The Increasing Complexity of the Oncofetal H19 Gene Locus: Functional Dissection and Therapeutic Intervention

Abstract

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.

Long non-coding RNA H19 enhances cell proliferation and anchorage-independent growth of cervical cancer cell lines

“…19,20 The imprinted, developmentally regulated lncRNA H19 is absent in most normal adult tissues; however, its reexpression has been detected in various cancers. [21][22][23] Since the discovery of H19 in 1984, 24 its function has remained enigmatic. Many studies using cell culture systems and mouse models have shown that H19 can function either as an oncogene [25][26][27] or a tumor suppressor.…”

The tissue specific nature of mesenchymal stem/stromal cells: gaining better understanding for improved clinical outcomes

“…The exact role of H19 in the maintenance of genomic stability and in the process of cellular transformation is unclear. However, previous studies showed that increased H19 expression levels can serve as a marker for tumor cells [21][22][23][24] , which lead to its use as a clinical bio-marker in the treatment of various cancer types [25] . In the recent work [20] it was unveiled that H19 expression is higher in proliferating cells, and is also elevated dramatically in cells exposed to UV light.…”

Long non-coding RNAs and hepatocellular carcinoma

“…Oncofetal H19 had been extensively investigated in cancer biology, even before research was focused on lncRNA (37,38). H19 is a paternally imprinted gene which locates at chromosome 11p15.5.…”

“…H19 is highly expressed during embryonic development, but is repressed right after birth in most tissues (39,40). H19 is highly expressed during tumorigenesis and was shown to possess tumorigenic properties in all types of tissues (37,(41)(42)(43).…”