Human snoRNA-93 is processed into a microRNA-like RNA that promotes breast cancer cell invasion.
Human snoRNA-93 is processed into a microRNA-like RNA that promotes breast cancer cell invasion.
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DOI：
10.1038/s41523-017-0032-8
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发表时间：
2017
影响因子：
5.9
通讯作者：
Borchert GM
中科院分区：
文献类型：
--
作者：
Patterson DG;Roberts JT;King VM;Houserova D;Barnhill EC;Crucello A;Polska CJ;Brantley LW;Kaufman GC;Nguyen M;Santana MW;Schiller IA;Spicciani JS;Zapata AK;Miller MM;Sherman TD;Ma R;Zhao H;Arora R;Coley AB;Zeidan MM;Tan M;Xi Y;Borchert GM
对肿瘤抑制因子的基因研究最近将小核仁RNA的错误调节与肿瘤发生联系起来。除了它们经典定义的功能之外，现在已知几种小核仁RNA被加工成短的microRNA样片段，称为小核仁RNA衍生的RNA。为了确定任何小核仁RNA衍生的RNA是否有助于乳腺癌，我们最近对两种乳腺癌细胞系（MCF-7和MDA-MB-231）的小核仁RNA衍生的RNA进行了基于RNA-seq的比较，并鉴定了来自MDA-MB-231中过表达的13种小核仁RNA的小核仁RNA衍生的RNA。重要的是，我们发现抑制MDA-MB-231细胞中这些小核仁RNA衍生RNA（sdRNA-93）的最差异表达主要导致侵袭性的丧失，而在任一细胞系中增加sdRNA-93表达相反地导致显著增强的侵袭。令人兴奋的是，我们最近确定了对应于116例患者肿瘤和正常乳腺对照的小RNA-seq数据中的sdRNA-93表达，并且虽然我们在任何对照中发现很少的sdRNA-93表达，并且在大多数亚型中仅零星表达，但我们发现92.8%的Luminal B Her 2+肿瘤中sdRNA-93的稳健表达。值得注意的是，我们的分析还表明，sdRNA-93的内源性作用中至少有一个是调节Pipox的表达，Pipox是一种肌氨酸代谢相关蛋白，其表达与乳腺癌的不同分子亚型显著相关。我们发现sdRNA-93可以通过标准的报告基因测定来调节Pipox 3′UTR，并且操纵内源性sdRNA-93水平与改变的Pipox表达呈负相关。总之，我们的研究结果强烈表明，sdRNA-93表达积极参与microRNA样调节乳腺癌的恶性表型。从小核仁RNA（称为snoRNA衍生的RNA或sdRNA）切除的短microRNA样片段有助于乳腺癌细胞的侵袭性。来自美国南亚拉巴马大学的Glen Borchert及其同事比较了原发性乳腺癌细胞系和转移性乳腺癌细胞系之间sdRNA的表达。他们鉴定了13种丰度明显不同的sdRNA。阻断具有最大表达差异的sdRNA-93-的sdRNA降低了细胞侵袭性，而增加其丰度增强了肿瘤细胞侵袭性。在人类组织中，sdRNA-93通常在从具有管腔HER 2阳性形式的乳腺癌患者中采集的活检组织中表达，在其他肿瘤类型中较少表达，并且几乎从未在健康乳腺样品中表达。研究人员暗示其功能，表明sdRNA-93靶向并调节一种导致乳腺癌特定分子亚型的基因。
Genetic searches for tumor suppressors have recently linked small nucleolar RNA misregulations with tumorigenesis. In addition to their classically defined functions, several small nucleolar RNAs are now known to be processed into short microRNA-like fragments called small nucleolar RNA-derived RNAs. To determine if any small nucleolar RNA-derived RNAs contribute to breast malignancy, we recently performed a RNA-seq-based comparison of the small nucleolar RNA-derived RNAs of two breast cancer cell lines (MCF-7 and MDA-MB-231) and identified small nucleolar RNA-derived RNAs derived from 13 small nucleolar RNAs overexpressed in MDA-MB-231s. Importantly, we find that inhibiting the most differentially expressed of these small nucleolar RNA-derived RNAs (sdRNA-93) in MDA-MB-231 cells results primarily in a loss of invasiveness, whereas increased sdRNA-93 expression in either cell line conversely results in strikingly enhanced invasion. Excitingly, we recently determined sdRNA-93 expressions in small RNA-seq data corresponding to 116 patient tumors and normal breast controls, and while we find little sdRNA-93 expression in any of the controls and only sporadic expression in most subtypes, we find robust expression of sdRNA-93 in 92.8% of Luminal B Her2+tumors. Of note, our analyses also indicate that at least one of sdRNA-93’s endogenous roles is to regulate the expression of Pipox, a sarcosine metabolism-related protein whose expression significantly correlates with distinct molecular subtypes of breast cancer. We find sdRNA-93 can regulate the Pipox 3′UTR via standard reporter assays and that manipulating endogenous sdRNA-93 levels inversely correlates with altered Pipox expression. In summary, our results strongly indicate that sdRNA-93 expression actively contributes to the malignant phenotype of breast cancer through participating in microRNA-like regulation. A short microRNA-like fragment excised from a small nucleolar RNA (called a snoRNA-derived RNA or sdRNA) contributes to the invasiveness of breast cancer cells. Glen Borchert from the University of South Alabama, USA, and colleagues compared the expression of sdRNAs between a primary breast cancer cell line and a metastatic one. They identified 13 sdRNAs with markedly different abundances. Blocking the sdRNA with the biggest expression differential sdRNA-93-decreased cellular invasion, whereas increasing its abundance enhanced tumor cell invasiveness. Looking at human tissues, sdRNA-93 was routinely expressed in biopsies taken from patients with the luminal HER2-positive form of breast cancer, less often in other tumor types and almost never in healthy breast samples. Hinting at its function, the researchers showed that sdRNA-93 targets and regulates a gene contributing to specific molecular subtypes of breast cancer.
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影响因子：
5.9
作者：
Dong, Xue-Yuan;Guo, Peng;Boyd, Jeff;Sun, Xiaodong;Li, Qunna;Zhou, Wei;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
3.5
作者：
Dong, Xue-Yuan;Rodriguez, Carmen;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C
影响因子：
9.8
作者：
John B;Enright AJ;Aravin A;Tuschl T;Sander C;Marks DS
通讯作者：
Marks DS
影响因子：
4.3
作者：
Grün D;Wang YL;Langenberger D;Gunsalus KC;Rajewsky N
通讯作者：
Rajewsky N