An antisense RNA-mediated regulatory program that drives cancer metastasis

项目总结 转录后调控程序在塑造异常基因表达格局中发挥着重要作用 这是癌症进展的一个标志。我们最近演示了特定类别的非编码 RNA，如tRNAs(Goodarzi等人，Cell，2016)和tRNA片段(Goodarzi等人，Cell，2015)起主要作用 作为基因表达的转录后调节因子在乳腺癌转移中的作用。然而，这些 调控RNA只是在高转移细胞中差异表达的非编码RNA的一小部分。 例如，反义RNA是一大类通常被忽视的非编码RNA，人们对其了解很少 在单元格中发挥作用。我们最近对一个小组中表达的反义RNA进行了系统的分析 低转移性和高转移性乳腺癌细胞。我们观察到数十个反义RNA与 转移能力。反义RNA可通过其形成能力发挥转录后调节作用 稳定的双链与其正义的对应物。然而，潜在的分子机制及其在其中的作用 基因表达调控在很大程度上仍不清楚。在这里，我们建议对我们的顶级 针对NQO1基因3‘非编码区的候选反义RNA，因此被命名为NQO1-AS，以及它的 具有促进乳腺癌转移的作用。我们假设NQO1-AS与NQO1-AS形成稳定的双链 NQO1的3‘非编码区，它排除了HNRNPC蛋白的结合。HNRNPC可能充当监管机构 NQO1mRNA中可选的Poly(A)位点选择，使平衡向截短为3‘的异构体移动 UTR.我们假设这个截短的转录本亚型具有较短的寿命。因此，通过过度表达 NQO1-AS高转移细胞转录后上调NQO1的表达。增强型NQO1 活性使癌细胞能够承受在转移过程中经历的氧化应激。在这项研究中，我们 试图对这一途径进行详细的解剖，了解其在转移中的作用，并测试其临床应用。 与患者的相关性。重要的是，可以利用高转移细胞中增强的NQO1活性，使用 辅助治疗，专门针对浸润性乳腺癌患者的转移细胞。

PROJECT SUMMARY Post-transcriptional regulatory programs play a major role in shaping the aberrant gene expression landscape that is a hallmark of cancer progression. We have recently demonstrated that specific classes of non-coding RNAs, such as tRNAs (Goodarzi et al, Cell, 2016) and tRNA fragments (Goodarzi et al, Cell, 2015), play major roles in breast cancer metastasis as post-transcriptional regulators of gene expression. However, these regulatory RNAs are but a fraction of non-coding RNAs that are differentially expressed in highly metastatic cells. For example, antisense RNAs are a large but often ignored class of non-coding RNAs with poorly understood functions in the cell. We recently performed a systematic analysis of antisense RNAs expressed in a panel of poorly and highly metastatic breast cancer cells. We observed tens of antisense RNAs that are associated with metastatic capacity. Antisense RNAs can function as post-transcriptional regulators through their ability to form stable duplexes with their sense counterparts. However, the underlying molecular mechanisms and their role in gene expression regulation remains largely unknown. Here, we propose a detailed dissection of our top candidate antisense RNA, which targets the 3' UTR of the gene NQO1 and is hence named NQO1-AS, and its function in promoting breast cancer metastasis. We hypothesize that NQO1-AS forms a stable duplex with the 3' UTR of NQO1 which precludes the protein HNRNPC from binding. HNRNPC likely acts as a regulator of alternative poly(A) site selection in NQO1 mRNA, shifting the equilibrium towards an isoform with a truncated 3' UTR. We hypothesize that this truncated transcript isoform has a shorter life-span. Thus, by over-expressing NQO1-AS, highly metastatic cells post-transcriptionally increase the expression of NQO1. Enhanced NQO1 activity enables cancer cells to withstand the oxidative stress experienced during metastasis. In this study, we seek to perform a detailed dissection of this pathway, understand its role in metastasis, and test its clinical relevance in patients. Importantly, the enhanced NQO1 activity in highly metastatic cells can be exploited, using adjuvant therapies, to specifically target metastatic cells in patients with invasive breast cancer.