Nature：CFIm25是调控肿瘤生长的开关
近日，休斯敦德克萨斯大学医学院Eric J. Wagner博士，Ann-Bin Shyu博士，和贝勒医学院李蔚博士共同领导的一项临床前研究，找到一种蛋白可用于抑制或加速小鼠脑瘤的生长*。这项研究成果发表在6月19日的《自然》上。研究人员采用了包括RNA干扰，转录组测序，新数据算法（DaPars），动物活体实验等多种技术，鉴定出CFIm25在控制可变聚腺苷酸化（APA）中发挥关键作用，在CFIm25表达下降的胶质母细胞瘤中鉴定出一组CFIm25调控的具有变短的3′ UTRs的APA基因。进一步活体实验发现，在胶质母细胞瘤细胞中CFIm25表达下调会促进致瘤性并增加肿瘤大小，而CFIm25过表达则会降低致瘤性并抑制肿瘤生长，进而找到了CFIm25与胶质母细胞瘤致瘤性的关联。具体内容见下方摘要。
此项研究中的转录组测序项目由联川生物承担完成。
此篇文章是联川生物客户发表的第18篇Cell，Nature，Science级文章。
摘要 信使RNA通过可变聚腺苷酸化（APA）在增强的细胞增殖过程中会进行整体性变短，这代表了一种重要的，但目前知之甚少的调控基因表达的机制。促生长mRNA转录本的3′非翻译区（UTR）截断会解除内在的microRNA和富含AU元件介导的抑制作用，已发现这与细胞性状转化相关；然而，潜在控制APA的RNA 3′末端加工因子对致瘤性的重要性仍然未知。在这里，我们鉴定出CFIm25是一个广泛的近端poly(A)位点使用的抑制子，当其被沉默，会促进细胞增殖。应用回归模型基于标准的转录组测序数据分析新的APA事件，我们发现至少有1,450个基因，在CFIm25被敲减后出现3′UTRs变短，这代表了人类细胞中11%显著表达的mRNA。作为CFIm25被沉默的后果，多个已知的癌基因表达显著上升，包括细胞周期蛋白D1。重要的是，我们在CFIm25表达下降的胶质母细胞瘤中鉴定出一组CFIm25调控的具有变短的3′ UTRs的APA基因。在胶质母细胞瘤细胞中CFIm25表达下调会促进致瘤性并增加肿瘤大小，而CFIm25过表达则会降低致瘤性并抑制肿瘤生长。上述研究成果确定了CFIm25在控制APA中具有举足轻重的作用，揭示出以前未知的CFIm25与胶质母细胞瘤致瘤性的关联。
CFIm25 links alternative polyadenylation to glioblastoma tumour suppression
Chioniso P. Masamha, Zheng Xia, Jingxuan Yang, Todd R. Albrecht, Min Li, Ann-Bin Shyu, Wei Li & Eric J. Wagner
Abstract The global shortening of messenger RNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression. The 3′untranslated region (UTR) truncation of growth-promoting mRNA transcrpts that relieves intrinsic microRNA- and AU-rich-element-mediated repression has been observed to correlate with cellular transformation; However, the importance to tumorigenicity of RNA 3′-end-processing factors that potentially govern APA is unknown. Here we identify CFIm25 as a broad repressor of proximal poly(A) site usage that, when depleted, increases cell proliferation. Applying a regression model on standard RNA-sequencing data for novel APA events, we identified at least 1,450 genes with shortened 3′ UTRs after CFIm25 knockdown, representing 11% of significantly expressed mRNAs in human cells. Marked increases in the expression of several known oncogenes, including cyclin D1, are observed as a consequence of CFIm25 depletion. Importantly, we identified a subset of CFIm25-regulated APA genes with shortened 3′ UTRs in glioblastoma tumours that have reduced CFIm25 expression. Downregulation of CFIm25 expression in glioblastoma cells enhances their tumorigenic properties and increases tumour size, whereas CFIm25 overexpression reduces these properties and inhibits tumour growth. These findings identify a pivotal role of CFIm25 in governing APA and reveal a previously unknown connection between CFIm25 and glioblastoma tumorigenicity.
Acknowledgements We would like to thank members of the E.J.W., A.-B.S. and W.L. laboratories for helpful discussions, P. Carpenter for reviewing the manuscript, and Q. Zhu and T. Shan of LC Sciences for their efforts on the RNA-seq. This work was supported by… …
*Masamha CP, Xia Z, Yang J, Albrecht TR, Li M, Shyu A, Li W, Wagner EJ. (2014) CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Nature 510(7505):412-6.
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