Department of Biological Chemistry, Institute of Life Sciences, the Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Int J Mol Sci. 2013 Feb 21;14(2):4298-316. doi: 10.3390/ijms14024298.
The field of the long non-coding RNA (lncRNA) is advancing rapidly. Currently, it is one of the most popular fields in the biological and medical sciences. It is becoming increasingly obvious that the majority of the human transcriptome has little or no-protein coding capacity. Historically, H19 was the first imprinted non-coding RNA (ncRNA) transcript identified, and the H19/IGF2 locus has served as a paradigm for the study of genomic imprinting since its discovery. In recent years, we have extensively investigated the expression of the H19 gene in a number of human cancers and explored the role of H19 RNA in tumor development. Here, we discuss recently published data from our group and others that provide further support for a central role of H19 RNA in the process of tumorigenesis. Furthermore, we focus on major transcriptional modulators of the H19 gene and discuss them in the context of the tumor-promoting activity of the H19 RNA. Based on the pivotal role of the H19 gene in human cancers, we have developed a DNA-based therapeutic approach for the treatment of cancers that have upregulated levels of H19 expression. This approach uses a diphtheria toxin A (DTA) protein expressed under the regulation of the H19 promoter to treat tumors with significant expression of H19 RNA. In this review, we discuss the treatment of four cancer indications in human subjects using this approach, which is currently under development. This represents perhaps one of the very few examples of an existing DNA-based therapy centered on an lncRNA system. Apart from cancer, H19 expression has been reported also in other conditions, syndromes and diseases, where deregulated imprinting at the H19 locus was obvious in some cases and will be summarized below. Moreover, the H19 locus proved to be much more complicated than initially thought. It houses a genomic sequence that can transcribe, yielding various transcriptional outputs, both in sense and antisense directions. The major transcriptional outputs of the H19 locus are presented here.
长链非编码 RNA（lncRNA）领域正在迅速发展。目前，它是生物和医学科学中最热门的领域之一。越来越明显的是，人类转录组的大部分都具有很小或没有蛋白质编码能力。历史上，H19 是第一个被鉴定的印迹非编码 RNA（ncRNA）转录本，自发现以来，H19/IGF2 基因座一直是研究基因组印迹的典范。近年来，我们广泛研究了 H19 基因在多种人类癌症中的表达，并探讨了 H19 RNA 在肿瘤发生发展中的作用。在这里，我们讨论了我们小组和其他小组最近发表的数据，这些数据进一步支持了 H19 RNA 在肿瘤发生过程中的核心作用。此外，我们还重点讨论了 H19 基因的主要转录调节因子，并在 H19 RNA 的肿瘤促进活性的背景下对它们进行了讨论。基于 H19 基因在人类癌症中的关键作用，我们开发了一种基于 DNA 的治疗方法，用于治疗 H19 表达上调的癌症。该方法使用在 H19 启动子调控下表达的白喉毒素 A（DTA）蛋白来治疗 H19 RNA 表达显著的肿瘤。在本综述中，我们讨论了使用该方法在人类受试者中治疗四种癌症适应症的情况，目前该方法正在开发中。这也许是极少数以 lncRNA 系统为中心的现有 DNA 治疗方法之一。除了癌症，H19 的表达也在其他疾病中被报道，在某些情况下，H19 基因座的印迹失调是明显的，下面将对此进行总结。此外，H19 基因座比最初想象的要复杂得多。它包含一个可以转录的基因组序列，在有义和反义方向上都能产生各种转录产物。这里介绍了 H19 基因座的主要转录产物。
