UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular role of hepatitis C virus (HCV) in liver disease has yet to be clarified. In this study, we analyzed the relationship of HCV replication with mRNA expression of growth factors and mutation of tumor suppressor gene, ie, transforming growth factor-beta 1 (TGF-beta 1), which promotes cirrhotic changes; TGF-alpha, insulin-like growth factor-II (IGF-II), which are both related to hepatocyte transformation; and tumor suppressor gene p53, which is associated with HCC progression. A semiquantitative RNA polymerase chain reaction (RNA-PCR) was used to analyze genetic expression in 31 cirrhotic liver specimens from patients with HCV. In order to detect HCV replication, the minus-strand RNA of HCV, which serves as a template for the synthesis of genomic plus-strand RNA, was examined. The expression of the growth factors was semiquantified by RNA-PCR, and the mutation of p53 was detected using PCR-single-strand conformation polymorphism. According to the semiquantitative analysis, HCV replication was not associated with the expression of TGF-beta 1 but was significantly so with the overexpression of TGF-alpha (r = 0.74) and IGF-II (r = 0.65) in the HCV-positive cirrhotic livers. No mutation of p53 was recognized in any of the samples. Our investigation thus suggested that the replication of HCV might mediate the coexpression of TGF-alpha and IGF-II and act as a possible initiating factor for hepatocarcinogenesis.
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PMID:Hepatitis C virus replication is associated with expression of transforming growth factor-alpha and insulin-like growth factor-II in cirrhotic livers. 856 58

TGF-beta 1 has been implicated in the pathogenesis of liver disease. The high frequency of detection of the hepatitis B virus X (HBx) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that expression of HBx and TGF-beta 1 may be associated. To test this possibility, we examined the expression of TGF-beta 1 in the liver of transgenic mice expressing the HBx gene. We show that the patterns of expression of TGF-beta 1 and Hbx protein are similar in these mice and that HBx activates transcription of the TGF-beta 1 gene in transfected hepatoma cells. The cis-acting element within the TGF-beta 1 gene that is responsive to regulation by Hbx is the binding site for the Egr family of transcription factors. We further show that the Egr-1 protein associates with the HBx protein, allowing HBx to participate in the transcriptional regulation of immediate-early genes. Our results suggest that expression of Hbx might induce expression of TGF-beta 1 in the early stages of infection and raise the possibility that TGF-beta 1 may play a role in hepatitis B virus pathogenesis.
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PMID:Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis. 856 59

Transforming growth factor beta 1 (TGF-beta 1) is reported to play an important role in the induction of liver cell apoptosis. In this report, we demonstrate that TGF-beta 1 induces apoptosis in a rat Morris hepatoma McA-RH8994 cell line and rat primary cultured hepatocytes at similar doses and in a similar manner. Using McA-RH8994 cells, we screened a number of chemical reagents, aqueous extracts of crude drugs, and herbal medicines for their inhibitory activities on TGF-beta 1-induced apoptosis. The results indicate that Artemisiae capillaris spica (ACS) and the ACS-containing herbal medicine Inchin-ko-to, which are used for treatment of various liver disorders, exhibited the most potent anti-apoptotic activity. Various chemicals that were reported as inhibitors of apoptosis in other experimental systems showed no evident activity. By contrast, two of nine ACS ingredients we tested, capillin and capillene, showed activity at concentrations of submicrogram per milliliter. The inhibitory effects of Inchin-ko-to, capillin and capillene were also confirmed on TGF-beta 1-induced apoptosis of rat primary cultured hepatocytes. Inhibition of undesired apoptosis induced by TGF-beta 1 is expected to be beneficial for the treatment of various inflammatory liver diseases. Our findings therefore suggest the possibility that therapeutic effects of Inchin-ko-to on liver diseases might be associated with its inhibitory activity on TGF-beta 1-induced liver cell apoptosis.
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PMID:The herbal medicine Inchin-ko-to inhibits liver cell apoptosis induced by transforming growth factor beta 1. 861 37

We have previously shown that co-expression of c-myc and transforming growth factor (TGF)-alpha as transgenes in mouse liver results in major enhancement of neoplastic development in this organ as compared with expression of either of these transgenes alone. In this report we describe in detail the progression from liver cell dysplasia to hepatocellular carcinomas (HCCs) occurring in the liver of c-myc/TGF-alpha and c-myc transgenic mice. Despite morphological similarities in the sequence of events between the two transgenic lines, the dramatic acceleration, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice clearly demonstrated the synergistic effects of this transgenic combination. Although c-myc/TGF-alpha and c-myc females displayed longer latency and lower tumor incidence, the pathological changes were the same as those seen in the male mice, including the formation of HCCs, which are absent in TGF-alpha single-transgenic females. Tumors in single- and double-transgenic mice showed induction of the endogenous c-myc and TGF-alpha and, most frequently, unchanged or decreased epidermal growth factor receptor, further indicating the collaborative role of c-myc and TGF-alpha in providing a selective growth advantage to tumor cells independently of the epidermal growth factor receptor levels. To identify possible tumor precursors, we focused particularly on the dysplastic changes preceding and accompanying the appearance of preneoplastic and neoplastic lesions in the double-transgenic mice. Early on, these changes were characterized by the appearance of large dysplastic hepatocytes, mostly pericentrally, expressing high levels of TGF-alpha and uPA, as well as TGF-beta 1, particularly in apoptotic cells. After a short period of replication and expansion into the liver parenchyma, as well as penetration into the central veins, these cells underwent apoptotic cell death while preneoplastic and neoplastic lesions were forming. The peritumorous tissues also contained small dysplastic hepatocytes and oval-like cells, similar to those found in the tumors. Transplantation of the transgenic liver tissues harboring only dysplasia with or without vascular lesions onto nude mice was able to yield HCCs composed of small diploid cells, suggesting that initiated cells are generated during the early dysplastic phase and can progress to HCC. It is therefore likely that large dysplastic hepatocytes undergo apoptosis, which may be closely associated with the up-regulation of TGF-beta 1 and uPA, whereas other cells evolve into the precursor population for HCC. Due to the simultaneous presence of c-myc, TGF-alpha, and dysplasia in premalignant human liver diseases, our transgenic mouse system appears to be an appropriate model for studying human hepatocarcinogenesis.
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PMID:Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha. 870 81

We screened genes responsive to transforming growth factor-beta (TGF-beta 1) protein in a human hepatoma cell line (Hep3B) using a PCR-mediated differential display technique, in order to investigate the mechanisms involved in TGF-beta-induced growth suppression. We found a gene that was down-regulated by TGF-beta 1 to be completely identical in an approx. 620 bp segment to the gene for the enzyme spermidine synthase, which mediates the conversion of putrescine into spermidine. Both spermidine synthase mRNA expression and its enzyme activity were decreased after TGF-beta 1 treatment of Hep3B cells. The inhibition of spermidine synthase gene expression by TGF-beta 1 protein was also observed in other hepatoma cell lines. The expression of genes for other biosynthetic enzymes in polyamine metabolism (ornithine decarboxylase and S-adenosylmethionine decarboxylase) was also inhibited to the same extent as for spermidine synthase, while the gene expression of spermidine/spermine N1-acetyltransferase, a catabolic enzyme, was relatively resistant to TGF-beta 1. Spermine levels in Hep3B cells were decreased by TGF-beta 1 treatment, although the levels of spermidine and putrescine were unchanged, probably due to compensation by remaining spermidine/spermine N1-acetyltransferase activity. Exogenously added spermidine or spermine, but not putrescine, partially antagonized the growth-inhibitor effects of TGF-beta 1 on Hep3B cells. Our data suggest that down-regulation of gene expression of the enzymes involved in polyamine metabolism, including spermidine synthase, may be associated with the mechanism of TGF-beta-induced growth suppression.
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PMID:Inhibition of spermidine synthase gene expression by transforming growth factor-beta 1 in hepatoma cells. 902 Aug 92

The factors which control the balance between proliferation and cell death in hepatocellular carcinoma (HCC) remain unclear. The kinetic state of the tumor growth was investigated in the present study with references to transforming growth factor (TGF)-alpha and -beta 1 in 50 resected HCCs without preceding therapies. three-micrometer sections were cut from formalin-fixed, paraffin-embedded tumors. Proliferating cell nuclear antigen (PCNA), Lewis Y antigen (LeY). TGF-alpha, and -beta 1 were immunohistochemically stained and quantitatively assessed with an image analyzer. By means of immunohistochemical staining, a reciprocal correlation was observed between PCNA and LeY. A similar pattern was found between TGF-alpha and -beta 1, although not so strikingly as in the case of PCNA and LeY. The expression of LeY and PCNA labeling index (LI) ranged from 0 to 56.1% and from 0 to 52.8%, respectively. A correlation was observed between LeY and tumor size (r = 0.302, p < 0.04), while there was no significant relationship between PCNA LI and tumor size (r = -0.048, p > 0.05). The positive area ranged from 0 to 61.6% for TGF-alpha, and from 0.6 to 71.5% for TGF-beta 1. Analysis of these data showed a significant correlation between TGF-beta 1 and tumor size (r = -0.327, p < 0.03). Among HCCs < 5 cm, PCNA LI positively correlated with tumor size (r = 0.399, p < 0.04), but negatively with TGF-beta 1 (r = -0.431, p < 0.03). In conclusion, the present investigation indicates that the simultaneous analyses of proliferating and apoptotic activities by means of PCNA and LeY could yield more accurate data to determine the kinetic state of the tumor growth compared with either alone. In addition, TGF-beta 1 might act as a suppressive factor in the growth of HCC < 5 cm.
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PMID:Growth kinetic study of human hepatocellular carcinoma using proliferating cell nuclear antigen and Lewis Y antigen: their correlation with transforming growth factor-alpha and beta 1. 914 7

To assess the clinical relevance of transforming growth factor-beta 1 (TGF-beta 1) in the urine of patients with hepatocellular carcinoma (HCC), TGF-beta 1 was measured, by radioimmunoassay, in 140 patients with HCC, 50 cirrhotic patients, 30 patients with chronic active hepatitis, and 50 healthy controls. The results indicate that there were significantly increased urinary TGF-beta 1 levels in patients with HCC. Raised TGF-beta 1 levels were associated, in a dose-related fashion, with increased risk for development of HCC (odds ratio, 1.05, 95% confidence interval, 1.03-1.07). HCC patients with raised TGF-beta 1 levels had shorter survival than those with normal TGF-beta 1 levels (p = 0.038). TGF-beta 1 levels decreased after successful anticancer therapy (p < 0.0001). There was an inverse correlation between TGF-beta 1 and serum alpha-fetoprotein (AFP) (r = -0.199, p < 0.04). Receiver operating characteristics (ROC) curve analysis indicated that parallel determination of TGF-beta 1 and AFP significantly increased the sensitivity and diagnostic accuracy, with a high specificity. In conclusion, raised urinary TGF-beta 1 was associated with HCC development. It is a predictor of poor prognosis, and a tumor marker for diagnosis and therapeutic follow-up of HCC.
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PMID:Clinical relevance of transforming growth factor-beta 1 in the urine of patients with hepatocellular carcinoma. 919 56

There is now good evidence that cytokines contribute to the regulation of tumor growth. The cytokine-driven modulation of tumor growth was investigated during the progression of a hepatocellular carcinoma (HCC) in SV40 large T tumor antigen transgenic mice. In vivo, an increased rate of liver growth correlated with increased transforming growth factor (TGF)-beta 1 mRNA expression, while the greatest amounts of tumor necrosis factor (TNF)-alpha mRNA were detected earlier during tumor development. Conversely, no particular alteration of IL-1 alpha, IL-1 beta, IL-6, IL-2, IL-4 and IFN-gamma mRNA production could be reported. In vitro, hepatocyte-like tumor cell lines established at two stages, either before or after HCC differentiation, were characterized. The early-stage-derived cell line produced TNF-alpha mRNA, but had barely detectable expression of TGF-beta 1 mRNA, while later-stage-derived cell lines showed the reciprocal pattern. All cell lines displayed a lack of sensitivity to TNF-alpha, although some degree of sensitivity to TNF-alpha could be observed in the presence of actinomycin-D or after treatment with IFN-gamma. The early-stage-derived cell line was sensitive to the growth inhibitory effects of TGF-beta 1, but late-stage-derived tumor cell lines displayed a loss of sensitivity to TGF-beta 1 which correlated with the increased expression of TGF-beta 1 mRNA. Altogether, this suggests that tumor cells contribute to the discrete TNF-alpha and TGF-beta 1 expression patterns during HCC progression. This model of HCC could be of valuable interest to assess the impact of various immunotherapeutic strategies on modulation of tumor growth.
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PMID:Critical stages of tumor growth regulation in transgenic mice harboring a hepatocellular carcinoma revealed by distinct patterns of tumor necrosis factor-alpha and transforming growth factor-beta mRNA production. 935 45

Characteristics of human hepatoma cell lines with the wild-type p53 were compared with those of human hepatoma cell lines with the mutant-type p53. The p21 protein located downstream of p53 was expressed in cell lines with the wild-type p53 but was not expressed in cell lines with the mutant-type p53. As to other tumor suppressor genes such as p16 and p27, there was no difference in their expression between both types of cell lines. In addition, no marked difference was observed in the activities of CDK2 and CDK4 between cell lines with the wild-type and the mutant-type p53. Phosphorylated Rb protein was detected in all cell lines except the HLE line, indicating that this cell line may have a deletion of and/or a mutation of the Rb gene. These results indicate that abnormalities of tumor suppressor genes other than p53, p16, p27, and Rb may be involved in hepatocarcinogenesis. The population doubling time of the wild-type p53 cells was significantly longer than that of the mutant p53 cells. Neither type of cell line showed a specific chromosome distribution which would indicate karyotype instability. The cell lines expressing the wild-type p53 produced tumors at lower frequency than those with the mutant p53 gene. Although there was no significant difference in effects of TGF-beta 1, EGF, cholera toxin, and db-cAMP on cell growth between the two types of cells, all three cell lines with the wild-type p53 were resistant to cytotoxicity of TNF-alpha, while two of the three with the mutant p53 were very sensitive to its cytotoxic effects.
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PMID:Comparison of cellular characteristics between human hepatoma cell lines with wild-type p53 and those with mutant-type p53 gene. 943 73

IL-6 is a pleiotropic cytokine that modulates the diverse functions of hepatocytes such as acute phase responses and inflammation. When human hepatoma cells, Hep3B cells, were treated with IL-6, p140 was phosphorylated rapidly and reached its maximal rate at 1 min after treatment. Okadaic acid, an inhibitor of protein phosphatase 1 and 2A, affected IL-6-induced p140 phosphorylation. Interferon regulatory factor-1 (IRF-1) is a transcription factor on the enhancer of type I interferons, and its gene expression is induced by IL-6. When IRF-1 promoter-luciferase construct was transfected into Hep3B cells, okadaic acid increased IL-6- induced IRF-1 promoter activity. In addition, co-transfection of protein phosphatase 2A (PP2A) antisense constructs further increased IL-6-induced IRF-1 promoter activity, suggesting that PP2A is involved in IL-6 signaling. In addition, IL-6 directly induced the PP2A phosphorylation. PP2A phosphorylation was maximal at 1 min after IL-6 stimulation, but it was not induced by other inflammatory cytokines such as TNF-alpha or TGF-beta. Furthermore, IL-6 activated PP2A activity simultaneously. Taken together, these data indicate that IL-6 modulates the functions of PP2A which is involved in downstream events of IL-6 signaling in Hep3B.
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PMID:Roles of protein phosphatase 2A in IL-6 signal transduction in Hep3B cells. 965 61

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