Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant adenoviruses were constructed in which the viral E1A gene was deleted and the E1B promoter was replaced by the rat albumin, mouse beta-major globin, or mouse immunoglobulin heavy-chain promoter. After infection of human or rat hepatoma cells, E1B-containing mRNAs could be detected only from the virus containing the albumin promoter. Conversely, only the immunoglobulin promoter was active in virus-infected myeloma cells. However, in hepatoma cells transcription from the albumin promoter in the virus was much less than that of the endogenous cellular albumin gene or of other viral genes. In primary mouse hepatocytes endogenous albumin gene transcription was high immediately after plating but declined within 24 h. Expression of the albumin promoter in the virus paralleled that of the cellular albumin gene. From these results it appears that cell-specific expression of albumin depends on the presence of tissue-specific trans-acting factors, but the presence of such factors does not suffice for a maximal rate of transcription, a conclusion that requires direct comparison within a differentiated cell of a newly introduced and preexisting active cell gene.
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PMID:Cellular promoters incorporated into the adenovirus genome: cell specificity of albumin and immunoglobulin expression. 294 8

Apoptin, a small protein derived from chicken anemia virus (CAV), induces apoptosis in human tumor cell lines regardless of whether these express p53 or not. We examined whether the small adenovirus 5 E1B protein of 21 kDa (E1B-21kD), also called E1B-19kD) and Bcl-2 could inhibit apoptin-induced apoptosis in human tumor cell lines and compared this with p53-induced apoptosis. E1B-21kD, but not Bcl-2 was found to inhibit apoptin-induced apoptosis in the osteosarcoma cell lines U2OS and Saos-2. However, neither expression of E1B-21kD nor of Bcl-2 resulted in inhibition of apoptin-induced apoptosis in Hep3B hepatoma cells and kidney rhabdoid tumor G401 cells. Both Bcl-2 and Ad5 E1B-21kD were able to inhibit p53-induced apoptosis in the human tumor cell lines Saos-2 and Hep3B. In Saos-2 and U2OS, but not in Hep3B and G401, expression of E1B-21kD leads to retention of apoptin in the cytoplasm, in that way preventing its nuclear function. These results indicate that proteins inhibiting the p53-induced apoptotic pathway do not block apoptin-induced apoptosis or do so only in a cell type-specific manner. The apoptin-induced apoptotic pathway is distinct from that induced by p53 and, therefore, apoptin is a potential antitumor agent.
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PMID:Differential sensitivity to Ad5 E1B-21kD and Bcl-2 proteins of apoptin-induced versus p53-induced apoptosis. 860 67

The Wilms' tumor 1 gene (WT1) encodes a transcription factor of the zinc-finger family. As a result of alternative RNA splicing, the gene can be expressed as four polypeptides that differ in the presence or absence of a stretch of 17 amino acids just NH2 terminal of the four zinc fingers and a stretch of three amino acids (+/-KTS) between zinc fingers 3 and 4. In this study, cDNA constructs encoding the four human Wilms' tumor 1 splice variants were transiently transfected into the p53-negative Hep3B and the p53-positive HepG2 hepatoma cell lines. Morphological assessment of the WT1-expressing cells showed that the WT1(-KTS) splice variants induced apoptosis in both cell lines, whereas the WT1(+KTS) isoforms did not. The induction of apoptosis by the WT1(-KTS) isoforms appears to be p53 independent in the hepatoma cell lines. Furthermore, it was found that the WT1(-KTS)-induced apoptosis could not be suppressed by coexpression of either the Mr 21,000 E1B, the Bcl-2, or the BAG-1 protein. Coexpression of either the epidermal growth factor receptor or the insulin receptor, however, partially rescued the cells from apoptosis.
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PMID:Wilms' tumor 1-KTS isoforms induce p53-independent apoptosis that can be partially rescued by expression of the epidermal growth factor receptor or the insulin receptor. 910 24

An E1B gene-attenuated adenovirus (dl1520) has been proposed to have a selective cytolytic activity in cancer cells with a mutation or deletion in the p53 tumor suppressor gene (p53-null), a defect present in almost half of human hepatocellular carcinomas (HCCs). In this study, the in vitro and in vivo antitumor activity of dl1520 was investigated focusing on two human HCC cell lines, a p53-wild type (p53-wt) cell line and a p53-null cell line. dl1520 was tested for in vitro cytopathic effects and viral replication in the human HCC cell lines Hep3B (p53-null) and HepG2 (p53-wt). The in vivo antitumor effects of dl1520 were investigated in tumors grown s.c. in a severe combined immunodeficient mouse model. In addition, the combination of dl1520 infection with systemic chemotherapy was assessed in these tumor xenografts. At low multiplicities of infection, dl1520 had an apparent p53-dependent in vitro viral growth in HCC cell lines. At higher multiplicities of infection, dl1520 viral replication was independent of the p53 status of the target cells. In vivo, dl1520 significantly retarded the growth of the p53-null Hep3B xenografts, an effect augmented by the addition of cisplatin. However, complete tumor regressions were rare, and most tumors eventually grew progressively. dl1520 had no effect on the in vivo growth of the p53-wt HepG2 cells, with or without cisplatin treatment. The E1B-deleted adenoviral vector dl1520 has an apparent p53-dependent effect in HCC cell lines. However, this effect is lost at higher viral doses and only induces partial tumor regressions without tumor cures in a human HCC xenograft model.
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PMID:p53 selective and nonselective replication of an E1B-deleted adenovirus in hepatocellular carcinoma. 1048 85

The signaling pathway leading to TGF-beta1-induced apoptosis was investigated using a TGF-beta1-sensitive hepatoma cell line, FaO. Cell cycle analysis demonstrated that the accumulation of apoptotic cells was preceded by a progressive decrease of the cell population in the G(1) phase concomitant with a slight increase of the cell population in the G(2)/M phase in response to TGF-beta1. TGF-beta1 induced a transient increase in the expression of Cdc2, cyclin A, cyclin B, and cyclin D1 at an early phase of apoptosis. During TGF-beta1-induced apoptosis, the transient increase in cyclin-dependent kinase (Cdk) activities coincides with a dramatic increase in the hyperphosphorylated forms of RB. Treatment with roscovitine or olomoucine, inhibitors of Cdc2 and Cdk2, blocked TGF-beta1-induced apoptosis by inhibiting RB phosphorylation. Overexpression of Bcl-2 or adenovirus E1B 19K suppressed TGF-beta1-induced apoptosis by blocking the induction of Cdc2 mRNA and the subsequent activation of Cdc2 kinase, whereas activation of Cdk2 was not affected, suggesting that Cdc2 plays a more critical role in TGF-beta1-induced apoptosis. In conclusion, we present the evidence that Cdc2 and Cdk2 kinase activity transiently induced by TGF-beta1 phosphorylates RB as a physiological target in FaO cells and that RB hyperphosphorylation may trigger abrupt cell cycle progression, leading to irreversible cell death.
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PMID:Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger apoptosis through the phosphorylation of retinoblastoma protein in FaO hepatoma cells. 1054 99

Epidemiology shows a clear correlation between chronic infection with the hepatitis B virus (HBV) and development of hepatocellular carcinoma (HCC). The potential role of the transactivating hepatitis B virus X protein (HBx) in transformation by HBV is controversial. Here we report that HBx suppresses transformation of primary rat embryo fibroblasts (REFs). Cooperating oncogenes like c-Ha-ras and c-myc transform REF very efficiently but cotransfection with HBx suppressed transformation of REFs down to 5%. Similarly, transfection of HBx together with the cooperating oncogenes Ha-ras and SV40 LTAg or c-Ha-ras and mutant p53 reduced the number of foci to 13%. Comparable results were obtained with HBx in the context of the whole HBV. Suppression of focus formation in REF could be partly relieved by cotransfection of apoptosis inhibitors Bcl-2 or E1B. However, cotransfection of apoptosis inhibitors crmA and p35 did not influence the proapoptotic functions of HBx. Thus, HBx may specifically activate the Bcl-2 sensitive pathway leading to apoptosis. Experiments with 13 HBx linker scanning mutants revealed that the domains necessary for HBx dependent transactivation overlap with the domains needed for the apoptotic/growth arrest functions of HBx.
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PMID:Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts. 1071 5

Gene therapy using replication-competent adenovirus that selectively propagates in tumor cells may be an effective treatment for cancer. We developed an adenovirus that would be replication specific for hepatocellular carcinoma (HCC). Based on our finding that the E1B55k-deficient adenovirus was able to replicate in human primary hepatocytes, we therefore designed an adenovirus carrying E1A and attenuated E1B gene driven by the alpha-fetoprotein promoter (Adv-AFP-E1AdB), thus restricting the replication specificity in AFP-producing HCC. Replication of Adv-AFP-E1AdB in primary hepatocytes was practically negligible 4 days after infection. Although Adv-AFP-E1AdB replicated slowly in AFP-producing HCC, it efficiently destroyed HCC cells independent of their p53 status. Experiments were conducted in vivo using systemic administration of Adv-AFP-E1AdB and we observed tumor size reduction in nude mice having liver cancer. The use of replication-competent adenovirus deficient of the E1B gene coupled to an AFP-targeting strategy may be a safe and efficacious treatment for HCC.
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PMID:Target gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by E1B55k-attenuated adenovirus. 1140 92

It has been suggested the E1B 55 kDa mutant adenovirus dl1520 can selectively kill p53-deficient human tumor cells. In this study, we examined the cytotoxic effect of dl1520 on nine human hepatocellular carcinoma (HCC) cell lines with different p53 genetic and functional status. The results showed that HCC cell lines with deleted or mutant p53 gene and reduced p53 transcriptional activities were more susceptible to dl1520-induced cytolysis. Hep3B (p53-null) and HepG2 (p53-wt) cells were arrested at G2/M phase when cytolysis occurred. Cyclin-dependent kinase inhibitor (CDKI) p21(Waf-1/Cip-1) was downregulated 24 hours after dl1520 infection in HepG2 cells and increased when cytolysis occurred. No p21 expression was detected in Hep3B cells. DNA fragmentation was found in both Hep3B and HepG2 cells after dl1520 infection. Bax expression increased in dl1520-infected HepG2 cells but not in Hep3B cells. Notably, three Bax-like proteins, molecular mass around 40 to 80 kDa, accumulated 48 hours after adenovirus infection in Hep3B cells but not in HepG2 cells. These results suggest that the susceptibility of HCC cells to dl1520-induced cytolysis is related to both p53 genotype and functional status, and is mediated by both cell cycle disturbance and apoptosis.
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PMID:The cytotoxic effect of E1B 55-kDa mutant adenovirus on human hepatocellular carcinoma cell lines. 1147 53

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world. Tumor resection remains the only curative treatment but is often not possible because of advanced stage and frequently unsuccessful because of intrahepatic or distant tumor recurrence. alpha-Fetoprotein (AFP), a tumor marker currently used for the diagnosis and management of HCC, is an oncofetal protein expressed in a majority of HCCs but rarely in normal hepatocytes. Because AFP gene expression is tightly regulated at the level of transcription, AFP transcriptional regulatory elements (TRE) are excellent candidates for generating HCC-specific oncolytic adenoviruses. We devised a new strategy for the AFP TRE to control an artificial E1A-IRES-E1B bicistronic cassette in an adenovirus 5 vector (Ad5) and constructed an HCC-specific oncolytic virus, CV890. In vitro, CV890 expression of the E1A and E1B genes, virus replication, and cytopathic effects were examined by Northern blot, Western blot, virus yield assay, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in AFP-producing cell lines (HepG2, Huh7, Hep3B, PLC/PRF/5, and SNU449), non-AFP-producing cell lines (Sk-Hep-1, Chang liver cell, LNCaP, HBL-100, PA-1, UM-UC-3, SW 780, Colo 201, and U118 MG), and non-AFP-producing human primary cells (lung fibroblast, bladder smooth muscle, and mammary epithelial). CV890 efficiently replicates in and destroys AFP-producing HCC cells as well as wild-type Ad5, but replication is highly attenuated in non-AFP-producing HCC cells or non-HCC cells. CV890 produced 5,000-100,000-fold less virus than wild-type Ad5 in non-AFP-producing cells. CV890 was attenuated 100-fold more than CV732, a virus containing the AFP TRE driving the E1A gene alone, in non-AFP-producing cells. These studies demonstrated that expression of both E1A and E1B genes under the control of a bicistronic AFP-E1A-IRES-E1B cassette yielded improvements in virus specificity equivalent to driving the E1A and E1B genes with two independent TREs yet requires only one TRE thereby conserving genomic space within the virus. Significantly, CV890 produced nearly the same yield of virus in cells that produced AFP over a 75-fold range, from a low of 60 ng AFP/10(6) cells/10 days to as high as 4585 ng AFP/10(6) cells/10 days. In vivo, antitumor efficacy of CV890 was examined in BALB/c-nu/nu mice containing large s.c. HepG2 or Hep3B tumor xenografts. Tumor volume of distant xenografts dropped below baseline 4 weeks after a single i.v. injection. Combination of CV890 with doxorubicin demonstrated synergistic antitumor efficacy, yielding complete elimination of distant Hep3B tumors 4 weeks after a single i.v. administration of both compounds. Our results support the clinical development of CV890 as an antineoplastic agent for the treatment of localized or metastatic HCC.
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PMID:A hepatocellular carcinoma-specific adenovirus variant, CV890, eliminates distant human liver tumors in combination with doxorubicin. 1152 37

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The prognosis of HCC is poor and current therapies are largely ineffective. Genetic abnormalities are commonly seen in HCC tumors particularly with inactivation of the p53 tumor suppressor. Gene therapy with E1B-deleted (dl1520) adenovirus could be of therapeutic value as it offers the potential of tumor growth control in patients with p53 mutation. Ten patients with posthepatitis cirrhosis and histologically proven HCC were enrolled into an open label, randomized prospective study. Randomization was to receive either percutaneous ethanol injection (control group) or dl1520. Toxicity and complications in the ethanol group were pain and fever, whereas in the gene therapy group complications were minimal. Grade I-II toxicity fever, stable performance status, and no significant rise in liver enzymes were observed in patients treated with dl1520. Analysis of patients' response to treatment in the gene therapy group showed one patient with a partial response and four patients with progressive disease. In the ethanol-treated group two patients had stable disease and three patients showed disease progression. In conclusion, this study showed that the adenovirus was well tolerated, but did not seem to offer significant tumor control. Although only a small number of patients were treated here it appears that more effective vectors are needed to achieve a useful clinical impact.
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PMID:Clinical trial of E1B-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma. 1189 41


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