The Increasing Complexity of the Oncofetal H19 Gene Locus: Functional Dissection and Therapeutic Intervention
| Autor: | Abraham Hochberg, Eitan Gershtain, Eli Raveh, Patricia Ohana, Abraham Czerniak, Imad Matouk, Michal Gilon, Nathan de Groot, Rasha Abu Lail |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Locus (genetics)
Review Biology medicine.disease_cause Catalysis Inorganic Chemistry Transcriptome lcsh:Chemistry Sense (molecular biology) medicine Physical and Theoretical Chemistry Molecular Biology lcsh:QH301-705.5 Spectroscopy Genetics long non-coding RNA sense and antisense transcripts Organic Chemistry RNA General Medicine Non-coding RNA DNA-based therapy Long non-coding RNA female genital diseases and pregnancy complications Computer Science Applications lcsh:Biology (General) lcsh:QD1-999 embryonic structures transcriptional modulators diphtheria toxin A Carcinogenesis Genomic imprinting |
| Zdroj: | International Journal of Molecular Sciences, Vol 14, Iss 2, Pp 4298-4316 (2013) International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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