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PubMed2004

Role of occludin, a tight junction protein, in blastocoel formation, and in the paracellular permeability and differentiation of trophectoderm in preimplantation mouse embryos.

Tight junctions (TJ) are critical for blastocoel formation in mammalian embryos. The present study aimed to examine the role of tight junctions in the differentiation of the trophectoderm (TE), and in the pluripotency of blastomeres, as well as in the formation and integrity of the blastocoel. We examined the effect of occludin antibody on blastocoel formation, blastocyst permeability, and expression of H19 and Oct-4, markers of TE differentiation and blastomere pluripotency, respectively. Eight-cell mouse embryos and morulae were cultured in the presence or absence of occludin antibody for 31 h. Occludin antibody inhibited blastocoel formation and increased permeability of the TE of nascent and expanding blastocysts to FITC-dextran (4 kDa), a permeability tracer. At the same time Oct-4 expression increased while expression of H19 became barely detectable. These observations indicate that occludin is involved in establishing the blastocoel, as well as in maintaining its impermeability, and that the development of tight junction is critical for TE formation in mouse embryos.

Animals↗
PubMed2004

Effect of all-trans retinoic acid on telomerase activity in ovarian cancer cells.

Vitamin A is an essential nutrient important for growth, vision, embryonic development, immune response and reproduction. Various retinoids have been shown to be effective chemotherapeutic and chemopreventive agents for a number of human cancers. Telomeres are nucleoprotein structures found at the end of chromosomes. During cellular division, the telomeres in normal cells shorten progressively and thus, function as a "molecular clock". Telomerase is a ribonucleoprotein complex that extends and maintains telomeres. Activation of telomerase is required for cells to overcome proliferative crisis. Telomerase activation is observed in 90% of human cancers, but not in normal somatic cells. We examined the role of telomerase in mediating the growth suppression of ovarian carcinoma cells by all-trans-retinoic acid (ATRA). Using a number of cell lines with varying levels of growth sensitivity to ATRA, we found that cells that exhibit ATRA-dependant suppression of growth also contained significantly reduced telomerase activity. We also observed a reduction in expression of the telomerase components, hTERT and hTR in ATRA treated ovarian carcinoma cells. Our results suggest that one mechanism by which ATRA acid inhibits cancer cell growth is by suppressing telomerase activity, thereby pushing cells to proliferative crisis.

Antineoplastic Agents↗
PubMed2004

Allele-specific methylation analysis on upstream promoter region of H19 by methylation-specific PCR with confronting two-pair primers.

H19 and IGF2 genes are imprinted genes and expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin; H19 is expressed only from the maternal allele and IGF2 only from the paternally inherited allele. The upstream promoter region of H19 has the imprinting-control region (ICR) or CTCF binding sites, where the methylation status of this region is critical to the regulation of imprinting of the H19/IGF2 locus located in chromosome 11p15. There are various reports on imprinting disorders in this region. In colorectal cancer aberrant biallelic methylation of CTCF binding site has been reported, and aberrant hypomethylation of this region in bladder cancer. Thus, certain human neoplasms have either hyper- or hypo-methylation in the ICR. Hence it is still difficult to analyze allele-specific methylation disorder of the region, or differentially methylated regions (DMR), locate upstream of H19. Here we report a new method, which could distinguish paternal epigenetic or maternal epigenetic pattern by a single PCR assay, to combine methylation-specific PCR and PCR with confronting two-pair primers (MSP-CTPP). Using this method, we investigated the region close to H19 ICR in 161 colorectal cancer and 65 gastric cancer cases.

Aged↗
PubMed2004

Genomic imprinting in mammals.

In contrast to the biallelic expression of most genes, expression of imprinted genes is monoallelic and depends on the sex of the transmitting parents. In humans it has been implicated in some developmental failures, neurodevelopmental and neurobehavioral disorders (such as Prader-Willi/Angelman, Silver-Russel or Beckwith-Wiedemann syndromes). The aim of this review is to present the phenomenon of parental imprinting as well as its molecular mechanism in various mammals. Several maternal and paternal imprinted genes and gene clusters are described.

Animals↗
PubMed2004

Loss of IGF2 imprinting: mechanisms and consequences.

Although the leading dogma for the origin of the diversity in cancer cell subpopulations is based on a stepwise selection and accumulation of genetic changes that allow uncontrollable malignant growth, there is an emerging understanding that the variability of heritable phenotypes in cancer and cancer-prone cells may also involve epigenetic mechanisms. This is exemplified by the unscheduled activation of the normally repressed maternal IGF2 allele in a wide range of human cancers. The notion that this so-called loss of imprinting (LOI) provides a proliferative advantage by increasing the levels of the IGF-2 ligand available to its receptors is supported by the overgrowth symptoms of neonatal mice, which has been genetically manipulated to express Igf2 biallelically. Although the mechanisms underlying IGF2 LOI in human cancer remains unknown, it is likely to directly or indirectly involve the H19 imprinting control region (ICR). This stretch of 2 kb sequence just upstream of the H19 promoter functions to block enhancer-Igf2 promoter communications by means of a DNA methylation-sensitive chromatin insulator. We discuss here the possibility that pathological mechanisms leading to IGF2 LOI use different strategies with the neutralization of the H19 ICR insulator function as a common denominator.

Animals↗
PubMed2005

Down-regulation of the IGF-2/H19 locus during normal and malignant hematopoiesis is independent of the imprinting pattern.

H19 and IGF-2 are two growth regulatory genes located on chromosome 11p15 implicated in tumorigenesis. Both genes are imprinted and regulated reciprocally under many circumstances. In order to elucidate the contribution of H19 and IGF-2 to leukemogenesis, the mRNA expression level of both genes were quantitated in bone marrow biopsies and peripheral blood samples from normal (n=98), chronic myelomonocytic leukemia (CMML, n=43), chronic myelogenous leukemia (CML, n=40) and, acute myelogenous leukemia (AML, n=32) cases. A concomitant reduction of H19 and IGF-2 expression was observed in all leukemic samples compared to the healthy controls. This down-regulation was not accompanied by changes in methylation of the differentially methylated region (DMR). Whereas the H19 gene showed strict monoallelic expression in all informative normal (n=31) and leukemic (n=54) samples, the imprinting pattern of the IGF2 gene was found to be heterogeneous. No correlations between imprinting status (mono- versus biallelic expression), quantitative mRNA expression levels and course of disease were found for the IGF-2 gene. The data suggest a disturbed regulation of the IGF-2/H19 locus in myeloid leukemias which is not caused by loss of imprinting.

Alleles↗
PubMedDate not supplied

Imbalance in expression levels of insulin-like growth factor 2 and H19 transcripts linked to progression of hepatocellular carcinoma.

BACKGROUND: The imprinted genes insulin-like growth factor 2 (IGF2) and H19 play important roles in various malignancies including hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We used DNA microarray and patient follow-up data to examine the relationship between expression of IGF2 and H19 and HCC. RESULTS: We found that imbalances in levels of IGF2 and H19 transcripts were correlated with advanced tumor stage and poor outcome in HCC patients. CONCLUSION: In addition to their known epigenetic or genetic abnormality in malignancies, these findings suggest that altered transcription of these two imprinted genes contributes to progression of HCC.

Aged↗
PubMed2006

Expression of human telomerase reverse transcriptase, Survivin, DD3 and PCGEM1 messenger RNA in archival prostate carcinoma tissue.

INTRODUCTION: The wide spectrum of biological behavior displayed by prostate cancer (PCa) warrants investigation of potential PCa-specific biomarkers that could identify more aggressive tumor types and therefore provide prognostic value. Upregulation of expression of human telomerase reverse transcriptase (hTERT), Survivin, DD3 and PCGEM1 mRNAs in PCa lesions has recently been described. The purpose of this study was to evaluate the clinical value of detection of over-expression of these biomarkers in the diagnosis and prognosis of PCa. MATERIAL AND METHODS: Archival formalin-fixed, paraffin-embedded (FFPE) prostatectomy tissue from 26 patients with PCa (Gleason score 3-9, mean 7) and 14 patients with benign prostatic hyperplasia (BPH) were analyzed by reverse transcription polymerase chain reaction (RT-PCR) for semiquantitative transcript levels of hTERT, Survivin, DD3 and PCGEM1. In addition, 25 matched normal (MN) tissue samples were examined. The expression of biomarker mRNA relative to b2-microglobulin mRNA was determined using AlphaImager 2200 data analysis software. RESULTS: The biomarkers had sensitivities ranging from 91% to 100%. Clinical specificities evaluated with the BPH tissue were the following: hTERT mRNA (93%), DD3 mRNA (57%), Survivin (29%) and PCGEM1 (14%). Biomarker expressions were up to 13.5-fold higher in PCa tissue as compared to MN tissue. None of the tumor biomarkers showed a positive correlation with pathological stage and Gleason score. CONCLUSIONS: The results of this study indicate potential utility of the hTERT mRNA and DD3 mRNA as diagnostic but not prognostic biomarkers for PCa.

Antigens, Neoplasm↗
PubMed1995

H19 expression and tumorigenicity of choriocarcinoma derived cell lines.

Certain embryonal tumors demonstrate a loss of heterozygosity at the parentally imprinted region of chromosome 11p15.5. It has been hypothesized that this implicates a tumor suppressor gene at this locus. The human H19 gene maps to 11p15.5, is expressed in fetal tissues including the placenta and is paternally imprinted. Here we show that the abundance of H19 transcripts in cells of two choriocarcinoma derived cell lines (JAr and JEG-3) differs greatly. While JAr cells express high levels of H19 RNA, the expression of H19 in JEG-3 cells is much lower than that of normal trophoblasts. Cells of these two cell lines were subcutaneously injected into nude mice with subsequent tumor formation. A fivefold increase in the H19 RNA level was measured in tumors derived from JEG-3 cell lines as compared to these cells before injection. However this increase in H19 RNA did not alter the clonogenicity in soft agar nor the growth rate of the cells derived from these tumors as compared to the original JEG-3 cells. Nevertheless, the cells retaining the elevated level of H19 transcripts were more tumorigenic than the original cells. We propose that there is a selection of cells expressing high levels of H19 from the total JEG-3 cell population during the microevolution of tumor formation. These observations, together with our previous publications on H19 expression in human cancers, do not support the notion of a tumor suppressor role for the H19 gene.

Animals↗
PubMed1995

Maintenance of normal imprinting of H19 and IGF2 genes in neuroblastoma.

H19 and insulin-like growth factor II (IGF2) are among a few genes which have been confirmed to be imprinted in normal human embryonal tissues. This results in monoallelic expression of maternal H19 and paternal IGF2. Loss of imprinting of these genes producing biallelic expression has been observed in Wilm's tumor and embryonal rhabdomyosarcoma, suggesting that an epigenetic change of DNA, in addition to a genetic change in oncogene(s) and/or tumor suppressor gene(s), may be involved in the development of these childhood cancers. Neuroblastoma, which is an embryonal tumor originating from neural crest-derived cells, occasionally occurs in individuals with the Beckwith-Wiedemann syndrome; Wilm's tumor and embryonal rhabdomyosarcoma occur even more frequently in the Beckwith-Wiedemann syndrome; and paternal uniparental disomy of H19 and IGF2 loci (chromosome 11p15) is present in the Beckwith-Wiedemann syndrome. Furthermore, neuroblastoma cell lines express IGF2, and autocrine/paracrine effects of IGF2 have been demonstrated in these cells. Thus, we examined for imprinting of both H19 and IGF2 in primary untreated neuroblastomas using the RsaI and ApaI polymorphisms within these genes, respectively. Seven of 15 tumors were informative for H19 and for IGF2, and all of these cases showed monoallelic expression of both of these genes. These results indicate that loss of imprinting of H19 and IGF2 does not occur in neuroblastomas.

Base Sequence↗
PubMed1993

Transport of BC1 RNA in hypothalamo-neurohypophyseal axons.

Ample evidence indicates that in nerve cells, several individual proteins are locally synthesized in postsynaptic domains in dendrites. By contrast, axonal terminals, at least in mammals, are generally thought to lack protein synthetic capacity. However, axonal nerve endings of the hypothalamo-neurohypophyseal tract have recently been shown to contain mRNAs encoding vasopressin, oxytocin, dynorphin, and neurofilament. In this report, we identify BC1 RNA, a small RNA polymerase III transcript that is specifically expressed in neurons, in hypothalamo-neurohypophyseal axons. BC1 RNA has previously been shown to be located in somatic and dendritic domains of various types of neurons in the rat nervous system. Here we present evidence to show that BC 1 RNA, like several neuropeptide mRNAs, is axonally transported from magnocellular hypothalamic neurons to neurosecretory nerve endings in the posterior pituitary. BC1 RNA, which has been reported to be a component of a ribonucleoprotein particle, is thus colocalized with dendritic mRNAs in dendritic domains and with axonal mRNAs in axonal domains, respectively. Such colocalization is indicative of functional interactions of BC1 RNA with those mRNAs that are targeted to extrasomatic domains of nerve cells.

Animals↗
PubMed1995

Coordinate regulation of Igf-2 and H19 in cultured cells.

The insulin-like growth factor 2 (Igf-2) and H19 genes are physically linked on mouse distal chromosome 7 and are reciprocally imprinted. We investigated the molecular basis of the parental imprints in somatic cell cultures derived from normal embryos or from their littermates with maternal uniparental disomy for distal chromosome 7 (MatDi7). In normal cells, the two genes appeared to respond to similar regulatory factor(s), since both genes were coordinately up-regulated upon growth arrest and cell clones which had lost expression of one gene had lost expression of the other. However, in a clone of MatDi7 cells (MatDi7 1-1a), which spontaneously began to express the maternally derived copy of Igf-2, Igf-2 and H19 were not coordinately regulated. MatDi7 1-1a cells showed de novo methylation of sites upstream of Igf-2 and also within the H19 promoter, epigenetic modifications normally seen only on the paternal chromosome. The data provide new experimental evidence for previously hypothesized mechanisms suggesting that Igf-2 and H19 are coordinately regulated.

Animals↗
PubMed1994

Small marker X chromosomes lack the X inactivation center: implications for karyotype/phenotype correlations.

The abnormal phenotype and/or mental retardation seen in persons with small marker X (mar(X)) chromosomes has been hypothesized to be due to the loss of the X inactivation center (XIC) at Xq13.2, resulting in two active copies of genes in the pericentromeric region. In order to define precisely the DNA content of mar(X) chromosomes and to correlate phenotype with karyotype, we studied small mar(X) chromosomes, using FISH with probes in the juxtacentromeric region. One of the probes was a 40-kb genomic cosmid for the XIST gene, which maps to the smallest interval known to contain the XIC and is thought to be involved in X inactivation. Our findings reveal that small mar(X) chromosomes do not include the XIC and therefore cannot be subject to X inactivation, supporting the premise that abnormal dosage of expressed genes in the pericentromeric region of the X generates the aberrant phenotype seen in patients with small mar(X) chromosomes.

Adult↗
PubMed1994

DNA replication analysis of FMR1, XIST, and factor 8C loci by FISH shows nontranscribed X-linked genes replicate late.

The relationship between the transcriptional state of a locus and the time when it replicates during DNA synthesis is increasingly apparent. Active autosomal genes tend to replicate early, whereas inactive ones are more permissive and frequently replicate later. Although the inactive X chromosome replicates later than its active homologue, little is known about the replication of X-linked genes. We have used FISH to examine the replication of loci on the active X chromosome that are not transcribed, either because the tissue analyzed was not the expressing tissue (F8C), because the locus is silent on all active X chromosomes (XIST), or because it has been mutated by expansion and methylation of a CpG island (FMR1). In this assay, an unreplicated locus is characterized by a single hybridization signal, and a replicated locus is characterized by a doublet hybridization signal. The percentage of doublets is used as a measure of relative time of replication in S phase. The validity of this approach has been established elsewhere, since results compare favorably with those obtained using traditional methods for studying DNA replication. Our results show that the FMR1 gene replicates relatively later in fragile X (fraX) males with the full mutation than in normal males, irrespective of the probe used. The F8C locus is late replicating in both normal and fraX males and replicates at nearly the same time on active and inactive X in females. The XIST locus replicates late in all the males studied and asynchronously in female cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1994

The severe phenotype of females with tiny ring X chromosomes is associated with inability of these chromosomes to undergo X inactivation.

Mental retardation and a constellation of congenital malformations not usually associated with Turner syndrome are seen in some females with a mosaic 45,X/46,X,r(X) karyotype. Studies of these females show that the XIST locus on their tiny ring X chromosomes is either not present or not expressed. As XIST transcription is well correlated with inactivation of the X chromosome in female somatic cells and spermatogonia, nonexpression of the locus even when it is present suggests that these chromosomes are transcriptionally active. We examined the transcriptional activity of ring X chromosomes lacking XIST expression (XISTE-), from three females with severe phenotypes. The two tiny ring X chromosomes studied with an antibody specific for the acetylated isoforms of histone H4 marking transcribed chromatin domains were labeled at a level consistent with their being active. We also examined tow of the XISTE- ring chromosomes to determine whether genes that are normally silent on an inactive X are expressed from these chromosomes. Analyses of hybrid cells show that TIMP, ZXDA, and ZXDB loci on the proximal short arm, and AR and PHKA1 loci on the long arm, are well expressed from the tiny ring X chromosome lacking XIST DNA. Studies of the ring chromosome that has XIST DNA but does not transcribe it show that its AR allele is transcribed along with the one on the normal X allele.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1996

High incidence of loss of heterozygosity and abnormal imprinting of H19 and IGF2 genes in invasive cervical carcinomas. Uncoupling of H19 and IGF2 expression and biallelic hypomethylation of H19.

The few imprinted genes characterized so far include the insulin-like growth factor-2 gene (IGF2) coding for a foetal growth factor and the H19 gene whose normal function is unknown but which is likely to act as an RNA with an antitumour effect. IGF2 is expressed by the paternal allele and H19 by the maternal allele. This reciprocal expression is quite interesting because both H19 and IGF2 genes are located close to each other on chromosome 11p15.5 in a region subject to loss of heterozygosity (LOH). Moreover, loss of imprinting (LOI) or biallelic expression has been proposed as an epigenetic mechanism for tumorigenesis in a variety of human cancers including Wilms' tumour. In this study we report the LOH, LOI and methylation status of H19 and IGF2 genes in 29 invasive cervical carcinomas of different clinical stages. Fourteen (48%) and 13 (45%) tumours were heterozygous for H19 and IGF2 respectively. LOH for H19 and IGF2 genes were found in 2 of 14 (14%) and 3 of 13 (23%) informative tumours, respectively. LOI of H19 and IGF2 was detected in 2 of 12 (17%) and 5 of 10 (50%) tumours with no LOH, respectively. More interestingly, monoallelic expression of the otherwise silent H19 allele (allele switch) was observed in 2 of 12 (17%) tumours and biallelic expression of IGF2 was detected in one specimen of normal cervix adjacent to the tumour. The expressing H19 allele, and to a lower degree also the silent allele, were hypomethylated in tumours suggesting that demethylation of both H19 alleles may be associated with an early step of imprinting alteration. In cervical cancer H19 and IGF2 expressions could be independently regulated. In conclusion, our data suggest that H19 and IGF2 genes, via deletions and/or abnormal imprinting, could play a crucial role in a large proportion (58%) of cervical cancers where they may be associated with disease progression.

Alleles↗