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At least 145 records · Page 8Linked to original sources

PubMed1983

Role in nude mice of interferon and natural killer cells in inhibiting the tumorigenicity of human hepatocellular carcinoma cells infected with hepatitis B virus.

The human hepatoma cell line, PLC/PRF/5, which is persistently infected with hepatitis B virus (HBV), has integrated HBV-DNA, secretes HBV surface antigen (HBsAg), and does not grow readily in congenitally athymic (nu/nu) mice. The present investigation was undertaken to ascertain whether the low tumorigenicity of this cell line was governed by a host immune response and/or was related to expression of HBsAg. Subcutaneous injection of 4-5 X 10(6) cells into BALB/c nude mice produced localized encapsulated tumors with morphologic features of primary hepatocellular carcinoma in 25% of the animals within 29-40 d. No tumor growth was observed at lower cell inocula. In contrast, SK-HEP-1, an HBV-negative human hepatoma cell line, produced tumors at 1-5 X 10(6) cells inocula in 66% of the animals. Immunosuppression of mice with antilymphocyte serum (ALS) or irradiation increased tumor incidence in mice inoculated with 1 X 10(6) PLC/PRF/5 cells to almost 100% and produced local invasiveness. Immunosuppression also reduced the latency, i.e., time to tumor appearance, and increased mean tumor weight. These results suggest that tumorigenicity was limited by the host immune response. The nature of the response was delineated by treating nude mice challenged with tumor cells with sheep anti-mouse interferon globulin (anti-IFN). When 2 X 10(6) cells were injected, tumor growth occurred in 75% of anti-IFN-treated mice, whereas controls injected with the same number of cells, but not receiving anti-IFN, failed to develop tumors. The tumors in the anti-IFN-treated mice were highly invasive and the latency period until tumor appearance was reduced to 3-5 d. An inverse correlation was found between susceptibility of the hepatoma cells to natural killer (NK) activity in vitro and resistance to tumor growth in vivo. In vitro cytotoxicity for PLC/PRF/5 cells was eliminated by anti-NK 1.1 and complement, establishing the effector cell as an NK cell. NK cell activity 14 d after inoculation of mice with PLC/PRF/5 cells was augmented against PLC/PRF/5 target cells but not against SK-HEP-1 cells. Treatment of mice with ALS, irradiation, or anti-IFN abolished NK activity against PLC/PRF/5 cells. Co-cultivation of nude mouse spleen cells with PLC/PRF/5 but not with HBsAg or SK-HEP-1 cells induced secretion of murine IFNalpha. These results suggest that the IFN/NK cell system may play a role in limiting tumorigenicity and invasiveness of HBV-infected human hepatocellular carcinoma cells by a mechanism similar to that found for other cells persistently infected with viruses.

Animals↗

PubMed1991

Estrogen receptors, progesterone receptors and heat-shock 27-kD protein in liver biopsy specimens from patients with hepatitis B virus infection.

It has been proposed that in the human liver, the estrogen receptor gene may become inappropriately expressed as a consequence of HBV integration, contributing to cell transformation. This study was undertaken to examine estrogen receptor status in patients with hepatitis B virus infection and to analyze the expression of progesterone receptor and of a heat-shock 27,000-D protein (hsp27), both of which are estrogen regulated in estrogen target tissues. Receptor proteins were detected in liver biopsy specimens by immunocytochemistry using antireceptor monoclonal antibodies; a monoclonal antibody was also used to detect hsp27. Estrogen receptor and progesterone receptor were mainly seen in the nuclei of hepatocytes. The presence of hepatitis B virus infection did not always result in elevated estrogen receptor expression, but in general the expression of this receptor protein was higher in hepatitis B virus-positive patients than in patients with the same pathological findings (hepatitis, cirrhosis, hepatocarcinoma) but without hepatitis B virus. This was more clearly seen in the patients with hepatitis. Although estrogen receptor expression was moderate to high in many samples, the expression of the two biochemical markers of estrogen action at postreceptor levels (progesterone receptor and hsp27) was low or absent in most of the liver tissues examined, suggesting that in the liver the interaction of estrogen-estrogen receptor-DNA has characteristics inherent to this tissue.

Adolescent↗

PubMedDate not supplied

Variable efficacy of interferon-alpha treatment on growth of human hepatoma cell lines in vitro.

Three human hepatoma cell lines, PLC/PRF/5, Mahlavu and Sk-Hep 1, two of which contain integrated HBV DNA, were grown in culture and treated with human alpha-IFN for up to 14 days. IFN treatment caused a varying suppression of cell growth of the three hepatoma cell lines. While doubling time and cloning efficiency were significantly reduced for all three hepatoma cell lines tested, 3[H]thymidine incorporation was markedly suppressed, in a dose-dependent fashion, only in treated PLC/PRF/5 cells but not in Sk-Hep 1 and Mahlavu cells. The inhibiting effect of interferon treatment on growth of PLC/PRF/5 cells in vitro was neutralized by antibodies to human IFN. IFN treatment caused a significant suppression of HBsAg and alpha FP secretion by PLC/PRF/5 hepatoma cells. This effect, while constant throughout the observation period for HBsAg, was cumulative for alpha FP secretion. Following discontinuation of treatment, suppression of PLC/PRF/5 hepatoma cell growth was rapidly reversed, and HBsAg and alpha FP secretion returned to their pretreatment levels. These experiments suggest that human alpha-IFN suppresses the growth of some human hepatoma cells in culture but that this effect is dependent on the continuous presence of IFN in the growth medium. Finally, the inhibitory effects of IFN on cell growth differed for the various hepatoma cell lines tested.

Animals↗

PubMedDate not supplied

A case of hepatocellular carcinoma in HIV-infected patient.

Persistent human immunodeficiency virus (HIV) infection induces an immuno-suppressive state and therefore malignant tumors are a very common complication. Hepatocellular carcinoma is very rare, however, because it is associated with chronic liver disease by the persistent infection of hepatitis B or C virus (HBV or HCV). We reported a case of HCC with HIV infection who had no evidence of HBV or HCV infection, and that had a rapid growth and active pulmonary metastases. Pathological findings of the resected liver showed moderately differentiated HCC and no chronic liver disease. Despite efforts to find potential HBV integration in tumor and non-tumor tissue, none was observed. To our knowledge, this is the first report of HCC in HIV-infected patient with no evidence of hepatitis virus infection.

Carcinoma, Hepatocellular↗

PubMed1988

Status of hepatitis B virus DNA in hepatocellular carcinoma: a study based on paired tumor and nontumor liver tissues.

To investigate the hepatitis B virus (HBV) DNA status in the liver when hepatocellular carcinoma (HCC) has developed, 35 paired nontumorous and tumorous liver tissues from 27 hepatitis B surface antigen (HBsAg)-seropositive and 8 HBsAg-negative patients with HCC were studied by Southern blot analysis. The hybridization patterns of HBV DNA were different in the nontumor and tumor parts in 26 (96.3%) of the 27 HBsAg-positive patients. In the nontumor parts, integration of HBV DNA into the host genome was significantly less when compared to the tumor parts (15/27 vs. 25/27, P less than 0.05), whereas free replicative viral forms were significantly more frequent (17/27 vs. 7/27). The integrated HBV DNA in the nontumor parts showed discrete band patterns in the majority of cases (13/15). Hepatitis B e antigen (HBeAg) was significantly associated with the expression of free replicative forms of HBV DNA in the tumor tissues. An integrated HBV DNA sequence was detected in the tumor part of one HBsAg-negative patient, but not in her nontumor counterpart. Our observation that discrete integrated HBV DNAs are present in the nontumor part, representing subclinical clonal expansion that precedes the development of HCC, suggests the risk of future new tumor growth from these cell clones.

Carcinoma, Hepatocellular↗

PubMed1990

Identification of integrated hepatitis B virus DNA sequences in human hepatocellular carcinomas in Korea.

The rate of HBV DNA integration into the genome of hepatocellular carcinoma (HCC) cells varies greatly among HCC tissues from different geographical districts. Because of the potential etiological significance of identifying HBV DNA integration in HCC tissues from Korea, we investigated 13 aseptically obtained HCC surgical specimens by Southern blot analysis. Among 13 HCCs, eight (61.5%) contained integrated HBV DNA. Of eight HBsAg-positive patients, six (75%) had integrated HBV DNA in their HCCs while two (40%) out of five HBsAg-negative patients had integrated HBV DNA. Those two HBsAg-negative patients with integrated HBV DNA were all anti-HBs-positive. However, it was not demonstrated in the patient without any HBV serological markers. These findings highly suggest a prominent etiologic role of HBV in the development of HCC. On the other hand, it also strongly favors a multifactorial etiology of human HCC in korea.

Adult↗

PubMed1988

Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors.

Hepatitis B virus (HBV) DNA integration has been shown to occur frequently in human hepatocellular carcinomas. We have investigated whether common cellular DNA domains might be rearranged, possibly by HBV integration, in human primary liver tumors. Unique cellular DNA sequences adjacent to an HBV integration site were isolated from a patient with hepatitis B surface antigen-positive hepatocellular carcinoma. These probes detected rearrangement of this cellular region of chromosomal DNA in 3 of 50 additional primary liver tumors studied. Of these three tumor samples, two contained HBV DNA, without an apparent link between the viral DNA and the rearranged allele; HBV DNA sequences were not detected in the third tumor sample. By use of a panel of somatic cell hybrids, these unique cellular DNA sequences were shown to be located on chromosome 4. Therefore, this region of chromosomal DNA might be implicated in the formation of different tumors at one step of liver cell transformation, possibly related to HBV integration.

Base Sequence↗

PubMed1990

[Human hepatitis B virus and hepatocellular carcinoma].

Hepatitis B virus (HBV) is the causative agent of hepatocellular carcinoma (HCC) in man. The HBV genome is a circular partially double-stranded DNA molecule of about 3.2 kb. The HBV genome contains four structural genes coding for the HBV envelope (HBsAg) and core (HBcAg/HBeAg) proteins, endogenous DNA-polymerase with the additional enzymatic activity of a reverse transcriptase and polypeptide X functioning as a trans-activator of cellular and viral genes. HBV DNA integration in the genomes of HCCs and hepatocytes of HBV carriers is an important evidence establishing a relationship between the HBV infection and the development of HCC. The mechanism of HBV DNA integration into the cellular genome and the possible role of integrated HBV DNA sequences in the malignant transformation of hepatocytes are discussed.

Carcinoma, Hepatocellular↗

PubMed1992

Hepatitis B virus DNA integration and expression of an erb B-like gene in human hepatocellular carcinoma.

Southern blot studies on Hepatitis B Virus (HBV) DNA integration in 13 human hepatocellular carcinomas (HCCs) patients revealed the presence of several distinct HBV integration sites in different human liver disease patients. In one HCC patient the DNA fragment containing the HBV integration also hybridized to an erb B probe. The erb B/HBV co-migrating DNA fragment was cloned and sequenced, and showed that HBV DNA is integrated next to a cellular DNA fragment which is homologous to the tyrosine protein kinase domain of the human epidermal growth factor receptor gene and other cell surface receptor genes. The virus-integrated cellular DNA sequence is expressed in this HCC patient, suggesting a possible role for this gene in hepatocarcinogenesis.

Adult↗

PubMed1986

Interaction of aflatoxin and hepatitis B virus in the pathogenesis of hepatocellular carcinoma.

Aflatoxin-B1 (AFB) and chronic hepatitis B virus (HBV) infection epidemiologically correlate with the geographic distribution of hepatocellular carcinoma (HCC). Integration of HBV DNA into the cellular genome of HCCs and the in vivo formation of adducts between AFB and nucleic acids lead us to suggest that hepatocytes with integrated HBV DNA preferentially accumulate AFB; the AFB-adducts formed may then initiate cell transformation by modifying the expression of critical host genes. The altered molecular biology of liver cells in HCC is evidenced by the fact that HBV does not replicate in HCC tissues or cell lines. The effect of AFB on the expression of cellular genes such as endogenous retrovirus(es) and possibly cellular oncogene(s) can be analyzed in HCC cell lines with and without integrated HBV DNA. In addition, human HCC tissues can be probed for HBV sequences and AFB-DNA adducts at the single-cell level. The presence of HBV and AFB can be correlated with the expression of putative transforming genes, providing a new insight into the interaction between liver cells, HBV and AFB in the pathogenesis of HCC.

Aflatoxin B1↗

PubMed1987

[HBV and hepatocellular carcinoma].

Significant research evidence has demonstrated an association between persistent infection with hepatitis B virus (HBV) and the generation of hepatocellular carcinoma (HCC). These findings are based on epidemiologic studies, molecular studies and studies of HBV like viruses. Epidemiologically, the geographic correlation between HBV infection and HCC, serum HBsAg in patients with HCC, familial clustering of HCC, prospective studies, and pathological studies are discussed. Molecular studies of HBV, the structure of HBV DNA as related to retroviruses and integration of HBV DNA into the host DNA are demonstrated. The structure and replication of HBV are somewhat similar to those of retroviruses. The incidence of HBV DNA integration into the host chromosome of the patients with HBV infection is high. The structure of integrated HBV DNA sequences and flanking sequences was analyzed in many cases. However, none of the classical mechanisms of viral oncogenesis has thus far been demonstrated. The role of HBV in HCC is not understood at the molecular level. HBV may act as just an initiator, or HBV DNA integration may have an active role in liver cancer. The woodchuck hepatitis virus (WHV) is the most oncogenic and suitable animal model. Using this model, we show some results of our experiments.

Animals↗

PubMed1988

Identification of a chromosomal aberration associated with a hepatitis B DNA integration site in human cells.

Hepatitis B virus (HBV) DNA integrates into human cellular DNA during long-term persistent infections, implicating integration as one of the steps leading to hepatocarcinogenesis. The present study demonstrates that the integration of HBV DNA can result in or be accompanied by interchromosomal exchange of genomic material containing the integrated DNA. Unique cellular DNA to the left of an HBV DNA integration site cloned from a primary tumor mapped to chromosome 18q (18q11.1-q11.2); right hand flanking DNA mapped to chromosome #17 at a near-terminal region. The presence of chromosomal rearrangements in association with HBV integration may play a role in multistage hepatocarcinogenesis.

Carcinoma, Hepatocellular↗

PubMed1983

Hepatitis B virus DNA in liver and white blood cells of patients with hepatoma.

Hepatitis B virus (HBV) DNA was studied in liver DNA of 23 patients with primary hepatocellular carcinoma and in white blood cell DNA of 11 of these patients by Southern blot hybridization analysis probed with 32P-labeled HBV DNA cloned in plasmid pBR325. Of the 23 hepatoma DNA samples, 16 were positive for HBV DNA, and 15 of these showed integration of HBV DNA into the host liver DNA. In 5 patients, free HBV DNA was found in addition to integrated HBV DNA and in only one was free HBV found alone. All patients serologically positive for HBV surface antigen (HBsAg) were positive for HBV DNA in tumor samples. The pattern and the degree of hybridization differed considerably among different cases. HBV DNA was found in tumor and in adjacent nontumor tissue in two patients. Of 11 white blood cell DNA samples, two were positive for HBV DNA. The HBV DNA in the white blood cells was not integrated into the host DNA. In the undigested white blood cell DNA, the free HBV DNA gave a positive signal at 5.5 kb and often also at 9.5 kb. After Eco RI digestion, these 5.5-kb and 9.5-kb positive fragments disappeared, while a strong positive band at 3.2-kb appeared. Hind III digestion produced the same positive fragments as in the undigested white blood cell DNA and failed to produce the 3.2-kb fragment. Sometimes, especially after Hind III digestion, a positive fragment at a position corresponding to about 16.2 kb was also demonstrable in addition to the 5.5-kb and 9.5-kb positive fragments.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Hepatocellular↗

PubMed1989

Hepatitis B virus DNA integration in hepatocellular carcinomas and their adjacent non-neoplastic liver tissues.

Hepatitis B virus (HBV) DNA integration was studied in 24 hepatocellular carcinoma (HCC) tissues obtained at operations or autopsies. In 11 cases whose sera were positive for hepatitis B virus surface antigen (HBsAg), HBV DNA integration was demonstrated by Southern blot analysis. Only one of 6 cases whose sera were positive for hepatitis B surface antibody (HBsAb) but negative for HBsAg revealed the integration and the other 5 cases revealed no HBV DNA integration. HBV DNA amplification was noted in 4 of these 6 cases in which HBV DNA integration was found when compared with the adjacent liver tissues. The integration pattern of HBV DNA was different in one case between primary HCC tissue and a metastasized lymph node. It is suggested that HBV DNA amplification is not directly related to the development of HCC and that there are polyclonal tumor cells which have different patterns of virus genome integrations.

Adult↗

PubMed1993

[Trans-activating function of integrated hepatitis B virus].

HBV DNAs are often found in integrated form in human hepatocellular carcinoma (HCC). Since transactivation of the X gene has been shown, surveys of collections of HBV integrants with flanking cellular sequence were performed to clarify whether they might exhibit a transactivation. The majority of integrants showed transactivation effect which may to be due to the virus-cell fusion products derived from the 3' truncated X gene. Additionally, it has been found that 3' truncated preS2/S gene in the integrant encodes a transactivator to which C terminal truncation is essential. These results suggest that the transactivating effect of integrated HBV DNAs plays a role in hepatocarcinogenesis by activating cellular genes.

Carcinoma, Hepatocellular↗

PubMed1993

Transactivating function of integrated hepatitis B virus.

HBV DNAs are often found in integrated forms in human hepatocellular carcinoma (HCC). Discovery of a transactivation function coded by a limited region of the HBV genome has promoted us to survey our collection of HBV integrants with flanking cellular sequences, asking whether they might exhibit a transactivation function. In transient cotransfection assays using the HepG2 cell line, six out of the twelve integrants showed transactivation effects on the expression of cellular genes such as c-fos. These results strongly demonstrate that the transactivating effects of integrated HBV DNA are widely distributed, and some of these effects might be correlated to hepatocarcinogenesis.

Carcinoma, Hepatocellular↗

PubMed1983

Integration of hepatitis B virus DNA: evidence for integration in the single-stranded gap.

The DNA of hepatitis B virus (HBV) can integrate into the genomes of infected human liver cells and may be related to the development of primary liver carcinoma (PLC). This report describes the analysis of three integrated HBV DNA sequences cloned from DNA of the human PLC cell line PLC/PRF/5. In all these sequences, integration of the viral DNA is at a site that is single-stranded (gap) in the unintegrated HBV DNA. Contrary to some speculations, there are no large terminal redundancies flanking the inserts as found in retroviral proviruses. The viral sequences show no obvious rearrangements in these clones, but integration can be associated with deletions in the viral DNA and also apparently in the host DNA.

Base Sequence↗

PubMed2005

Alteration of gene expression in human hepatocellular carcinoma with integrated hepatitis B virus DNA.

PURPOSE: Integration of hepatitis B virus (HBV) DNA into the human genome is one of the most important steps in HBV-related carcinogenesis. This study attempted to find the link between HBV DNA, the adjoining cellular sequence, and altered gene expression in hepatocellular carcinoma (HCC) with integrated HBV DNA. EXPERIMENTAL DESIGN: We examined 15 cases of HCC infected with HBV by cassette ligation-mediated PCR. The human DNA adjacent to the integrated HBV DNA was sequenced. Protein coding sequences were searched for in the human sequence. In five cases with HBV DNA integration, from which good quality RNA was extracted, gene expression was examined by cDNA microarray analysis. RESULTS: The human DNA sequence successive to integrated HBV DNA was determined in the 15 HCCs. Eight protein-coding regions were involved: ras-responsive element binding protein 1, calmodulin 1, mixed lineage leukemia 2 (MLL2), FLJ333655, LOC220272, LOC255345, LOC220220, and LOC168991. The MLL2 gene was expressed in three cases with HBV DNA integrated into exon 3 of MLL2 and in one case with HBV DNA integrated into intron 3 of MLL2. Gene expression analysis suggested that two HCCs with HBV integrated into MLL2 had similar patterns of gene expression compared with three HCCs with HBV integrated into other loci of human chromosomes. CONCLUSIONS: HBV DNA was integrated at random sites of human DNA, and the MLL2 gene was one of the targets for integration. Our results suggest that HBV DNA might modulate human genes near integration sites, followed by integration site-specific expression of such genes during hepatocarcinogenesis.

Adult↗