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At least 19 recordsLinked to original sources
PubMed1991

Hepatitis B virus integration in hepatitis B virus-related hepatocellular carcinoma in childhood.

In Taiwan, hepatocellular carcinoma is one of the major malignancies in children between 5 and 14 yr of age. We studied the status of hepatitis B virus DNA in the hepatocellular carcinoma and nontumorous liver tissues of eight children with positive serum HBsAg and maternal HBsAg. The hepatocellular carcinoma tissues from five of the eight children showed integration of hepatitis B virus DNA into host cellular DNA sequences. A pattern of single-site integration in four children and a multiple-site integration pattern in one child were demonstrated. In the remaining three children, hepatitis B virus DNA could not be demonstrated in the tumor tissues. Using subgenomic fragments of the hepatitis B virus genome as probes, we found that the X gene fragment and the surface antigen gene fragment were the most conserved sequences. The single-site integration of hepatitis B virus DNA in childhood hepatocellular carcinoma may have hit the critical region, resulting in insertional mutagenesis and early development of hepatocellular carcinoma. With a short incubation period and less exposure to environmental carcinogens during early life, childhood hepatocellular carcinoma may provide a good model to study the carcinogenic potential of hepatitis B virus.

Adolescent↗
PubMed1991

Chromosome deletions associated with hepatitis B virus integration.

Integrated hepatitis B virus (HBV) DNA is often found in hepatocellular carcinomas which develop in HBV carriers. We previously found that chromosomal abnormalities such as translocations and inversions are often associated with HBV integration. Here we report deletions that were found with three integrants, by comparing the physical maps of the flanking cellular DNA of the integrants with those of the unoccupied cellular sequences. The sizes of the deletions were 25, 12, and 11 kb, respectively. Each integrant carried only a small fragment of the viral genome, from which the cohesive end region, the preferred site of integration, was deleted. We speculate that these deletions were made from primary integrants by recombination of regions between the viral DNA and the flanking cellular sequence.

Base Sequence↗
PubMed1992

Clonal growth of hepatitis B virus-integrated hepatocytes in cirrhotic liver nodules.

A total of 83 cirrhotic nodules (pseudolobules) individually collected from 11 cirrhotic livers of hepatitis B virus carrier patient were analyzed for the frequency and mode of hepatitis B virus integration as well as histological features. Southern blot analysis disclosed discrete bands at higher molecular weight region in 26 of 83 nodules (31.3%), indicating a clonal growth of hepatocytes with viral integration. Considerable variation (0-75%) existed in the positive rates for discrete bands in nodules among livers. Molecular cloning revealed the sequence flanking an integrated viral sequence to be host DNA and thus confirmed true integration. Histological analysis, however, did not reveal any neoplastic-appearing foci of growth within nodules, despite the fact that the detection sensitivity would predict clones of more than 10(5) cells to give rise to clonal integration patterns on Southern blot analysis. The question of whether clonal expansion of hepatocytes reflects any viral integration-associated growth advantage and/or a preneoplastic condition awaits future studies.

Adult↗
PubMed1989

The human homolog of the Moloney leukemia virus integration 2 locus (MLV12) maps to band p14 of chromosome 5.

The Moloney leukemia virus integration 2 (MLV12) locus represents a common region for proviral integration and a putative oncogene involved in the induction of thymic lymphomas in rodents. The human homolog of the MLV12 locus has been cloned and studies have been initiated to determine its possible role in the induction and progression of human neoplasms. In this study we used a panel of human X rodent somatic cell hybrids and in situ hybridization to metaphase chromosomes to map MLV12 to the short arm of the human chromosome 5, band p14.

Animals↗
PubMed1986

Hepatitis B virus integration site in hepatocellular carcinoma at chromosome 17;18 translocation.

Integrated hepatitis B virus (HBV) DNA is almost invariably found in hepatocellular carcinomas (HCC) which develop in HBV carriers. Integrated HBV DNAs from two single-integration HCCs (C3 and C4) have been cloned, and the cellular integration sites have been analyzed. Integrated HBV DNA of C3 is present in chromosome 6 and contains a nearly complete linear HBV genome. The HBV DNA integration in tumor C3 was not associated with major rearrangements of cellular DNA. In contrast, the integrated HBV DNA in C4 contains a large inverted repeat of HBV DNA, in which each repeat consists of a linear HBV DNA segment similar to that present in C3. The C4 integration was also accompanied by a cellular DNA translocation at the HBV integration site. The translocation occurred between chromosomes 17 and 18, along with a deletion of at least 1.3 kilobases of chromosome 18 DNA at the translocation site. Our data support a model in which postintegration rearrangement of integrated HBV and cellular DNA results in the generation of chromosomal aberrations. These chromosomal aberrations may function in a multistage mechanism leading to fully malignant HCC.

Base Sequence↗
PubMed1989

Multicentric independent development of hepatocellular carcinoma revealed by analysis of hepatitis B virus integration pattern.

Two separate nodular lesions of hepatocellular carcinoma (HCC) were surgically removed from a patient with positive serum hepatitis B surface antigen. Southern blot analysis of DNA from the two separate HCC lesions showed different restriction patterns of integrated hepatitis B virus DNA, indicating their independent origins. The two lesions were composed mainly of poorly differentiated HCC; however, well-differentiated HCC was also observed in the periphery of the lesions. This histological finding is consistent with the multistep and independent development of HCC in each site of the liver.

Aged↗
PubMed1991

Chromosomal sites for hepatitis B virus integration in human hepatocellular carcinoma.

The discovery that hepatitis B virus (HBV) integrates into host chromosomes raises the question of whether such viral DNA integration correlates directly with the activation of specific oncogenes or the inactivation of anti-oncogenes. To obtain insight into this problem, we randomly collected HBV integrant samples from different human hepatocellular carcinomas and identified the site of chromosomal integration by using in situ hybridization and/or linkage analysis with the flanking cellular DNAs as probes. Our findings did not specifically identify particular HBV DNA integration sites in chromosomes, although chromosomes 11 and 17 seemed to have more than the average number of integrants.

Alleles↗
PubMed1985

Insertion of long interspersed repeated elements at the Igh (immunoglobulin heavy chain) and Mlvi-2 (Moloney leukemia virus integration 2) loci of rats.

Restriction enzyme analysis of normal DNA derived from individual rats of the National Institutes of Health outbred Osborn-Mendel colony revealed that two independent single-copy loci, the Igh (immunoglobulin heavy chain) locus and the Mlvi-2 (Moloney leukemia virus integration 2) locus, a putative oncogene, are polymorphic (i.e., exhibit allelic variation). The polymorphism at both loci was due to the presence or absence of a long interspersed repeated DNA element (LINE). The LINE insertion in the Igh locus occurred in the joining (J) region, which is involved in the physiological rearrangement of this locus. The LINE insertion in the Mlvi-2 locus has occurred approximately 6 kilobases from the region of provirus integration in Moloney murine leukemia virus-induced rat thymomas. The two inserts are colinear with each other and with other randomly selected cloned copies of the rat LINE family, the general characteristics of which we also present. LINE insertion in the Mlvi-2 locus was observed in several rat strains, established from independent rat colonies, suggesting that LINE-containing Mlvi-2 alleles may be widespread in the rat population. LINE insertion in the Igh locus was observed in 1 of 27 rats. The detection of a LINE-related polymorphism at two nonselected loci indicates that LINEs are transposable. The presence or absence of these long (greater than 5 kilobases), highly transcribed elements at single-copy loci could have profound effects on gene activity. Furthermore, LINE-containing single-copy loci could be affected by homologous interaction between the resident LINE and any of the other 50,000 or so copies of these elements in the rat genome.

Animals↗
PubMed1990

Human homologue of Moloney leukemia virus integration-4 locus (MLVI-4), located 20 kilobases 3' of the myc gene, is rearranged in multiple myelomas.

The structure of the c-myc locus and the flanking chromosomal region was investigated by Southern blot analysis of DNA from bone marrow aspirates from 42 patients with multiple myeloma. The main abnormality detected was the rearrangement of the MLVI-4 locus, 20 kilobases 3' of c-myc, which was observed in seven cases (16%). Two of these rearrangements were detected at the time of the initial diagnosis, four during treatment, and one at relapse, and their presence correlated with unresponsiveness to therapy. The MLVI-4 locus represents the human homologue of the Moloney leukemia virus integration-4 locus (Mlvi-4), a common region for provirus integration in Moloney murine leukemia virus-induced T-cell lymphomas in rodents. Provirus integration in this locus activates c-myc, and two additional genes, Mlvi-4 and Mlvi-1. The c-myc gene was rearranged in one patient; mutations involving the first exon of c-myc, frequently detected by altered restriction enzyme recognition sites in Burkitt's lymphomas, were not observed in these myelomas.

Chromosome Mapping↗
PubMed1986

A common mouse mammary tumor virus integration site in chemically induced precancerous mammary hyperplasias.

Mammary carcinomas can be induced by chemical and hormonal as well as viral carcinogens. Irrespective of the class of inducer, these tumors develop in discrete stages, of which alveolar hyperplasia is one of the earliest identifiable. Since carcinogenesis by the mammary tumor virus is now thought to involve proviral activation of adjacent cell genes at specific loci, we sought to determine if a similar mechanism also played a role in chemical and hormonal carcinogenesis and if its role was stage specific. Three high-tumor-incidence BALB/c hyperplastic alveolar nodule outgrowths of two different etiologies were found to have exogenous mouse mammary tumor virus proviruses integrated at the same site in the genome. This common site of integration is not within the bounds of the int-1 and int-2 loci into which proviruses detected at these loci are clustered in MMTV-induced mammary tumors. All three HANs are commonly impaired in end-point differentiation. We propose that mouse mammary tumor virus integration at this site is responsible for a specific abnormality in differentiation associated with the preneoplastic phenotype.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Multiple rearrangements and activated expression of c-myc induced by woodchuck hepatitis virus integration in a primary liver tumour.

Woodchuck hepatitis virus (WHV) is a small, partially double-stranded DNA virus. Like the related human hepatitis B virus (HBV), WHV induces acute and chronic hepatitis and hepatocellular carcinoma (HCC) in its natural host. WHV DNA integration into c-myc and N-myc, resulting in deregulated expression of these genes, has been described previously in woodchuck HCC. We have analysed a woodchuck liver tumour in which WHV DNA was integrated in the c-myc gene. The virus insertion provoked multiple alterations in one c-myc allele, probably involving secondary deletions and mutations. Integrated viral DNA, including promotor and enhancer sequences, acted as an insertional mutagen, leading to enhanced expression of heterogenous c-myc transcripts ranging from 7.2 to 14 kb in size, strikingly longer than normal 2.3-kb c-myc RNA. These results provide an additional example in which the oncogenic activation of a myc gene by cis-acting effect of WHV insertion may play a critical role in virus-induced woodchuck HCC.

Animals↗
PubMed1985

The PLC/PRF/5 human hepatoma cell line. II. Chromosomal assignment of hepatitis B virus integration sites.

The chromosomal sites at which hepatitis B virus (HBV) DNA is integrated into the genome of the hepatocellular carcinoma (HCC) cell line, PLC/PRF/5 were investigated in an attempt to understand the mechanisms by which hepatitis B virus may induce malignant transformation. In situ hybridization of an HBV DNA probe to metaphase chromosomes of the PLC/PRF/5 cell line, followed by statistical analysis, identified three integration sites; these were 15q22-q23, 11q22, and 18q12. In particular, hybridization to chromosome #15, which is present in four copies in complete metaphases of this cell line, was highly significant (p much less than 0.0005).

Adult↗
PubMed1985

Hepatitis B virus integration in hepatocellular carcinoma DNA: duplication of cellular flanking sequences at the integration site.

The integrated form of hepatitis B virus (HBV) in the human hepatoma cell line huH2-2 and its cellular counterpart sequence have been cloned and analyzed. Blot hybridization analysis and nucleotide sequencing indicated that a single copy of the 1895-base-pair (bp) subgenomic region of HBV DNA, spanning from the middle of pre-S to the end of gene X, was integrated and flanked by the 12-bp directly repeating cellular sequences. A comparison of the sequencing data with that of the cellular counterpart DNA indicated the absence of deletion and rearrangement in the cellular flanking DNA following integration of the 1895-bp HBV DNA, except for generation of the 12-bp direct repeat at the virus-cell junction. A possible model for the mechanism of HBV integration is proposed.

Base Sequence↗
PubMed1990

Human immunodeficiency virus integration protein expressed in Escherichia coli possesses selective DNA cleaving activity.

The human immunodeficiency virus (HIV) integration protein, a potential target for selective antiviral therapy, was expressed in Escherichia coli. The purified protein, free of detectable contaminating endonucleases, selectively cleaved double-stranded DNA oligonucleotides that mimic the U3 and the U5 termini of linear HIV DNA. Two nucleotides were removed from the 3' ends of both the U5 plus strand and the U3 minus strand; in both cases, cleavage was adjacent to a conserved CA dinucleotide. The reaction was metal-ion dependent, with a preference for Mn2+ over Mg2+. Reaction selectivity was further demonstrated by the lack of cleavage of an HIV U5 substrate on the complementary (minus) strand, an analogous substrate that mimics the U3 terminus of an avian retrovirus, and an HIV U5 substrate in which the conserved CA dinucleotide was replaced with a TA dinucleotide. Such an integration protein-mediated cleavage reaction is expected to occur as part of the integration event in the retroviral life cycle, in which a double-stranded DNA copy of the viral RNA genome is inserted into the host cell DNA.

Base Sequence↗
PubMed1987

[Hepatitis B virus integration and oncogene activation].

In hepatitis B virus (HBV) related hepatoma samples there is a high frequency of HBV-DNA integration into the chromosome, but the frequency of integration in the early-stage of carcinogenesis is expected to be even higher. Structural an analysis of integrated HBV-DNA and chromosomal flanking DNAs disclosed that the marked rearrangement of chromosomal DNA is not directly linked to carcinogenesis. HBV-DNA integration and chromosomal DNA depletion occur even in chronic hepatitis tissues. Integration is, therefore, thought to trigger a series of reactions which lead to carcinogenesis. However, the oncogene is not detected within the HBV genome, and the HBV integration site in the chromosome is variable. As one approach to clarifying the cause and effect relationship between HBV-DNA integration and liver carcinogenesis DNA transfection experiments were conducted using mouse NIH3T3 cells to detect hepatoma-related oncogenes. As a result, the well-known N-ras gene and an unknown oncogene were independently isolated from different hepatoma tissues.

Carcinoma, Hepatocellular↗
PubMed1992

The open reading frames in the 3' long terminal repeats of several mouse mammary tumor virus integrants encode V beta 3-specific superantigens.

Mice expressing the minor lymphocyte stimulation antigens, Mls-1a, -2a, or -3a, singly on the B10.BR background have been generated. Mls phenotypes correlate with the integration of mouse mammary tumor viruses (MTV) in the mouse genome. The open reading frames within the 3' long terminal repeats of the integrated MTVs 1, 3, 6, and 13 encode V beta 3-specific superantigens. Sequence data for these viral superantigens is presented, indicating that it is the COOH-terminal portion of the viral superantigen that interacts with the T cell receptor V beta element.

Amino Acid Sequence↗
PubMed1989

Comparison of non-ionic detergents for extraction and ion-exchange high-performance liquid chromatography of Sendai virus integral membrane proteins.

The integral membrane proteins of Sendai virus haemagglutinin-neuraminidase (HN) and fusion protein (F) were extracted from purified virions with 2% of a non-ionic detergent, i.e., polyoxyethylene alkyl ethers varying by 8-14 hydrocarbon units in the alkyl chain and by 4-8 ethylene glycol units in the oxyethylene chain. Triton X-100 and octyl glucoside were included as reference detergents. The hydrophile-lipophile balance (HLB) and the critical micelle concentration (CMC) of the detergents were determined. A decrease in length of the oxyethylate by 8-5 ethylene glycol units and an increase in the alkylate by 8-12 hydrocarbon units resulted in higher yields of extracted proteins. The highest yields were obtained for C12E5 with an HLB of 11.7. Yields of extracted protein could be correlated with the HLB values of the polyoxyethylene alkyl ethers. The structural integrity of HN and F was not affected during extraction by either detergent as measured by their reactivity with monoclonal antibodies directed against native HN and F. Extracts were subjected to anion-exchange high-performance liquid chromatography (HPLC) on a Mono Q column in the presence of 0.1% of the detergent used for extraction. Eluate fractions were analysed by sodium dodecyl polyacrylamide gel electrophoresis and recoveries of HN and F protein were determined by size-exclusion HPLC. The immunological activity of HN and F was tested in an enzyme-linked immunosorbent assay. The highest recoveries of HN and F (80%) were obtained with C10E5 in the elution buffer. HN and F were partially purified and the immunological activity was well preserved.

Animals↗
PubMed1990

Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma.

Hepatitis B virus (HBV) DNA frequently integrates into the genome of human primary liver cancer cells, but the significance of this integration in liver carcinogenesis is still unclear. Here we report the cloning of a single HBV integration site in a human hepatocellular carcinoma at an early stage of development, and of its germline counterpart. The normal locus was found to be transcribed into two polyadenylated messenger RNA species of 1.8 and 2.7 kilobases. We have isolated a complementary DNA clone from a normal adult human liver cDNA library which has an open reading frame with a coding capacity for a protein of 432 amino acids and relative molecular mass 48,536. The strong homology of the C-terminal half of the protein to the A-type cyclins of clam and Drosophila identifies it as a human cyclin A. The cyclin A gene has several exons, and the HBV integration occurs within an intron. As cyclins are important in the control of cell division, the disruption of a cyclin A gene by viral insertion might contribute to tumorigenesis.

Amino Acid Sequence↗