The H19 locus acts in vivo as a tumor suppressor

Abstract

The H19 locus belongs to a cluster of imprinted genes that is linked to the human Beckwith-Wiedemann syndrome. The expression of H19 and its closely associated IGF2 gene is frequently deregulated in some human tumors, such as Wilms' tumors. In these cases, biallelic IGF2 expression and lack of expression of H19 are associated with hypermethylation of the imprinting center of this locus. These observations and others have suggested a potential tumor suppressor effect of the H19 locus. Some studies have also suggested that H19 is an oncogene, based on tissue culture systems. We show, using in vivo murine models of tumorigenesis, that the H19 locus controls the size of experimental teratocarcinomas, the number of polyps in the Apc murine model of colorectal cancer and the timing of appearance of SV40-induced hepatocarcinomas. The H19 locus thus clearly displays a tumor suppressor effect in mice.genomic imprinting ͉ Igf2 ͉ murine models T he H19-Igf2 locus is subject to genomic imprinting and has often been used as a paradigm for the study of this particular epigenetic regulation. The H19 locus produces a 2.5-kb noncoding, spliced, and polyadenylated RNA of yet-unknown function (1, 2). The Igf2 gene encodes a fetal growth factor, insulin-like growth factor 2. These two genes are located 90 kb apart and are oppositely imprinted: H19 is maternally expressed and Igf2 paternally expressed (1, 3). They belong to a large imprinted domain localized on chromosome 7 in mice and chromosome 11p15.5 in humans. The imprinting of Igf2 and H19 is controlled by a region located 4 kb upstream from the H19 transcription unit, defined as the H19 differentially methylated region (DMR) or imprinting control region (ICR) (4).The 11p15.5-imprinted domain is linked to the BeckwithWiedemann syndrome (BWS), which is characterized by overgrowth phenotypes of affected children as well as a predisposition to develop embryonal tumors such as Wilms' tumor or rhabdomyosarcomas (5). Among the molecular alterations involved in BWS, certain cases (20%) show paternal uniparental disomy (UPD); other cases (5-10%) have hypermethylation of the H19 DMR; and both lead to lack of expression of H19 as well as activation of IGF2. These patients have higher risk of developing tumors than patients with other molecular defects (6). Genetic and epigenetic alterations at 11p15.5 similar to those found in the BWS have also been demonstrated in nonsyndromic Wilms' tumors. A great number of these cases have either loss of the maternal allele (LOH) or LOI (7,8). It has thus been suggested that the H19 gene could have a possible tumor suppressor function (9). The first direct evidence for this tumor suppressor function was provided by in vitro experiments in which transfection of H19 cDNA into G401-transformed kidney cells resulted in loss of tumorigenicity of these cells (10). Subsequent experiments performed with in vitro culture systems suggested that H19 played a role as an oncogene rather than a tumor suppressor gene (11,12). This controversy has not yet been reso...

Analysis of the miRNA–mRNA–lncRNA networks in ER+ and ER− breast cancer cell lines

“…Overexpression of H19 resulted in an increase of anchorage‐independent growth in MDA‐MB‐231 BC cells and therefore H19 has been considered as and oncogenic RNA in BC cell lines 12. However, in other works, introduction of H19 into several tumour cell lines caused tumour suppressor effects 57. So it needs further verification.…”

Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes

“…H19DMR regulates the expression of two oppositely imprinted genes: 10 H19 encodes an untranslated RNA with tumour suppressor activity 11 and it is expressed from the maternal allele; insulin growth factor 2 (IGF2) encodes a growth factor essential for development 12 and it is expressed from the paternal allele. H19DMR harbours several CTCF-(CCCTC-binding factor) binding sites.…”

Parthenogenetic embryonic stem cells with H19 siRNA-mediated knockdown as a potential resource for cell therapy

“…All of the ESH cell lines showed an increased Igf2 expression and decreased H19 expression compared with the ESP cells. Mice that have a deletion in the H19 transcribed region show an overgrowth phenotype that is concomitant with increased Igf2 expression in mesoderm-derived tissues including muscle, tongue, diaphragm and heart; this deletion also significantly affected six imprinting genes including IGN (24,26). Among these genes, the H19 RNA has inhibitory effects on Igf2 transcription.…”