Biallelic expression of the H19 gene during spontaneous hepatocarcinogenesis in the albumin SV40 T antigen transgenic rat

Abstract

Previous studies in this laboratory have demonstrated that the earliest cytogenetic alteration in the development of hepatic neoplasms in a transgenic strain of rats bearing the albumin Simian virus 40 T antigen (Alb SV40 T Ag) construct was a duplication of the chromosome 1q4.1-1q4.2 band. In this region, in the rat genome a cluster of linked imprinted genes occurs. One of these imprinted genes, H19, which is expressed in fetal liver but not in adult liver, was found to be expressed in virtually all neoplasms investigated. A single-nucleotide polymorphic marker in the H19 coding sequence was identified in two rat strains and utilized for the investigation of H19 imprinting. Our results reveal monoallelic expression of the maternal gene in fetal liver, but biallelic expression of the H19 gene in liver neoplasms, thus demonstrating the basis for the deregulation of the imprinted gene expression during hepatocarcinogenesis. These results suggest that the loss of genomic imprinting of the H19 gene found in the liver neoplasms of the Alb SV40 T Ag rat may result not from allelic loss, but from adverse changes in the epigenetic imprints present in the 5'-upstream region of the H19 promoter of the parental alleles.

The H19 Non-Coding RNA Is Essential for Human Tumor Growth

“…Interestingly, H19 RNA is upregulated in HBV-associated HCC [30]. Furthermore, a biallelic expression of H19 gene was found in human HCC patients [31] and in liver neoplasms of albumin SV40 T-antigen-transgenic rats [32].…”

A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas

“…One of the better elucidated large ncRNAs is Xist (X chromosome inactive specific transcript) that presents as a 17-kb (human) and a 15-kb (mouse) molecule responsible for somatic X-chromosome dosage compensation (Brockdorff et al, 1992;Brown et al, 1992;Plath et al, 2002). Another example is a paternally imprinted gene H19 (O'neill, 2005), with a conserved secondary structure but non-conserved ORFs, that functions as a tumor suppressor in some tumor types and may play a significant role in tumorigenesis in other types (Steenman et al, 1994;Lottin et al, 2002;Manoharan et al, 2003). Recently, Willingham et al (2005) identified an ncRNA designated NRON that is a repressor of nuclear factor of activated T cells.…”

Hepatocellular carcinomas of the albumin SV40 T‐antigen transgenic rat display fetal‐like re‐expression of Igf2 and deregulation of H19

“…H19 has been shown to follow the same expression patterns as Igf2 in both the mouse and rat, although it is expressed from the opposite allele 17. While Igf2 is expressed exclusively from the paternal allele, H19 is expressed solely from the maternal allele.…”

“…The cytogenetic changes during the development of hepatomas in the transgenic rat have been shown to be quite similar to those during virally‐ and chemically‐induced hepatoma development 16, and it is for that reason that our lab is attempting to further characterize the process of hepatocarcinogenesis in the SD Alb SV40 T Ag transgenic rat. Dragan et al 16 and Manoharan et al 17 have previously shown the duplication of 1q3.7‐4.3 correlates with re‐expression of Igf2 and H19 in most female hepatic neoplasms of the SD Alb SV40 T Ag transgenic rat. Additionally, Manoharan et al determined that expression of H19 in these hepatic neoplasms was biallelic, which implied a loss of regulation at the Igf2 / H19 locus 17.…”

“…Dragan et al 16 and Manoharan et al 17 have previously shown the duplication of 1q3.7‐4.3 correlates with re‐expression of Igf2 and H19 in most female hepatic neoplasms of the SD Alb SV40 T Ag transgenic rat. Additionally, Manoharan et al determined that expression of H19 in these hepatic neoplasms was biallelic, which implied a loss of regulation at the Igf2 / H19 locus 17. Because Igf2 is regulated by the same mechanism as H19 , it should follow that Igf2 expression in the same neoplasms was biallelic.…”