Genomic Imprinting of IGF-II and H19 in Adult Human Pancreatic Tissues

Abstract

Background/Aim: Genomic imprinting is a chromosomal modification causing differential expression of maternal and paternal alleles. Loss of imprinting (LOI) of IGF-II and H19 has been suggested to be an early oncogenic event in cancerogenesis. Aim of the present study was to describe the status of IGF-II and H19 imprinting in adult human pancreatic tissues. Methods: Allele-specific gene expression was studied using RNA and DNA from human pancreatic cancer, chronic pancreatitis, and normal pancreas tissues heterozygous for ApaI (IGF-II) or RsaI (H19) restriction fragment length polymorphism. Reverse-transcriptase polymerase chain reaction products were digested with either ApaI or RsaI and analyzed on agarose gels to study the status of allelic expression. The expression level of H19 and IGF-II was studied on Northern blots or by polymerase chain reaction. Results: H19 was imprinted in normal pancreas and in chronic pancreatitis. H19 LOI was observed in 1 of 4 informative cancer tissues and was not associated with increased H19 transcript levels. Biallelic expression of IGF-II was found in 6 of 10 informative cancer tissues and in 6 of 9 informative normal tissues. In chronic pancreatitis, the IGF-II gene was imprinted in all informative samples. IGF-II mRNA was not overexpressed in the tissues showing LOI. Conclusion: Low frequencies of H19 LOI and the lack of correlation between biallelic expression and overexpression observed for both H19 and IGF-II suggest that LOI of H19 and IGF-II is not a relevant oncogenic factor during human exocrine pancreatic cancerogenesis.

Reduced expression of the H19 long non-coding RNA inhibits pancreatic cancer metastasis

“…These findings suggest that H19 contributes to the normal and regenerative process of smallsized ductal cells during pancreatic inflammation. Conversely, Micha et al [27]. reported that H19 was imprinted in the normal pancreas and in chronic pancreatitis and that loss of imprinting was observed in one of four pancreatic cancer tissues but was not associated with increased transcript levels.…”

Gene Expression Profile of Neuronal Progenitor Cells Derived from hESCs: Activation of Chromosome 11p15.5 and Comparison to Human Dopaminergic Neurons

“…It is noteworthy, however, that imprinting of genes in this region appears to have a role in the regulation of insulin secretion [50] , [51] . H19 and IGF2 are expressed in the adult pancreas [52] . The present data suggest that the H19-IGF2 region may be involved in dopamine neuron specification as well.…”

Biology and significance of signalling pathways activated by IGF-II

“…Interestingly, Tag mice that carried a disruption in either the paternal or maternal Igf2 allele developed tumours of a similar size and histology to wild type Tag mice, indicating that both the developmentally expressed paternal allele or the inactive maternal allele could contribute to tumour development [102]. In humans, evidence of a role for IGF-II in pancreatic cancer is mixed: a nested case-control study has shown no correlation between increased serum concentration of IGF-II and increased risk of pancreatic cancer [103], and no change in IGF-II mRNA expression was observed in human pancreatic cancer samples, despite biallelic Igf2 expression [104]. However, a recent study has reported hypermethylation of the Igf2 DMR2 in insulinomas, which was associated with LOI and overexpression of IGF-II at the mRNA and protein level [105].…”