癌症中研究RNA编辑调节蛋白表达的机制

Numerous studies show that RNA editing plays a crucial role in cancer and other complex diseases, such as neurological diseases; however, the functional significance for most of these RNA editing events is unknown. Our published results predicted that several RNA binding proteins (RBP) such as RPS14 lead to the abnormal RNA editing levels in the transcriptome of tumors, and RNA editing may regulate translation by abolishing the interaction between microRNA and mRNA. However, only limited number of RNA editing sites can be explained by this model, thus we performed preliminary analyses using proteomes, transcriptomes and subcellular transcriptomes to search for additional mechanisms. We observed that the global RNA editing profiles in the nucleus and cytosol showed distinct patterns, and further analyses showed that some of these RNA editing sites may affect the steady-state protein levels. Therefore, we presume that RNA editing may regulate mRNA translation by affecting their sub-cellular localization. In this study, we thus propose an overall hypothesis: ”Some specific RBPs cause aberrant RNA editing patterns in tumors, changing protein translation by abolishing the microRNA-mRNA interaction or regulating the mRNA subcellular localization, which eventually promotes tumor proliferation and metastasis”. We will perform integrative analyses on multi-omics data from ovarian cancer and breast cancer, and we will develop novel computational methodologies to infer key regulatory RBPs, RNA editing sites that affect the sub-cellular localization and/or translation. Finally, we will experimentally validate these data-driven hypotheses and follow up with additional assays to further characterize these mechanisms. We believe this proposed study will shed insight on how RNA editing mediates tumor progression and metastasis, which may eventually lead to the discovery of novel therapeutic and diagnostic strategies.

越来越多的研究表明RNA编辑在肿瘤中发挥重大作用，但编辑位点发挥功能的机制仍知之甚少。申请人发表结果预测RPS14等RNA结合蛋白（RBP）可调控癌症中编辑水平，且部分RNA编辑可帮助mRNA逃脱microRNA（miR）对翻译的抑制。我们前期发现细胞核与核外RNA的编辑模式差异明显，进而分析表明核内外特异的编辑可能调控蛋白表达，提示RNA编辑通过影响RNA核内外定位来调控翻译。申请者由此提出“癌症中差异RNA编辑变化受特定RBP调控，RNA编辑的改变影响miR结合或RNA定位来调控效应基因的翻译，并影响肿瘤的增殖和转移表型”的假说。后续拟整合分析公共数据进行生信预测，并实验验证在卵巢、乳腺癌中潜在调控RNA编辑的RBP，及RNA编辑对mRNA定位的影响，进而对候选基因是否影响细胞增殖和迁移进行验证。这一研究可从新的角度帮助我们理解RNA编辑在癌症发病转移中的机制，并提供干预的新靶点。

本项目原计划通过整合RNA定位，RNA结合蛋白，RNA编辑位点等多种信息理解RNA编辑在癌症或者其他生物学过程中的机制。在这个项目进行过程中，我们建立了多种和原计划相关的新的算法和工具，此外我们在RNA编辑和RNA定位方面也发现一些新的机制，目前有部分结果已经发表还有部分还在投稿进行中。在我们验证计算预测的功能RNA编辑位点过程中，我们发现在多种生物学过程中发挥功能的方式可能不主要是和RNA编辑位点调控有关，更多是和与RNA编辑调控的dsRNA感应和免疫调控相关，这个结果目前也在他人已发表的工作中也得到了印证。