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)

We have established two cell lines of hepatocellular carcinoma [Hep-KANO, clone 1 (CL-1) and clone 2 (CL-2)] from tissue obtained at autopsy of a hepatitis B virus (HBV) carrier without histological signs of hepatitis or liver cirrhosis. These cell lines differed considerably from each other in morphology, proliferation pattern, alpha-fetoprotein secretion, albumin synthesis, cytokine secretion, modal chromosome number and transplantability to nude mice. Histologic examinations also revealed differences between them. Amplification of N-myc, L-myc, H-ras, K-ras, N-ras, c-erb-B and c-erb-B-2 and rearrangement of p53 were not found in either of the cell lines. However, CL-1 and CL-2 showed an identical HBV-DNA integration pattern. A 4-fold amplification of c-myc was observed in CL-1, but not in CL-2. Hep-KANO cell lines, CL-1 and CL-2 may be useful in clarifying the question of whether hepatocarcinogenesis is directly caused by HBV infection.
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PMID:Characteristics of human hepatocellular carcinoma cell lines (Hep-KANO) derived from a non-hepatitic, non-cirrhotic hepatitis B virus carrier. 782 95

In the present studies, insulin was found to stimulate in a rat hepatoma cell line (called FAO cells) the tyrosine phosphorylation of the 60-kilodalton p21ras GTPase-activating protein (GAP)-associated protein called p60. Surprisingly, the tyrosine phosphorylation of this protein was also almost equally stimulated by an activator of protein kinase C (PKC), the phorbol ester phorbol 12-myristate 13-acetate (PMA). The tyrosine phosphorylation of p60 induced by either agent correlated with the formation of the GAP-p60 complex in situ and an increase in the ability of p60 to directly bind to the SH2 domain of GAP in vitro. Several lines of evidence indicated that the PMA-induced tyrosine phosphorylation of p60 occurred through a different mechanism than that induced by insulin. First, the stimulation of tyrosine phosphorylation of p60 by maximal concentrations of the two agents was almost additive. Second, down-regulation of PKC or pretreatment with a specific inhibitor of PKC abolished the ability of PMA to stimulate tyrosine phosphorylation of p60 but had no effect on the insulin stimulation. And third, long-term pretreatment with insulin abolished the insulin response but did not affect the response to PMA. The PMA effect did seem to be mediated via a tyrosine kinase, since it was blocked by quercetin, an inhibitor of tyrosine kinases. These results indicate that both PMA and insulin can equally stimulate in FAO cells the tyrosine phosphorylation of p60 and its association with GAP, although these two agents seem to act via different signaling systems.
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PMID:Activation of protein kinase C stimulates the tyrosine phosphorylation and guanosine triphosphatase-activating protein association of p60 in rat hepatoma cells. 783 79

Hepatic tumors were generated in mice by repeated administration of carbon tetrachloride (CCl4). Eight transgenic (Tg) mice carrying a human c-H-ras proto-oncogene (rasH2 line) and 9 non-Tg mice were killed at 20 weeks. Tg mice developed more tumors than did non-Tg littermates. Most tumors were neoplastic nodules, but 1 hepatocellular carcinoma (HCC) was found in a Tg mouse at 20 weeks. Three Tg and 2 non-Tg mice were kept without further administration of CCl4. Two Tg mice died at 30 weeks of HCC with intra-abdominal bleeding, and 1 Tg mouse developed HCC with a mesenteric metastasis at 32 weeks. No HCC was found in 2 non-Tg mice at 32 weeks. Although mutations at codon 12, 13, and 61 of the H-ras gene are often found in murine hepatocarcinogenesis, neither the tumors, including one HCC, nor the normal cells revealed any such mutations. These results showed that the unmutated human c-H-ras gene facilitates malignant transformation of hepatocytes when continuous liver-cell death and regeneration is caused by repeated administration of CCl4.
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PMID:Hepatic tumors induced by carbon tetrachloride in transgenic mice carrying a human c-H-ras proto-oncogene without mutations. 796 Feb 26

Modulation of cell growth by a combination of pravastatin [a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor] and d-limonene (an inhibitor of protein isoprenylation) was studied using Hep G2, a human hepatoma-derived cell line. Pravastatin, at 0.1 mM, produced 85% inhibition of cholesterol biosynthesis in Hep G2 cells. The combination of 0.1 mM pravastatin and 1.0 mM d-limonene had no further effect on the reduction seen with pravastatin alone. Addition of 0.1 mM pravastatin or 1.0 mM d-limonene did not significantly suppress DNA synthesis by the cells, whereas the combination suppressed it to 50% of the control level. Production of m-p21ras was markedly decreased to 35% of the control level by the combination of these two inhibitors. Both the reduction by pravastatin of farnesylpyrophosphate as substrate for protein:farnesyl transferase and inhibition of protein farnesylation by d-limonene seem to be responsible for the profound suppression of m-p21ras formation in the cells. However, dolichol synthesis was not suppressed by the combination of these inhibitors. In human fibroblasts, the combination suppressed m-p21ras production but not DNA synthesis. These findings suggest that the combination of pravastatin and d-limonene acts on cancer cell growth through inhibition of the post-translational processing of cellular proteins including p21ras, rather than through the suppression of cholesterol and dolichol biosynthesis. Thus, the combination of an HMG-CoA reductase inhibitor and an inhibitor of protein isoprenylation offers potential as a new approach for cancer therapy.
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PMID:Modulation of the mevalonate pathway and cell growth by pravastatin and d-limonene in a human hepatoma cell line (Hep G2). 819 62

It has been suggested that hepatocytes have the ability to form bile ductal structures during normal development and in various pathological conditions of the liver. In the present study, we attempted to establish an in vitro model of ductal morphogenesis of hepatocytic cells by combining an aggregate culture and a type I collagen gel culture. When spheroidal aggregates of rat or mouse primary hepatocytes were embedded within the collagen gel matrix and then cultured with a medium containing a fibroblast-conditioned medium, the aggregates extended many dendritic processes composed of a trabecular arrangement of cells. Dendritic morphogenesis was also seen in embedded aggregates of immortal liver epithelia] cell lines, which spontaneously emerged during long-term cultures of mouse primary hepatocytes. A similar morphogenesis was induced by the presence of insulin in the medium. Although epidermal growth factor (EGF) and hepatocyte growth factor (HGF) showed only a small effect on the morphogenesis of most of the hepatocytic cells when used alone, these factors, especially EGF, enhanced the morphogenetic effect of insulin. Electron microscopical observations revealed luminal structures lined by microvilli within these dendritic processes, indicating ductal differentiation. Immunocytochemically, the dendritic processes were positive for cytokeratin 19, a marker for bile duct cells. On the other hand, an H-ras-transformed mouse liver epithelial cell line and rat hepatocellular carcinoma cell lines did not demonstrate the organized morphogenesis. Our results indicate that hepatocytic cells can produce bile duct-like structures in the presence of the type I collagenous matrix and soluble morphogenetic factors.
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PMID:Hepatocytic cells form bile duct-like structures within a three-dimensional collagen gel matrix. 860 13

We have previously demonstrated that hepatitis C virus (HCV) core protein regulates cellular protooncogenes at the transcriptional level; this observation implicates core protein in the alteration of normal hepatocyte growth. In the present study, the transforming potential of the HCV core gene was investigated by using primary rat embryo fibroblast (REF) cells which were transfected with or without cooperative oncogenes. Integration of the HCV core gene resulted in expression of the viral protein in REF stable transformants. REF cells cotransfected with HCV core and H-ras genes became transformed and exhibited rapid proliferation, anchor-independent growth, and tumor formation in athymic nude mice. Results from these studies suggest that the core protein plays an important role in the regulation of HCV-infected cell growth and in the transformation to tumorigenic phenotype. These observations suggest a possible mechanism for this viral protein in the pathogenesis of hepatocellular carcinoma in HCV-infected humans.
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PMID:Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. 867 67

In order to investigate the action of oncogenes in experimental hepatocarcinogenesis, the expression of c-myc, N-ras and H-ras were studied during early and late stages of DENA induced hepatocarcinogenesis in rats by using in situ hybridization. The results showed that overexpression of c-myc and N-ras was presented in teh proliferation hepatocytes and alternated hepatocytes foci during the early stage of hepatocarcinogenase, and with the formation and progression of hyperplastic hepatocytic nodules, the overexpresion cells of both were increased and often accompanied each other. Overexpression of H-ras appeared in the middle stage of hepatocarcinogenesis. The data obtained indicate that the abnormal expression of N-ras and c-myc in the hepatocarcinogenesis is not only an earlier molecule event which may relate to the initiation of HCC, but also the molecular basis for the morphogenesis of HCC, and these two functions took synergically. However, the abnormal expression of H-ras may have a promotive effect on the development of preneoplastic lesions, and also suggests that the malignant transformation of hepatocyte needs the cooperation of multiple oncogenes.
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PMID:[In situ expression of c-myc, N-ras during diethylnitrosamine induced hepatocarcinogenesis]. 874 81

The expression of PCNA and the protooncogenes of ras family (N-ras, H-ras and Ki-ras) in hepatocarcinoma cells and the proliferating liver cells in precancerous, hyperplastic nodules during experimental hepatocarcinogenesis, induced by diethylnitrosamine in rat liver was observed immunohistochemically and by in situ hybridization. The results indicated that there was a positive expression of PCNA in both the carcinomas cells and precancerous liver cells. The amount of PCNA-positive cells exhibited a negative correlation with the amount of infiltrating mast cells surrounding carcinoma cell nests and the hyperplastic, precancerous nodules. These results basically coincided with that of the separate observation of the expression of protooncogenes in the same study.
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PMID:[Expression of PCNA and protooncogenes during experimental hepatocarcinogenesis in rats]. 876 41

IRS-1 has been found to relay the signals from the receptors for insulin, insulin-like growth factor-1, growth hormone, and many cytokines for the downstream effects in the various cell types tested. For interleukin 4 signaling, most studies were performed on hematopoietic cells and cell lines transfected with rat liver IRS-1 cDNA. In a liver cell lineage, IRS-1 expression has been found to be increased in hepatoma cells and hepatocytes in regenerating liver. To elucidate the possible function and the signal transduction pathway for interleukin 4, in comparison with insulin, in liver cells, we used the Hep 3B hepatoma cell line as a model system. Following insulin and interleukin 4 stimulation, rapid tyrosyl phosphorylation of IRS-1 occurred. Interleukin 4, but not insulin, stimulated the tyrosine phosphorylation of JAK1 and, to a lesser extent, JAK2. In contrast to the other cell types, the association of IRS-1 and Grb2 through the SH2 of Grb2 was demonstrated after IL-4 and insulin stimulation of the Hep3B hepatoma cells. Both insulin and interleukin 4 stimulated tyrosine phosphorylation and the enzyme activity of Erk1 kinase. Our results indicate that interleukin 4 and insulin might modulate hepatic cell growth and differentiation through many different or common pathways for the activation of JAK kinases and the usage of IRS-1 as a docking protein. The binding of IRS-1 with Grb2 after IL-4 as well as insulin stimulation may lead to MAP kinase activation, probably through the Grb2/sos/p21ras pathway.
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PMID:Signal transduction pathways for interleukin 4 and insulin in human hepatoma cells. 886 52

Recent findings suggest that over-expression of activated H-ras inhibited apoptotic cell death by blocking the activity of apoptotic endonuclease(s). This study was designed using antisense H-ras oligodeoxynucleotides (ODN) to evaluate whether alterations of H-ras expression in BEL-7402 human hepatocellular carcinoma cells could influence the induction of apoptosis in vitro and in vivo. We found that, in vitro, continuous suppression of H-ras expression could decrease the proliferation of BEL-7402 cells and inhibit H-ras-induced entry into S phase. In situ end labeling showed that a large number of cells underwent apoptotic cell death after treatment with antisense H-ras ODN (P < 0.01), and gel electrophoresis of DNA extracted from these cells demonstrated a typical DNA ladder, characteristic of apoptosis. In vivo study indicated that pretreatment with antisense H-ras significantly retarded tumor growth in comparison with the untreated controls or tumors treated with non-specific ODN (P < 0.01, P < 0.01). In situ end-labeling revealed that pronounced apoptotic nuclei were also present in the tissue treated with antisense H-ras ODN (P < 0.01). Immunocyto-histochemical study showed that expression of p21H-ras was significantly decreased after treatment with antisense H-ras. These results indicate that suppression of H-ras over-expression by antisense ODN could effectively inhibit tumor growth and revive the apoptotic pathway by releasing the activity of apoptotic endonuclease(s). The data also suggest the need for further studies to elucidate molecular events involved in antisense H-ras-released apoptosis and evaluate its therapeutic implications.
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PMID:Apoptosis of human BEL-7402 hepatocellular carcinoma cells released by antisense H-ras DNA--in vitro and in vivo studies. 899 37


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