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

For colorectal carcinomas, the rate of tumor development is proportional to the fourth to sixth power of elapsed time, suggesting that four to six independent events are necessary. Although similar calculations have not been made for HBV-associated HCCs, it is likely that this is also the case for HCCs, since individuals with persistent HBV infection do not usually develop HCC until they are 45 or greater years old. As evidence for specific genetic and epigenetic changes in HCCs accumulate, the important players in multistep hepatocarcinogenesis are becoming clearer. However, even though Myc family oncogenes are clearly implicated in woodchuck HCC, similar integrations have not been found in human HCCs. Therefore, although rodent and human systems have many similarities, we must realize that important differences may also exist. Regarding tumor suppressor genes, the evidence for p53 alterations in HCC is strong. A growing body of evidence suggests further that alterations in the retinoblastoma gene and one or more tumor suppressor genes on chromosome 11 are also involved in HCC. HBV integrations may certainly play a role in the generation of chromosome aberrations leading to loss of tumor suppressor alleles, since chromosomes 11 and 17 are the most common integration sites. Finally, the role of X proteins as participants in malignant transformation has been demonstrated for certain immortalized, nontransformed hepatocytes. Altered autocrine mechanisms of cell growth control, possibly involving IGF-II, are clearly implicated in HCC. Paracrine mechanisms for the control of hepatocyte growth and differentiated functions may also be altered as a result of the synthesis and secretion of a complex array of interleukins, HGF, and basic and acidic FGFs by cells in the inflammatory and cirrhotic lesions of precancerous livers. Whether the order of molecular changes in the hepatocyte is important for malignant progression is presently not clear. What is clear, however, is that hepatocarcinogenesis involves alterations in the concerted action of protooncogenes, growth factor, and tumor suppressor genes. How these factors interact will provide a more complete understanding of the mechanism or mechanisms of hepatic oncogenesis.
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PMID:Cellular and molecular mechanisms of hepatocarcinogenesis. 143 79

Using an automated cell analyzer system, the effect of hepatocyte growth factor/scatter factor (HGF/SF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), endothelial acidic fibroblast growth factor (a-FGF), platelet derived growth factor (PDGF), and recombinant human insulinlike growth factor (IGF) on the motility and morphology of Madin-Darby canine kidney (MDCK), rat hepatomas, C2, and H5-6 and murine mammary carcinoma (EMT-6) cells was investigated. Treatment of MDCK cells with HGF/SF, bFGF, EGF, and a-FGF resulted in an increase in average cell velocity and in the fraction of moving cells. Cells treated with the PDGF and IGF did not show significant alterations in velocity. MDCK cells treated with each growth factor were classified into groups of "fast" and "slow" moving cells based on their average velocities, and the average morphologic features of the two groups were quantitated. Fast-moving cells had larger average area, circularity, and flatness as compared to slow-moving cells. Factors that stimulated cell movement also induced alterations in cell morphologic parameters including spreading, flatness, area, and circularity. HGF/SF also scattered and stimulated motility of C2 and H5-6 hepatoma cells. In contrast to MDCK cells, there was no significant difference between the morphology of the fast moving and slow moving C2 and H5-6 cells. These studies suggest that growth factor cytokines have specific effects on motility of normal and tumor cells.
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PMID:Effect of hepatocyte growth factor/scatter factor and other growth factors on motility and morphology of non-tumorigenic and tumor cells. 751 97

The growth characteristics of a newly established cell line, Hep40, derived from a human hepatoma are described. An absolute requirement was found for serum to mediate cell growth. Neither EGF, TGF-alpha, nor HGF altered cell growth in the presence or absence of serum. A partial suppression of cell growth was achieved by several TGF-beta family proteins. Affinity crosslinking gels using 125I-labeled TGF-beta showed a significant decrease in the TGF-beta cell-surface type II receptor in Hep40 cells, compared to the TGF-beta-sensitive Hep3B cell line. However, growth could be completely suppressed by addition of vitamins K to the culture medium in both Hep40 and several other hepatoma cell lines. Growth suppression by vitamins K was accompanied by an increased level of transcripts for c-myc, c-jun, and prothrombin genes, in contrast to the actions of TGF-beta 1 protein, which caused a decrease in the level of c-myc transcripts. These data show that this new human hepatoma cell line has partial resistance to growth inhibition by TGF-beta with a unique TGF-beta receptor defect. However, growth was completely suppressed by vitamins K. The differing gene expression patterns in response to TGF-beta as compared to vitamin K suggest that these two growth inhibitors act through differing pathways.
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PMID:Growth control and gene expression in a new hepatocellular carcinoma cell line, Hep40: inhibitory actions of vitamin K. 759 24

Adhesion of cancer cells to vascular endothelium is an important step in haematogenous metastasis of cancer. A human hepatocellular carcinoma cell line, HepG2, strongly adheres to human umbilical vein endothelial cells (HUVECs) through the interaction of E-selectin and its carbohydrate ligand sialyl Lewis X. In this study, we investigated alteration in integrin expression on HepG2 cells, which follows the selectin-mediated initial adhesion of HepG2 cells to HUVECs. Expression of alpha2beta1 integrin was markedly increased when the HepG2 cells adhered to HUVECs. Among the tested cytokines that are known to be produced by endothelial cells, recombinant hepatocyte growth factor (rHGF) could replace the effect of HUVECs, and a similar increase in integrin expression was observed by the addition of 20 ng ml-1 rHGF to HepG2. The increment of alpha2beta1 integrin expression was significantly inhibited by anti-HGF neutralizing antibody treatment. HepG2 cells expressed alpha2, alpha6, beta1, and beta4 integrin subunits, but expression of integrins other than alpha2beta1 was not affected by the rHGF treatment. The rHGF treatment of HepG2 cells resulted in augmented adhesion to immobilized collagen. This augmentation in adhesion to collagen was completely blocked by the addition of anti-alpha2- or anti-beta1-integrin antibody. In double-chamber chemoinvasion experiments, transmigration of the HepG2 cells through extracellular matrix (ECM) gel was significantly accelerated by co-cultivation with HUVECs. A similar level of enhancement in transmigration activity of the cancer cells was observed by the addition of rHGF. Our interpretation of the results described above is that the cancer cells received stimulation from cytokines, such as HGF, presented by vascular endothelial cells, following the initial adhesion of cancer cells via selectins. This resulted in the secondary increment in the expression of cell adhesion molecules, such as the alpha2beta1 integrin, and led to the augmented adhesive activities of cancer cells towards extracellular matrices at vascular walls. We suggest that this sequence of events is involved in the facilitated migration of some cancer cells to extravascular tissues.
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PMID:Involvement of hepatocyte growth factor in increased integrin expression on HepG2 cells triggered by adhesion to endothelial cells. 900 May 97

Acute phase protein expression is regulated by a variety of cytokines such as IL-1, IL-6, IL-11, tumour necrosis factor alpha, interferon-gamma, oncostatin-M, leukemia inhibitory factor, ciliary neurotrophic factor and cardiotrophin-1. Presently, IL-6 is regarded as the most potent mediator of acute phase protein (APP) synthesis. It was shown that IL-6 and IL-6-type cytokines activate the so-called JAK/STAT pathway and finally regulate APP expression in liver cells. Since HGF/SF is also capable of regulating APP expression, we asked whether it might also signal via the JAK/STAT pathway. Here we show that incubation of human hepatocytes as well as hepatoma cells (HepG2) with HGF/SF results in activation of the transcription factor STAT3. This STAT3 activation after HGF/SF did not occur before 5-7 h and was maintained up to 28 h. These observations are in contrast to the rapid and transient activation of STAT1 and STAT3 mediated by IL-6.
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PMID:Hepatocyte growth factor/scatter factor (HGF/SF) signals via the STAT3/APRF transcription factor in human hepatoma cells and hepatocytes. 909 33

Regenerating liver, hepatocyte primary cultures and differentiated hepatoma cell lines are widely used to study the proliferation/differentiation/apoptosis equilibrium in liver. In hepatocytes, priming factors (TNF alpha, IL6) target G0/G1 transition while growth factors (HGF, EGF, TGF alpha) control a mid-late G1 restriction point. A characteristic pattern of cdk/cyclin expression is observed in hepatocytes, presumably related to their ability to proliferate a limited number of times and to undergo a reversible differentiation. Interestingly, cell-cell interactions between hepatocytes and liver biliary cells in co-cultures, result in a cell cycle arrest in mid G1 of hepatocytes which are insensitive to mitogens. Apoptosis exists in hepatocytes but is still poorly documented. However, hepatoma cell lines stimulated by TGF beta undergo cell death in a p53-independent pathway. In conclusion, the interplay of growth and apoptosis regulators and cell-cell interactions control the proliferation/differentiation/apoptosis balance which is a specific feature of hepatocytes.
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PMID:Progression through G1 and S phases of adult rat hepatocytes. 955 81

Activities of nuclear type 1 protein phosphatase (PP1) were significantly elevated in human HepG2 and rat AH13 hepatoma cells compared with primary cultured hepatocytes. We examined and compared the nuclear PP1 activities during the cell cycle between synchronized HepG2 cells and HGF-stimulated hepatocytes. Nuclear PP1 activity was significantly and more elevated at the G1/S transition in hepatoma cells compared with hepatocytes, although the amounts of PP1 isoforms remained constant. On the contrary, it was found that the basal levels of nuclear PP1 activity were significantly higher in hepatoma cells and that the amounts of PP1alpha and PP1delta were dramatically increased in the nuclear fraction of hepatoma cells.
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PMID:Up-regulation of nuclear PP1alpha and PP1delta in hepatoma cells. 986 17

Hepatocyte growth factor/scatter factor (HGF/SF) has been shown to play an important role in tumor migration and metastasis. We therefore investigated the relationship between HGF/SF expression and metastasis of human liver tumors. The serum HGF/SF levels in 41 patients with primary hepatocellular carcinoma (HCC; 22 patients with metastasis, 19 patients without metastasis); 4 patients with benign hepatic tumor, 4 patients with secondary hepatic carcinoma, and 12 healthy blood donors, were measured by sandwich enzyme-linked immunosorbent assay (ELISA) in this study. Our results show that liver tumor patients have significantly higher serum levels of HGF/SF compared to healthy blood donors. However, there is no difference between the serum HGF/SF levels in patients with primary HCC and patients with secondary HCC or benign hepatic tumors. In addition, we measured significantly higher levels of HGF/SF in serum from HCC patients with metastasis compared to HCC patients without metastasis, indicating that the elevations in serum HGF/SF level correlated positively with the tumor metastasis in human HCC. These findings appear to suggest that HGF/SF may be a useful serological biomarker for clinical diagnosis and follow-up of HCC metastasis, and suggest that larger scale studies in patients with hepatomas are warranted.
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PMID:Increased level of serum hepatocyte growth factor/scatter factor in liver cancer is associated with tumor metastasis. 1036 75

MAP kinase cascade-dependent responses were investigated during scattering of HepG2 human hepatoma cells stimulated by HGF or phorbol ester. Inhibition of phosphatidylinositol 3-kinase with LY294002 prevented completely the dissociation of cells. Inhibition of MAP kinase kinase (MEK) with PD98059 prevented the development of characteristic morphological changes associated with cell migration. EGF, which failed to induce cell scattering, caused a short-term increase in the phosphorylation of Erk1/Erk2 MAP kinases. On the contrary, HGF or phorbol ester stimulated the phosphorylation of MAP kinases for a long time. Experiments performed with LY294002 indicated that phosphatidylinositol 3-kinase contributed to the HGF-stimulated phosphorylation of Erk1/Erk2. This finding was confirmed by the demonstration that the MAP kinase cascade-dependent expression of a high-Mr (>300 kDa) protein pair appearing in the course of cell scattering was inhibited by LY294002 in HGF-induced cells but was not inhibited in phorbol ester-treated cells.
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PMID:Phosphatidylinositol 3-kinase contributes to Erk1/Erk2 MAP kinase activation associated with hepatocyte growth factor-induced cell scattering. 1065 96

The effects of HGF on albumin gene expression in HepG2 human hepatoma cells and rat hepatocytes were investigated. HGF reduced the levels of albumin mRNA in HepG2 cells but the level was augmented in rat hepatocytes. By the transfection assay, HGF stimulated albumin promoter activity but repressed alpha-fetoprotein (AFP) enhancer activity regulating both AFP and albumin promoters in HepG2 cells. In contrast, HGF stimulated albumin promoter and AFP enhancer activities in rat hepatocytes. These results suggest that HGF elicits diverse responses of albumin gene expression in HepG2 cells and rat hepatocytes through the different biological actions on AFP enhancer in these cells.
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PMID:Diverse regulations of albumin gene expression by hepatocyte growth factor in HepG2 human hepatoma cells and primary culture of rat hepatocytes. 1081 87


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