were performed. Herein, we have identified a 33 nt tiRNA-Gly significantly increases in papillary thyroid cancer (PTC) based on tRFs & tiRNAs sequencing. The ectopic expression of tiRNA-Gly promotes cell proliferation and migration, whereas down-regulation of tiRNA-Gly exhibits reverse effects. Mechanistic investigations reveal tiRNA-Gly directly bind the UHM domain of a splicing-related RNA-binding protein RBM17. The interaction with tiRNA-Gly could translocate RBM17 from cytoplasm into nucleus. In addition, tiRNA-Gly increases RBM17 protein expression via inhibiting its degradation in a ubiquitin/proteasome-dependent way. Moreover, RBM17 level in tiRNA-Gly high-expressing human PTC tissues is upregulated. In vivo mouse model shows that suppression of tiRNA-Gly decreases RBM17 expression. Importantly, tiRNA-Gly can induce exon 16 splicing of MAP4K4 mRNA leading to phosphorylation of downstream signaling pathway, which is RBM17 dependent. Our study firstly illustrates tiRNA-Gly can directly bind to RBM17 and display oncogenic effect via RBM17-mediated alternative splicing. This fully novel model broadens our understanding of molecular mechanism in which tRNA fragment in tumor cells directly bind RNA binding protein and play a role in alternative splicing. The online version contains supplementary material available at 10.1186/s13046-021-02024-3.
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影响因子：
4.6
作者：
Nientiedt M;Deng M;Schmidt D;Perner S;Müller SC;Ellinger J
通讯作者：
Ellinger J
影响因子：
14.9
作者：
Chan PP;Lowe TM
通讯作者：
Lowe TM
DOI：
10.1083/jcb.130.5.1017
发表时间：
1995-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Corbett AH;Koepp DM;Schlenstedt G;Lee MS;Hopper AK;Silver PA
通讯作者：
Silver PA
影响因子：
14.9
作者：
Liu Y;Conaway L;Rutherford Bethard J;Al-Ayoubi AM;Thompson Bradley A;Zheng H;Weed SA;Eblen ST
通讯作者：
Eblen ST
MAP4K4 是肺腺癌维持所需的新型 MAPK/ERK 通路调节因子
影响因子：
6.6
作者：
Gao X;Chen G;Gao C;Zhang DH;Kuan SF;Stabile LP;Liu G;Hu J
通讯作者：
Hu J