|, ASM, ASM1, BWS, D11S813E, LINC00008, NCRNA00008, PRO2605, WT2, imprinted maternally expressed transcript (non-protein coding)|
|RNA expression pattern|
H19 is a gene for a long noncoding RNA, found in humans and elsewhere. H19 has a role in the negative regulation (or limiting) of body weight and cell proliferation. This gene also has a role in the formation of some cancers and in the regulation of gene expression. .
The H19 gene is expressed exclusively on one parental allele in a phenomenon known as imprinting. H19 is only transcribed from the maternally inherited allele; the paternal H19 allele is not expressed.
H19 was first named ASM (for Adult Skeletal Muscle) because of its expression in adult skeletal muscle ("ASM") in rats. H19 is also known as BWS because aberrant H19 expression can be involved in Beckwith-Wiedemann Syndrome ("BWS"), as well as Silver-Russell syndrome.
- 1 Gene characterization
- 2 RNA product
- 3 Expression timeline
- 4 Epigenetics
- 5 Replication
- 6 As an oncogene
- 7 Role in cancer
- 8 Participation in signaling pathways
- 9 IGF2
- 10 Cancer therapy
- 11 References
- 12 External links
The H19 gene contains 3 Sp1 binding sites, however these 3 sites are present in a part of the sequence that has shown no transcriptional activity in deletion assays. As a result, these Sp1 binding sites are not expected to contribute much to the regulation of H19 gene transcription. The H19 gene sequence also contains binding sites for the C/EBP family of transcription factors. One of these C/EBP transcription factor binding sites also contains a CpG site. In vitro methylation of this CpG site on a DNA construct strongly inhibited transcription of the H19 gene.
In cell lines derived from human choriocarcinomas, Kopf et al. found that transcription of H19 was under the simultaneous control of both a 5’ upstream and a 3’ downstream region. Kopf et al. have suggested that this simultaneous and bidirectional regulation of H19 may involve a member of the AP2 transcription factor family.
After many studies, researchers finally concluded that the end product of the H19 gene is a RNA strand for the following reasons:
- The H19 RNA product is evolutionarily conserved at the nucleotide level in humans and rodents
- There is no known open reading frame; the H19 mRNA contains stop codons in all 3 reading frames 
- The cDNA version of the human H19 does not contain the short introns that are characteristic of imprinted genes 
- Although the RNA sequence was highly conserved evolutionarily, at the amino acid level, there was a complete absence of conservation 
- Free energy (thermodynamics) analysis of the H19 RNA sequence revealed a multitude of possible secondary RNA structures, including 16 helices and various hairpin loops 
- In situ hybridization of the H19 RNA revealed that it localizes in a cytoplasmic ribonucleoprotein particle, leading some to suggest that the H19 RNA functions as a riboregulator.
Loss of function and overexpression experiments on H19 have revealed two things:
Mice with a loss of H19 function express an overgrowth phenotype similar to babies with BWS. This has led researchers to suggest that perhaps the only function of H19 RNA expression is to regulate the expression of IGF2 (Insulin Growth Factor 2). Overexpression of IGF2 can be responsible for overgrowth, and generally, IGF2 is expressed in the absence of H19. Mouse embryos overexpressing H19 tend to die between embryonic day 14 and birth. Brunkow et al. have suggested two reasons for the lethality of H19 overexpression in embryonic mice:
- The overexpression of H19 in tissues where it is normally expressed (e.g., liver and gut) caused its lethal effects
- This implies that H19 gene dosage is under strict control in the fetus
- The expression of H19 in tissues where it is normally not expressed (e.g., brain) caused its lethal effects
After 10 weeks gestation and in full term placentae, there is exclusive expression of H19 from the maternal chromosome. In the embryo, maternal expression of H19 is present in endodermal and mesodermal tissues. The regulated expression of H19, from biallelic to monoallelic, throughout embryonic development suggests that regulation is essential for the growth of embryonic and extraembryonic tissues. Immediately after birth, H19 expression is downregulated in all tissues except for skeletal muscle.
Studies by Tanos et al. suggest that the accumulation of H19 RNA in skeletal muscle cells is solely due to the stabilization of that RNA in the muscle cells during differentiation.
In females, H19 is expressed postnatally during puberty and pregnancy in the mammary glands, and in the uterus during pregnancy.
A study by Shoshani et al. suggests that H19 is continued to be expressed in high amounts in the liver after birth, specifically in diploid hepatocytes.
Genomic imprinting is surmised to have arisen due to the conflicting interests of maternal and paternal genes within a pregnancy.
Within a pregnancy, the father wants the mother to devote as much of her resources as possible towards the growth (benefit) of his offspring. However, within the same pregnancy, the mother wants to conserve as much of her resources as possible towards future births without compromising the health of the child(ren) she is currently carrying.
H19 contains a differentially methylated region that is also an imprinting control region. This imprinting control region is differentially methylated at its CpGs according to parental inheritance. Usually, the paternal copy of H19 is methylated and silent while the maternal copy is hypomethylated or unmethylated and expressed in the offspring cell. Methylation of the H19 promoter is negatively correlated with H19 expression.
As methylation of the promoter reaches 100%, H19 expression from that promoter approaches 0. At the same time as H19 expression decreases, the expression of IGF2, a neighboring gene on chromosome 11, increases.
Cells treated with Azad, a demethylating agent, grow much slower than cells cultured in the absence of Azad. At the same time, H19 expression increases while IGF2 expression decreases in the presence of Azad. The reduction of IGF2 expression could be a reason for the slower growth of cells treated with Azad. As well, in a mouse bladder carcinoma cell line, where transfection of a human H19 DNA construct results in high expression of H19, the methylation of the H19 promoter reduces H19 expression. The paternal H19 allele, which is silent postnatally, shows increasing methylation of CpGs in its promoter with gestation time in the fetus. It appears conclusive that the H19 gene is epigenetically controlled via methylation, where methylation on or near the vicinity of one allele prevents the expression of that allele. As well, based on the results from Banet et al., it appears that functional H19 imprinting occurs during early placenta development.
A common characteristic of imprinted genes is asynchronous replication during the DNA synthesis phase of the mitotic cycle. The replication of two alleles of the same gene can differ according to which parent the allele originated from. On the human chromosome 11p15, the methylated paternal H19 allele replicates early in the S phase while the hypomethylated maternal allele replicates later. Studies by Bergstrom et al. have determined that the later-replicating maternal H19 allele is CTCF-bound, and that it is this CTCF binding that determines the time of H19 replication.
As an oncogene
Evidence for the identification of H19 as an oncogene:
- Overexpression of H19 appears to be important in the development of and cells
- Cells expressing H19 are able to form bigger colonies in soft agar in anchorage-independent growth assays as compared to the control.
- Downregulation of H19 in breast and lung cancer cells decreases their clonogenicity and anchorage-dependent growth
- Subcutaneous injection of H19 into mice promoted tumor progression
- Tumors formed by injection of bladder carcinoma cells into mice express H19; prior to the injection, these bladder carcinoma cells did not express H19.
- Ectopic H19 expression in vivo enhances the tumorigenic potential of carcinoma cells
- c-Myc, an oncogene that functions as a regulator of gene transcription, induces H19 expression
- Knocking down H19 in hypoxic stress diminishes p57 induction
Evidence against the identification of H19 as an oncogene:
- The amount of H19 RNA transfected into breast cancer cells did not affect: cell proliferation, cell cycle timing or anchorage-dependent growth
- Tumorigenic mesenchymal stem cells express high levels of H19 compared with non-tumorigenic mesenchymal stem cells. Knock-down of H19 in the tumorigenic cells reduced their tumor forming capacity significantly
As an oncofetal RNA gene
Definition of an oncofetal gene:
- A gene expressed in tumors arising from tissues that express this gene in fetal life
H19, while possessing oncogenic properties, is best defined as an oncofetal RNA gene because:
- The final product of the H19 gene is RNA
- H19 is highly expressed prenatally and downregulated postnatally
- Postnatally, H19 is expressed at high levels in cancer cells
Role in cancer
Increased H19 expression is found in the following cancers: adrenocortical neoplasms, choriocarcinomas, hepatocellular carcinomas, bladder cancers, ovarian serous epithelial cancers, head and neck carcinomas, endometrial cancer, breast cancer, acute T cell leukemia/lymphoma, Wilms' tumor, testicular germ cell cancer, esophageal cancer and lung cancer.
Cellular DNA integrity is often compromised in cancer. Genome instability can refer to the accumulation of extra copies of DNA/chromosomes, chromosomal translocations, chromosomal inversion, chromosome deletions, single stranded breaks in DNA, double stranded breaks in DNA, the intercalation of foreign substances into the DNA double helix, or any abnormal changes in DNA tertiary structure that can cause either the loss of DNA, or the misexpression of genes. It appears that H19 expression is tightly linked to the ploidy of the cell. Diploid liver cells express high levels of H19, whereas the polyploid cell fraction do not express H19. Also, diploid mesenchymal stem cells express high levels of H19 compared to polyploid mesenchymal stem cells. Knock-down of H19 lead to increased polyploidization of mesenchymal stem cells, and induced polyploidy resulted in reduced expression of H19, providing a direct link between H19 expression and the amount of DNA within the cell.
In contrast to most other cancers, adrenocortical neoplasms appear to have decreased expression of H19. To determine a possible cause for the downregulation of H19, Gao et al. studied the methylation of 12 CpG sites in the H19 promoter in normal, hyperplasia, adenoma and carcinoma adrenals. They found that in carcinomas, there was more methylation of CpGs than in normal, hyperplasia and adenoma adrenals. Consequently, normal H19 expression was detectable in normal and hyperplasia adrenals, but in carcinomas and surprisingly, adenomas, there was a lower H19 expression that was coupled with detectable (increased) IGF2 expression.
The presence of IGF2 RNA expression when H19 RNA was downregulated provides further evidence that IGF2 expression is tightly coupled to and dependent on the absence of H19 expression. As well, the loss of H19 in adrenal cancers may be indicative of tumor suppressor activity by H19, leading Gao et al. to suggest that the loss of H19 and subsequent gain of IGF2 may be involved in adrenal cancer induction. Although Gao et al. found that there was not one CpG methylation site that was more important than the others in downregulating H19 expression, they did find that the increase in CpG methylation in adrenal carcinomas followed the pattern of methylation of the normal, hyperplasia and adenoma adrenals. The mean percent methylation of H19 CpGs peaked at sites 9 and 10 in normal, hyperplasia, adenoma and carcinoma adrenals and the lowest mean percent methylation of H19 CpGs dipped at site 7 in normal, hyperplasia, adenoma and carcinoma adrenals.
It is interesting to note that the mean percent methylation of H19 CpGs at sites 13 and 14, after the transcription start site, is insignificant between normal, hyperplasia, adenoma and carcinoma adrenals. This is because methylation of CpGs after the transcription start site is assumed to interfere with RNA polymerase II during transcription. Another point of interest is the significant difference in CpG methylation at site 11 between normal and hyperplasia adrenals. The mean percent CpG methylation at site 11 for hyperplasia and adenoma adrenals is significantly different from that of normal adrenals and carcinoma adrenals, leading Gao et al. to suggest that site 11 is the initial methylated CpG that eventually leads to widespread methylation of the H19 promoter.
Choriocarcinomas, in contrast to adrenal carcinomas, have upregulated H19 and downregulated IGF2 expression. The upregulated H19 expression, however, came from alleles that were fully methylated. Surgically removed choriocarcinomas from human patients also exhibited a heavily methylated H19 promoter with enhanced H19 expression. This led researchers Arima et al. to suggest that in cases of choriocarcinomas, the H19 promoter was mutated, allowing it to overcome the transcriptional repression of promoter CpG methylation.
In hepatocellular carcinoma, the expression of H19 and IGF2 usually changes from monoallelic to biallelic. In in vitro studies, culturing hepatocellular carcinoma cell lines in hypoxic condition upregulated H19 expression. Whether or not the loss of imprinting for the H19 promoter is a characteristic of hepatocellular carcinoma is not known, as some cell lines exhibit loss of imprinting while others did not.
Bladder mucosa is one of the tissues that express high levels of H19 RNA prenatally. In bladder cancers, H19 is also upregulated and present in most stages. The presence of H19 RNA was strongest in bladder carcinomas (sampled in situ) that tend to progress rapidly to invasive cancer as well as invasive transitional cell carcinomas.
In samples of bladder carcinoma, loss of imprinting at the H19 loci were observed. Verhaugh et al. investigated various polymorphisms in the H19 gene and found that some heterozygous SNP polymorphisms, such as rs2839698 TC, were associated with a decreased risk of developing non-muscle invasive bladder cancer as well as bladder cancer overall; however, this association disappeared for homozygotes (CC).
In normal endometrial tissue, there is no H19 expression; however, in endometrial cancer, H19 is expressed. The expression level of H19 RNA in the epithelial cells of the endometrium increases as tissue differentiation is lost in endometrial cancer.
Normal breast tissue does not express H19 RNA, except during puberty and pregnancy in the mammary glands.
However, in breast cancer, 72.5% of the breast adenocarcinomas studied by Adriaenssens et al. displayed increased H19 expression when compared to normal breast tissue. Of the tissues with upregulated H19, 92.2% are stromal cells and only 2.9% are epithelial cells. Studies by Berteaux et al. have also found that the overexpression of H19 in breast cancer cells promotes proliferation. The expression of H19 in these cells is also independent of the tumor suppressor protein p53 and the cell cycle marker Ki-67. However, the presence of tumor suppressor protein pRb and transcription factor E2F6 is sufficient to repress H19 expression in breast cancer cells.
In experiments conducted by Doyle et al., it was found that MCF-7, a breast adenomacarcinoma cell line, did not express the H19 gene; however a subline of MCF-7 with a multidrug resistance phenotype, MCF-7/AdrVp, had upregulation of H19. Curiously, mutant revertant MCF-7/AdrVp cells that lost their multidrug resistance and became drug-sensitive also lost H19 expression. Drug-resistant MCF-AdrVp cells do not overexpress P-glycoprotein, a cell membrane efflux pump commonly found in multidrug resistant cells; instead, they overexpress a 95kD membrane glycoprotein p95. p95, or NCA-90, is related to carcinoembryonic antigens, which have been found to reduce drug toxicity by Kawaharata et al.
NCI-H1688, a human lung carcinoma cell line that displays multidrug resistance, also overexpress p95 (NCA-90) and H19. No other cell lines with the multidrug resistance phenotype have been found to overexpress p95 (NCA-90) in conjunction with H19.
H19 is overexpressed in laryngeal squamous cell carcinomas that relapse as compared to those that do not relapse. In a pilot study aimed at the development of a prognostic classifier for this cancer H19 was the strongest predictor of relapse. It was overexpressed in cancers that later developed local or distant recurrence. Interestingly, its expression did not correlate with the expression of IGF2 and H19 overexpression is unlikely to be a simple consequence of loss of imprinting of the locus containing H19 and IGF2 
Participation in signaling pathways
The exact role of H19 RNA within the cell is currently not known. There are various known substances and conditions that are known to activate H19 transcription and there are various known effects of H19 RNA on cell cycle activity/status, although precisely how H19 RNA exerts these effects is still unknown.
Upstream effectors – hormonal regulation
A previous study conducted by Adriaenssens et al. on H19 correlated an overexpression of H19 with the presence of steroid receptors.
Further studies found that 17-β-estradiol, the dominant form of estrogen, and corticosterone were able to individually stimulate H19 transcription in the uterus, while the presence of progesterone inhibited this effect. Tamoxifen is a competitive binder of the estrogen receptor and is often used in chemotherapy treatment of breast cancer. While 17-β-estradiol alone stimulated H19 transcription in MCF-7 cells, the addition of tamoxifen inhibited H19 transcription, demonstrating that there is a putative role of hormones in H19 transcription.
Downstream effects – angiogenesis, metabolism, tissue invasion and migration
When a cancer bladder cell line, T24P, which does not express H19 was transfected with a DNA construct expressing the H19 gene under the control of the cytomegalovirus promoter, many changes were seen in the resulting cells when compared to both the original T24P cell line and a H19-antisense DNA construct transfected T24P cell line. While there was no difference in proliferation in 10% FCS (normal condition) between the 3 cell lines, when grown in 0.1% FCS (starved serum), the H19-transfected cells maintained their rate of growth while both the control and the antisense H19 transfected cells decreased their rate of proliferation by approximately 50%.
When p57 induction in 0.1% FCS media was measured in the 3 cell lines, both the control and antisense H19 transfected cells had significantly upregulated p57; however, the H19-transfected cells showed a significant downregulation of p57 in 0.1% FCS as compared to 10% FCS. In addition, while the expression of PCNA, required for progression of the cell cycle beyond the S phase, was significantly downregulated in all 3 cell lines, the reduction was approximately 80%-90% in the control and antisense H19 transfected cells and only 30% in the H19 transfected cells.
An examination of the differences in gene expressed between the H19 transfected cells and the antisense H19 transfected cells showed that the following genes were upregulated: uPar, c-src kinase, tyrosine kinase 2 mitogen-activated protein kinase kinase, tyrosine kinase 2, c-jun, JNK1, Janus kinase 1, TNF-a, interleukin-6, heparin-binding growth factor-like growth factor, intracellular adhesion molecule 1, NF-κB, ephrin A4 and ezrin. It is also suggested that angiogenin and FGF18 may be potential transcriptional targets of the H19 RNA. As a result of the functions and signaling pathways that H19 RNA-upregulated genes are involved in, it has been suggested that H19 RNA plays crucial roles in tissue invasion, migration and angiogenesis in tumorigenesis.
Lottin et al. also found that the overexpression of H19 positively regulates post-transcriptionally thioredoxin. Thioredoxin is a protein crucial to the reduction-oxidation reactions involved in metabolism within a cell, and is often found at high levels in cancerous tissues that also overexpress H19 RNA.
H19 and IGF2 expression are closely linked, as they are expressed in the same tissues during fetal development, albeit from differing parental alleles.
The hypermethylation of the H19 promoter on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2. In DNMT-null mice, the paternal allele of IGF2 is also silenced as the paternal H19 promoter is no longer methylated and repressed. A reason for the close coupling of H19 and IGF2 expression may be that they share the same 3’ gene enhancer. When this 3’ enhancer was deleted, researchers Leighton et al. found decreased H19 and IGF2 RNA expressions in the gut, liver and kidney; however, the methylation status of these genes were not affected by the deleted enhancer. Suggestions for why H19 is preferentially activated by the 3’ enhancer instead of IGF2 are that H19 has a stronger promoter than IGF2 and that the H19 gene is physically closer to the 3’ enhancers than the IGF2 gene.
It is of interest to note that mice inheriting a deleted maternal H19 and a deleted paternal IGF2 gene were indistinguishable from wildtype mice in birth weight and postnatal growth. Mice inheriting only a deleted maternal H19 gene, however, displayed somatic overgrowth while mice inheriting only a deleted paternal IGF2 gene displayed somatic undergrowth when compared to wildtype mice. This indicates that the loss of H19 is not lethal, H19 expression governs IGF2 repression, and the overexpression of IGF2 is responsible for the overgrowth phenotype observed in the maternal inheritance of a deleted H19 gene.
While the functions of the H19 RNA in the cell are still unclear, its presence in the many types of carcinoma cells suggest that it can be used as a tumor marker for initial diagnosis, cancer recurrence and malignant potential.
The activation of the H19 promoter in cancerous cells (and its silence in normal tissues) has led to the suggestion of using the H19 promoter in gene therapy to drive the expression of cytotoxic genes in tumorigenic cells. Gene therapy trials utilizing the H19 promoter to drive the expression of cytotoxic genes are currently being tested on mice.
A plasmid composed of the H19 gene regulatory sequences that drive the expression of the 'A' strand of Diphtheria Toxin (DT-A), is undergoing clinical testing as a treatment for superficial bladder cancer, ovarian cancer and pancreatic cancer. The plasmid, designated BC-819 (or DTA-H19), embodies a targeted therapy approach, in that the plasmid enters all dividing cells, but the DT-A expression is triggered by the presence of H19 transcription factors found only in tumor cells, thus destroying the tumor without affecting normal cells.
In a double-center, dose escalation Phase I/IIa clinical trial of BC-819 as a treatment for superficial bladder cancer, no severe adverse events related to the plasmid were detected, and tumor responses were observed in more than 70% of patients, including those with a still not-optimized therapeutic dose and regimen.
BC-819 was previously tested in human compassionate use for the treatment of superficial bladder cancer, ovarian cancer and metastatic liver cancer. The bladder cancer patient, who was a candidate for radical cystectomy when he was treated in 2004, reported no cancer recurrence and no side effects. The ovarian cancer patient experienced a 50% decline in the amount of the ovarian cancer marker protein CA-125 in her blood as well as a significant decrease in the number of cancerous cells in her ascitic fluid. The patient suffering from metastatic liver cancer was treated with direct injection of BC-819 into the tumor, with considerable tumor necrosis observed.
While the expression profile of H19 in most cancer types is known, the role of H19 RNA in influencing cancer cell response to drug treatment is still unknown. However, recent studies have discovered the expression of thioredoxin and p95 (NCA-90) in cancer cells when H19 RNA is present in high quantities. This knowledge can lead to a more personalized cancer treatment plan; for example, the expression of p95 in a H19-overexpressing cancer cell may indicate higher tolerance of drug toxicity, so cancer treatment for an individual with high levels of H19 (and p95) may focus more on radiotherapy or immunotherapy instead of chemotherapy.
It is not currently known if H19 expression can be used to induce an anti-cancer response in immune cells.
- "Human PubMed Reference:".
- Gabory; et al. (2009). "H19 acts as a trans regulator of the imprinted gene network controlling growth in mice". Development.
- "H19: imprinted maternally expressed transcript (non-protein coding) (Homo sapiens)". Entrez Gene. National Center for Biotechnology Information. Retrieved 2008-06-06.
- Zhang Y, Tycko B (April 1992). "Monoallelic expression of the human H19 gene". Nat. Genet. 1 (1): 40–4. doi:10.1038/ng0492-40. PMID 1363808.
- Rachmilewitz J, Goshen R, Ariel I, Schneider T, de Groot N, Hochberg A (August 1992). "Parental imprinting of the human H19 gene". FEBS Lett. 309 (1): 25–8. doi:10.1016/0014-5793(92)80731-U. PMID 1380925.
- Leibovitch MP, Nguyen VC, Gross MS, Solhonne B, Leibovitch SA, Bernheim A (November 1991). "The human ASM (adult skeletal muscle) gene: expression and chromosomal assignment to 11p15". Biochem. Biophys. Res. Commun. 180 (3): 1241–50. doi:10.1016/S0006-291X(05)81329-4. PMID 1953776.
- Online 'Mendelian Inheritance in Man' (OMIM) H19 Gene -103280
- Jinno Y, Ikeda Y, Yun K, Maw M, Masuzaki H, Fukuda H, Inuzuka K, Fujishita A, Ohtani Y, Okimoto T, Ishimaru T, Niikawa N (July 1995). "Establishment of functional imprinting of the H19 gene in human developing placentae". Nat. Genet. 10 (3): 318–24. doi:10.1038/ng0795-318. PMID 7670470.
- Kopf E, Bibi O, Ayesh S, et al. (August 1998). "The effect of retinoic acid on the activation of the human H19 promoter by a 3' downstream region". FEBS Lett. 432 (3): 123–7. doi:10.1016/S0014-5793(98)00841-2. PMID 9720909.
- Takeuchi S, Hofmann WK, Tsukasaki K, et al. (May 2007). "Loss of H19 imprinting in adult T-cell leukaemia/lymphoma". Br. J. Haematol. 137 (4): 380–1. doi:10.1111/j.1365-2141.2007.06581.x. PMID 17408396.
- Berteaux N, Lottin S, Monté D, Pinte S, Quatannens B, Coll J, Hondermarck H, Curgy JJ, Dugimont T, Adriaenssens E (August 2005). "H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1". J. Biol. Chem. 280 (33): 29625–36. doi:10.1074/jbc.M504033200. PMID 15985428.
- Brunkow ME, Tilghman SM (June 1991). "Ectopic expression of the H19 gene in mice causes prenatal lethality". Genes Dev. 5 (6): 1092–101. doi:10.1101/gad.5.6.1092. PMID 2044956.
- Brannan CI, Dees EC, Ingram RS, Tilghman SM (January 1990). "The product of the H19 gene may function as an RNA". Mol. Cell. Biol. 10 (1): 28–36. PMC . PMID 1688465.
- Bergström R, Whitehead J, Kurukuti S, Ohlsson R (February 2007). "CTCF regulates asynchronous replication of the imprinted H19/Igf2 domain". Cell Cycle. 6 (4): 450–4. doi:10.4161/cc.6.4.3854. PMID 17329968.
- Szymanski M, Erdmann VA, Barciszewski J. "Eurekah - Riboregulators: An Overview". Bioscience Chapter Database. Landes Bioscience. Retrieved 2008-06-06.
- Leighton PA, Saam JR, Ingram RS, Stewart CL, Tilghman SM (September 1995). "An enhancer deletion affects both H19 and Igf2 expression". Genes Dev. 9 (17): 2079–89. doi:10.1101/gad.9.17.2079. PMID 7544754.
- Arima T, Matsuda T, Takagi N, Wake N (January 1997). "Association of IGF2 and H19 imprinting with choriocarcinoma development". Cancer Genet. Cytogenet. 93 (1): 39–47. doi:10.1016/S0165-4608(96)00221-X. PMID 9062579.
- Banet G, Bibi O, Matouk I, et al. (September 2000). "Characterization of human and mouse H19 regulatory sequences". Mol. Biol. Rep. 27 (3): 157–65. doi:10.1023/A:1007139713781. PMID 11254105.
- Tanos V, Ariel I, Prus D, De-Groot N, Hochberg A (2004). "H19 and IGF2 gene expression in human normal, hyperplastic, and malignant endometrium". Int. J. Gynecol. Cancer. 14 (3): 521–5. doi:10.1111/j.1048-891x.2004.014314.x. PMID 15228427.
- Adriaenssens E, Lottin S, Dugimont T, Fauquette W, Coll J, Dupouy JP, Boilly B, Curgy JJ (August 1999). "Steroid hormones modulate H19 gene expression in both mammary gland and uterus". Oncogene. 18 (31): 4460–73. doi:10.1038/sj.onc.1202819. PMID 10442637.
- Shoshani O, Massalha H, Shani N, Kagan S, Ravid O, Madar S, Trakhtenbrot L, Leshkowitz D, Rechavi G, Zipori D (December 2012). "Polyploidization of murine mesenchymal cells is associated with suppression of the long noncoding RNA H19 and reduced tumorigenicity". Cancer Research. 72 (24): 6403–13. doi:10.1158/0008-5472.CAN-12-1155. PMID 23047867.
- Moore T, Haig D (February 1991). "Genomic imprinting in mammalian development: a parental tug-of-war". Trends Genet. 7 (2): 45–9. doi:10.1016/0168-9525(91)90230-N. PMID 2035190.
- Gao ZH, Suppola S, Liu J, Heikkilä P, Jänne J, Voutilainen R (March 2002). "Association of H19 promoter methylation with the expression of H19 and IGF-II genes in adrenocortical tumors". J. Clin. Endocrinol. Metab. 87 (3): 1170–6. doi:10.1210/jc.87.3.1170. PMID 11889182.
- Hibi K, Nakamura H, Hirai A, Fujikake Y, Kasai Y, Akiyama S, Ito K, Takagi H (February 1996). "Loss of H19 imprinting in esophageal cancer". Cancer Res. 56 (3): 480–2. PMID 8564957.
- Lottin S, Adriaenssens E, Dupressoir T, Berteaux N, Montpellier C, Coll J, Dugimont T, Curgy JJ (November 2002). "Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells". Carcinogenesis. 23 (11): 1885–95. doi:10.1093/carcin/23.11.1885. PMID 12419837.
- Barsyte-Lovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL, Tsao MS, Penn LZ (May 2006). "The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis". Cancer Res. 66 (10): 5330–7. doi:10.1158/0008-5472.CAN-06-0037. PMID 16707459.
- Elkin M, Shevelev A, Schulze E, Tykocinsky M, Cooper M, Ariel I, Pode D, Kopf E, de Groot N, Hochberg A (October 1995). "The expression of the imprinted H19 and IGF-2 genes in human bladder carcinoma". FEBS Lett. 374 (1): 57–61. doi:10.1016/0014-5793(95)01074-O. PMID 7589512.
- Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E (2007). Wölfl S, ed. "The H19 non-coding RNA is essential for human tumor growth". PLoS ONE. 2 (9): e845. doi:10.1371/journal.pone.0000845. PMC . PMID 17786216.
- Ariel I, Ayesh S, Perlman EJ, Pizov G, Tanos V, Schneider T, Erdmann VA, Podeh D, Komitowski D, Quasem AS, de Groot N, Hochberg A (February 1997). "The product of the imprinted H19 gene is an oncofetal RNA". MP, Mol. Pathol. 50 (1): 34–44. doi:10.1136/mp.50.1.34. PMC . PMID 9208812.
- Tanos V, Prus D, Ayesh S, Weinstein D, Tykocinski ML, De-Groot N, Hochberg A, Ariel I (July 1999). "Expression of the imprinted H19 oncofetal RNA in epithelial ovarian cancer". Eur. J. Obstet. Gynecol. Reprod. Biol. 85 (1): 7–11. doi:10.1016/S0301-2115(98)00275-9. PMID 10428315.
- el-Naggar AK, Lai S, Tucker SA, Clayman GL, Goepfert H, Hong WK, Huff V (November 1999). "Frequent loss of imprinting at the IGF2 and H19 genes in head and neck squamous carcinoma". Oncogene. 18 (50): 7063–9. doi:10.1038/sj.onc.1203192. PMID 10597307.
- Doyle LA, Yang W, Rishi AK, Gao Y, Ross DD (July 1996). "H19 gene overexpression in atypical multidrug-resistant cells associated with expression of a 95-kilodalton membrane glycoprotein". Cancer Res. 56 (13): 2904–7. PMID 8674037.
- Ariel I, de Groot N, Hochberg A (March 2000). "Imprinted H19 gene expression in embryogenesis and human cancer: the oncofetal connection". Am. J. Med. Genet. 91 (1): 46–50. doi:10.1002/(SICI)1096-8628(20000306)91:1<46::AID-AJMG8>3.0.CO;2-I. PMID 10751088.
- Ariel I, Lustig O, Schneider T, Pizov G, Sappir M, De-Groot N, Hochberg A (February 1995). "The imprinted H19 gene as a tumor marker in bladder carcinoma". Urology. 45 (2): 335–8. doi:10.1016/0090-4295(95)80030-1. PMID 7855987.
- Verhaegh GW, Verkleij L, Vermeulen SH, den Heijer M, Witjes JA, Kiemeney LA (February 2008). "Polymorphisms in the H19 Gene and the Risk of Bladder Cancer". Eur. Urol. 54 (5): 1118–26. doi:10.1016/j.eururo.2008.01.060. PMID 18262338.
- Adriaenssens E, Dumont L, Lottin S, Bolle D, Leprêtre A, Delobelle A, Bouali F, Dugimont T, Coll J, Curgy JJ (November 1998). "H19 overexpression in breast adenocarcinoma stromal cells is associated with tumor values and steroid receptor status but independent of p53 and Ki-67 expression". Am. J. Pathol. 153 (5): 1597–607. doi:10.1016/S0002-9440(10)65748-3. PMC . PMID 9811352.
- "Breast Cell Line MCF-7". Cancer Biology - Breast Cancer Cell Line Database. University of Texas M. D. Anderson Cancer Center. Retrieved 2008-06-06.
- Ross DD, Gao Y, Yang W, Leszyk J, Shively J, Doyle LA (December 1997). "The 95-kilodalton membrane glycoprotein overexpressed in novel multidrug-resistant breast cancer cells is NCA, the nonspecific cross-reacting antigen of carcinoembryonic antigen". Cancer Res. 57 (24): 5460–4. PMID 9407950.
- Kawaharata H, Hinoda Y, Itoh F, Endo T, Oikawa S, Nakazato H, Imai K (July 1997). "Decreased sensitivity of carcinoembryonic antigen cDNA-transfected cells to adriamycin". Int. J. Cancer. 72 (2): 377–82. doi:10.1002/(SICI)1097-0215(19970717)72:2<377::AID-IJC29>3.0.CO;2-B. PMID 9219849.
- Mirisola V, Mora R, Esposito AI, Guastini L, Tabacchiera F, Paleari L, Amaro A, Angelini G, Dellepiane M, Pfeffer U, Salami A (August 2011). "A prognostic multigene classifier for squamous cell carcinomas of the larynx". Cancer Letters. 307 (1): 37–46. doi:10.1016/j.canlet.2011.03.013. PMID 21481529.
- Ayesh S, Matouk I, Schneider T, Ohana P, Laster M, Al-Sharef W, De-Groot N, Hochberg A (October 2002). "Possible physiological role of H19 RNA". Mol. Carcinog. 35 (2): 63–74. doi:10.1002/mc.10075. PMID 12325036.
- Lottin S, Vercoutter-Edouart AS, Adriaenssens E, Czeszak X, Lemoine J, Roudbaraki M, Coll J, Hondermarck H, Dugimont T, Curgy JJ (February 2002). "Thioredoxin post-transcriptional regulation by H19 provides a new function to mRNA-like non-coding RNA". Oncogene. 21 (10): 1625–31. doi:10.1038/sj.onc.1205233. PMID 11896592.
- Kim KS, Lee YI (November 1997). "Biallelic expression of the H19 and IGF2 genes in hepatocellular carcinoma". Cancer Lett. 119 (2): 143–8. doi:10.1016/S0304-3835(97)00264-4. PMID 9570364.
- Leighton PA, Ingram RS, Eggenschwiler J, Efstratiadis A, Tilghman SM (May 1995). "Disruption of imprinting caused by deletion of the H19 gene region in mice". Nature. 375 (6526): 34–9. doi:10.1038/375034a0. PMID 7536897.
- Ariel I, Sughayer M, Fellig Y, Pizov G, Ayesh S, Podeh D, Libdeh BA, Levy C, Birman T, Tykocinski ML, de Groot N, Hochberg A (December 2000). "The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma". MP, Mol. Pathol. 53 (6): 320–3. doi:10.1136/mp.53.6.320. PMC . PMID 11193051.
- "Phase 2b, Trial of Intravesical DTA-H19/PEI in Patients With Intermediate-Risk Superficial Bladder Cancer". ClinicalTrials.gov. U.S. National Institutes of Health. 2009-08-31. Retrieved 2010-01-14.
- "Phase 1/2a Study of DTA-H19 in Advanced Stage Ovarian Cancer With Symptomatic Ascites". ClinicalTrials.gov. U.S. National Institutes of Health. 2009-12-03. Retrieved 2010-01-14.
- "Phase 1/2a DTA-H19 in Patients With Unresentable Pancreatic Cancer". ClinicalTrials.gov. U.S. National Institutes of Health. 2009-11-09. Retrieved 2010-01-14.
- Sidi AA, Ohana P, Benjamin S, Shalev M, Ransom JH, Lamm D, Hochberg A, Leibovitch I (December 2008). "Phase I/II Marker Lesion Study of Intravesical BC-819 DNA Plasmid in H19 Over Expressing Superficial Bladder Cancer Refractory to Bacillus Calmette-Guerin". The Journal of Urology. 180 (6): 2379–2383. doi:10.1016/j.juro.2008.08.006. ISSN 0022-5347. PMID 18950807.