Hepatocellular carcinomas of the albumin SV40 T-antigen transgenic rat display fetal-like re-expression of lgf2 and deregulation of H19

• Published in: Molecular carcinogenesis 2007-09, Vol.46 (9), p.747-757
• Main Authors: Czarny, Matthew J, Babcock, Karlee, Baus, Rebecca M, Manoharan, Herbert, Pitot, Henry C
• Format: Article
• Language: English
• Subjects: Albumins - genetics; Alleles; Animals; Animals, Genetically Modified; Antigens, Polyomavirus Transforming - genetics; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Transformation, Neoplastic - genetics; Crosses, Genetic; Female; Fetus; Gene Expression Regulation, Neoplastic - genetics; Insulin-Like Growth Factor Binding Protein 2 - metabolism; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - pathology; Polymorphism, Single Nucleotide; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; RNA, Long Noncoding; RNA, Untranslated - genetics; RNA, Untranslated - metabolism; Sequence Analysis, DNA; Transgenes
• ISSN: 0899-1987
• DOI: 10.1002/mc.20286

Previous studies in our laboratory have shown that one of the earliest events during hepatocarcinogenesis in the albumin SV40 T antigen (Alb SV40 T Ag) transgenic rat is the duplication of chromosome 1q3.7-4.3, a region which contains the imprinted and coordinately regulated genes Igf2 and H19. We have also shown that this duplication is associated with the biallelic expression of the normally monoallelically-expressed H19. These results, however, are seemingly at odds with studies in the mouse that have shown a conservation of fetal regulatory patterns of these two genes in hepatic neoplasms. We therefore aimed in this study to determine the allelic origin of Igf2 expression in hepatocellular carcinomas of the Alb SV40 T Ag transgenic rat. Sprague-Dawley Alb SV40 T Ag transgenic rats and Brown Norway rats were reciprocally mated and the expression of Igf2 in hepatocellular carcinomas of the resulting F(1) transgene-positive female rats was analyzed by Northern blotting and RT-PCR. We determined that Igf2 was expressed exclusively from the paternal allele, which prompted the study (by the same methods) of the allelic origin of H19 in the same hepatocellular carcinomas in order to determine if the two genes remained coordinately regulated. Our results demonstrate fetal-like re-expression of Igf2 and deregulation of H19 in singular hepatocellular carcinomas of the rat. These results imply that another regulatory mechanism other than the generally accepted ICR/CTCF mechanism may play a role in the control of Igf2 and H19 expression.