Role of human noncoding RNAs in the control of tumorigenesis
Role of human noncoding RNAs in the control of tumorigenesis
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人类非编码RNA在控制肿瘤发生中的作用
DOI：
10.1073/pnas.0906005106
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发表时间：
2009-08-04
影响因子：
11.1
通讯作者：
Song, Xu
中科院分区：
文献类型：
--
作者：
Li, Ling;Feng, Tingting;Song, Xu
相关研究表明，PSF 蛋白抑制原癌基因转录，而 VL30-1 RNA（一种小鼠非编码逆转录元件 RNA）与原癌基因结合并释放 PSF，激活转录。在这里，我们展示了这种机制通过人类 RNA 取代 VL30-1 RNA 来调节人类细胞的肿瘤发生。使用人类 RNA 片段文库，通过亲和层析分离出 5 个与人类 PSF (hPSF) 结合的非编码 RNA 片段，从原癌基因中释放 hPSF 并激活转录。 5 个 RNA 片段中的每一个都映射到不同的人类基因。通过确定 RNA 对琼脂中集落形成和小鼠肿瘤的影响，在人黑色素瘤系和小鼠成纤维细胞系中测试了 hPSF 结合 RNA 的致瘤功能。 (i)在人黑色素瘤细胞中表达RNA片段单独促进致瘤性。 (ii)在人黑色素瘤细胞中表达shRNA，其导致RNA片段所源自的内源RNA降解，从而抑制致瘤性。 (iii)在小鼠NIH/3T3细胞中单独表达RNA片段导致向致瘤细胞的转化。 (iv) 9 个人类肿瘤系的筛选显示，相对于人类成纤维细胞中的水平，每个系都表达高水平的几种 hPSF 结合 RNA。我们得出结论，人类 hPSF 结合 RNA 通过逆转 PSF 介导的原癌基因转录抑制来驱动转化和肿瘤发生，并且人类 hPSF 结合 RNA 表达的功能失调调节在人类癌症的病因学中具有核心作用。
Related studies showed that the protein PSF represses protooncogene transcription, and VL30-1 RNA, a mouse noncoding retroelement RNA, binds and releases PSF from a proto-oncogene, activating transcription. Here we show that this mechanism regulates tumorigenesis in human cells, with human RNAs replacing VL30-1 RNA. A library of human RNA fragments was used to isolate, by affinity chromatography, 5 noncoding RNA fragments that bind to human PSF (hPSF), releasing hPSF from a protooncogene and activating transcription. Each of the 5 RNA fragments maps to a different human gene. The tumorigenic function of the hPSF-binding RNAs was tested in a human melanoma line and mouse fibroblast line, by determining the effect of the RNAs on formation of colonies in agar and tumors in mice. (i) Expressing in human melanoma cells the RNA fragments individually promoted tumorigenicity. (ii) Expressing in human melanoma cells a shRNA, which causes degradation of the endogenous RNA from which an RNA fragment was derived, suppressed tumorigenicity. (iii) Expressing in mouse NIH/3T3 cells the RNA fragments individually resulted in transformation to tumorigenic cells. (iv) A screen of 9 human tumor lines showed that each line expresses high levels of several hPSF-binding RNAs, relative to the levels in human fibroblast cells. We conclude that human hPSF-binding RNAs drive transformation and tumorigenesis by reversing PSF-mediated repression of proto-oncogene transcription and that dysfunctional regulation of human hPSF-binding RNA expression has a central role in the etiology of human cancer.