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)

The incidence of hepatocellular carcinoma (HCC) is increasing in the United States. Several modalities are available for the treatment of HCC, and decisions regarding the optimal choice of therapy are based on tumor burden and severity of liver disease. Classification systems are helpful for prognostic purposes and to guide in the choice of therapy. Surgical resection is a mainstay of therapy for patients with solitary small tumors and preserved liver function (noncirrhotic or Child-Pugh class A cirrhotic patients without portal hypertension). Unfortunately, a minority of patients is eligible for resection, and postoperative recurrence or de novo HCC is common. Liver transplantation offers the best chance of curing HCC in cirrhotic patients. Patients with a solitary tumor less than 5 cm or no more than three tumors each 3 cm or less have a survival rate of 70% with less than 20% recurrence at 5 years. Access to liver transplantation is limited by organ availability, and tumor progression during the waiting period can lead to ineligibility. Ethanol injection and radiofrequency ablation are effective modalities to ablate small tumors (generally <5 cm) in patients who are not candidates for resection or liver transplantation. These modalities can also be used to treat HCC prior to liver transplantation. Transarterial chemoembolization is used to treat patients with multifocal or large HCC who are ineligible for other therapies. Chemotherapeutic agents are infused into the tumor via the hepatic artery along with embolic material in order to induce tumor necrosis. This technique should be used in selective patients with relatively preserved liver function, absence of portal vein thrombosis, or encephalopathy. Limited data exist to support the use of this modality as a primary treatment option for small HCC. Chemotherapeutic or hormonal therapies have a limited role in the management of patients with HCC. Despite mixed outcomes, we routinely use the somatostatin analog octreotide in advanced, multifocal HCC. Emerging therapies should focus on treatment of small tumors and targeted pharmacologic therapy for advanced disease.
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PMID:Treatment of Hepatocellular Carcinoma. 1458 35

The Hep G2 human hepatoma cell line has been recognized as an excellent in vitro human model system. For this reason, this line was used to study the effect of ethanol on HMG-CoA reductase activity concerning cell growth and cholesterol metabolism. Cells were incubated in ethanol-containing medium (0-400 mmol/L) for up to 102 h. Ethanol caused an inhibition in the growth rate and in HMG-CoA reductase activity that could be reverted by the removal of ethanol from the culture medium, indicating no cellular damage. These changes cannot be ascribed to the regulatory effect of cholesterol levels, since its content was not modified either in the cells or in the medium. The addition of mevalonate to the culture medium could not revert the growth rate inhibition evoked by ethanol. Moreover, ethanol produced an increment in the cholesterol efflux in [3H]cholesterol-prelabeled cells. We conclude that the decrease in HMG-CoA reductase activity evoked by ethanol treatment on Hep G2 cells would not be the cause but the consequence of the impairment in cellular growth, since this impairment could not be reverted by the addition of mevalonate to the culture medium.
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PMID:Effect of ethanol on cell growth and cholesterol metabolism in cultured Hep G2 cells. 1466 4

This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.
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PMID:Oxidative stress, toxicology, and pharmacology of CYP2E1. 1474 37

Due to modern diagnostic imaging and the sensitive alpha-fetoprotein test, small hepatocellular carcinoma can now be detected at an early stage. Studies have shown that surgical resection of the tumors is a valuable treatment. Local treatment under ultrasound guidance was initially considered as an alternative when patients' liver reserves were not good enough for surgical resection; however, this technique has been improved and the results indicate that its survival rate can compete with that of surgical resection. In follow-up studies of patients with small hepatocellular carcinoma, a 5-year survival of 60% has been achieved after percutaneous ethanol injection therapy. Percutaneous microwave coagulation therapy and percutaneous radiofrequency ablation therapy have been shown to have some advantages over percutaneous ethanol injection therapy, although the follow-up durations of these studies were not long enough. Percutaneous ethanol injection therapy, percutaneous microwave coagulation therapy and percutaneous radiofrequency ablation therapy have become the 3 most widely used techniques for the treatment of hepatocellular carcinomas that are less than 5 cm in diameter and have a tumor number less than 3. In general, a tumor size of 3 to 5 cm is a good candidate for radiofrequency ablation and a tumor size of 2 to 3 cm is suitable for radiofrequency ablation or microwave coagulation. If the tumor size is around 2 cm or less, microwave coagulation or ethanol injection is often chosen due to the relatively low cost and similar efficacy. Ethanol injection also has the advantage of needing only a fine needle for injection. Informed selection of the appropriate technique, or combining a technique with transcatheter hepatic arterial embolization according to the tumor size and number, might provide the most effective treatment and achieve better results for hepatocellular carcinoma, even if the liver reserve is not good. However, large-scale, randomized, controlled trials are required before a definitive conclusion can be reached.
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PMID:Current role of local ablative treatments for hepatocellular carcinoma. 1527 82

Chronic ethanol consumption leads to cell injury in virtually every tissue. Tumor necrosis factor-alpha (TNF-alpha) constitutes a major factor in the development of alcohol-induced liver injury. In alcohol-dependent subjects, elevated levels of plasma TNF-alpha are strongly predictive of mortality. Binding of TNF-alpha to TNF-alpha receptor-1 (TNF-R1) activates death domain pathways, leading to necrosis and apoptosis in most tissues, and it also increases the expression of intercellular adhesion molecules (i.e., ICAM-1), which promote inflammation. We determined whether ethanol exposure leads to increases in cellular TNF-R1. We incubated HepG2 human hepatoma cells and H4-II-E-C3 rat hepatoma cells with 25, 50, and 100 mM ethanol for various intervals of time up to 48 h. Human colonic adenocarcinoma cells (Caco-2 cells) and neonatal rat primary cardiomyocytes were also incubated with different concentrations of ethanol. Levels of TNF-R1 were measured either by a sandwich enzyme-linked immunosorbent assay (ELISA) method or by determining the extracellular transmembrane domain of TNF-R1 by an intact-cell ELISA method. Ethanol exposure for 48 h increased TNF-R1 levels in human hepatoma cells in a dose-dependent manner. Levels increased significantly by 164% at 50 mM and by 240% at 100 mM ethanol. Effects were time dependent and did not reach a plateau at 48 h. Similar increases in TNF-R1 were also observed in rat hepatoma cells (90% at 50 mM and 230% at 100 mM ethanol). Under similar conditions, Caco-2 cells showed a significant 80% increase in TNF-R1 levels at 200 mM ethanol, a concentration found in intestine. Neonatal rat primary cardiomyocytes showed TNF-R1 increases of 36% at 50 mM and 44% at 100 mM ethanol. These results indicate that exposure of different cell types to pharmacologic concentrations of ethanol increases TNF-R1 levels and may augment TNF-alpha-mediated cell injury in different tissues.
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PMID:Ethanol increases tumor necrosis factor-alpha receptor-1 (TNF-R1) levels in hepatic, intestinal, and cardiac cells. 1535 69

Ethanol consumption represents a major risk factor for cancer development, and a significant fraction of hepatocarcinomas arises in alcoholic liver cirrhosis. Increasing evidence indicates that ethanol acts as a tumor promoter on genetically initiated cells, by increasing the intracellular concentration of reactive oxygen species and promoting tissue necrosis/regeneration and cell proliferation. The tumor suppressor p53 restrains the expansion of carcinogen-initiated cells by inducing cell cycle arrest and apoptosis; accordingly, p53-deficient mice develop spontaneous and chemically induced neoplasms at a much higher frequency than normal mice. In normal mice exposed to a subacute (3 weeks) ethanol intoxication, a significant increase in the number of apoptotic hepatocytes was observed in concomitance with the up-regulation of the mitochondrial superoxide scavenger MnSOD, a reliable indicator of oxidative stress. Cell death occurred in the absence of liver inflammation and necrosis. Ethanol-induced hepatocyte apoptosis was completely abrogated in the p53 null background, suggesting that the tumor suppressor is necessary for hepatocyte death by ethanol. Accordingly, p53 -/- MEF were, unlike wild type cells, completely insensitive up to 0.5M ethanol in the culture medium. Strikingly, marked and widespread signs of dysplasia, with nuclear pleomorphisms and initial loss of normal architecture, heralding malignant transformation, were scored in all the mutant mice exposed to ethanol, but not in the control-fed littermates nor in ethanol-fed normal mice. These observations suggest that p53-dependent apoptosis restrains the tumorigenic effect of ethanol on liver cells, in agreement with the frequent loss of p53 function in HCC, and reveal an unexpected carcinogenic potential of alcohol which appears to be independent from the induction of cirrhosis and hepatocyte regeneration.
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PMID:Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice. 1552 6

Image-guided percutaneous ablation is currently accepted as the best therapeutic option for nonsurgical patients with early-stage hepatocellular carcinoma. Ethanol injection is the seminal technique for local tumor treatment, and may achieve 50% 5-year survival in selected Child A patients. Radiofrequency ablation constitutes the most assessed alternative technique. On the basis of the identified evidence, radiofrequency ablation seems to reach higher recurrence-free survival rates compared with ethanol injection. Further randomized trials are needed to establish the clinical efficacy of radiofrequency ablation with respect to other percutaneous treatments and to devise an unbiased therapeutic strategy.
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PMID:A critical appraisal of the literature on local ablative therapies for hepatocellular carcinoma. 1583 Dec 75

Hepatocellular carcinoma is the eighth most frequent cancer in the world, accounting for approximately 500,000 deaths per year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly within the context of known risk factors, with hepatic cirrhosis being the most common precursor to the development of hepatocellular carcinoma. After ethanol ingestion, the liver represents the major site of metabolism. Ethanol metabolism by alcohol dehydrogenase leads to the generation of acetaldehyde and free radicals that bind rapidly to numerous cellular targets, including components of cell signaling pathways and DNA. In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic ethanol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde and, in doing so, causes further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants as therapeutic agents. Included in this group are S-adenosyl-L-methionine and plant-derived flavanoids.
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PMID:Alcohol and liver cancer. 1605 81

Chronic and excessive alcohol consumption is an important and modifiable risk factor for type 2 diabetes. We previously reported elevations in hepatic Class 1 alcohol dehydrogenase (ADH) expression in ethanol-fed rats correspondent with reduced levels of mature, nuclear sterol-regulatory element-binding protein-1 (SREBP-1), an insulin-induced transcriptional repressor of the ADH gene. In this report, we have studied the effects of insulin and ethanol on ADH gene expression in a highly differentiated rat hepatoma cell line (FGC-4), as well as the in vivo effects of chronic intake of an ethanol-containing diet on hepatic insulin signaling. Insulin inhibited ADH gene expression, and this was abolished by LY294002 (a phosphatidylinositol 3-kinase inhibitor) and small interfering RNA knockdown of SREBP-1. Chronic ethanol intake led to decreased phosphorylation of Akt (protein kinase B) at Thr308, increased phosphorylation of Akt at Ser473, and decreased phosphorylation of glycogen synthase kinase-3beta (a downstream effector of Akt). Hepatic membrane-associated Akt content was decreased and cytosolic Akt content was increased in rats fed an ethanol-containing diet. Thus, disruptive effects of ethanol on insulin signaling occurred via impaired phosphorylation of Akt at Thr308. TRB3, a negative regulator of Akt, was induced in liver of ethanol-fed rats. In ethanol-treated FGC-4 cells, small interfering RNA knockdown of TRB3 increased membrane-associated Akt and the phosphorylation of Akt at Thr308. Our results suggest that ethanol induces TRB3, which, through binding to the pleckstrin homology domain of Akt, prevents its plasma membrane association, Akt-Thr308 phosphorylation, and subsequent Akt-mediated signaling. Ethanol inhibition of insulin signaling reduces nuclear SREBP accumulation and results in disinhibition of Class 1 ADH transcription.
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PMID:Chronic ethanol intake impairs insulin signaling in rats by disrupting Akt association with the cell membrane. Role of TRB3 in inhibition of Akt/protein kinase B activation. 1645 80

Corticosteroid-binding globulin (CBG) is a plasma glycoprotein that is primarily synthesized in the liver and binds cortisol and progesterone with high affinity. In this study, a CBG secreting hepatocellular carcinoma derived cell line (HepG2) was used to investigate the hormonal regulation of hepatic CBG synthesis. HepG2 cells were grown for 72 h in 30, 300 and 3000 nM concentrations of estradiol (E2), testosterone (T), insulin, thyroxin (T4) and dexamethasone (DMZ) and the secreted CBG quantified by a novel enzyme-linked immunosorbent assay (ELISA). Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) was carried out to determine the effects of these hormones on the relative distribution of CBG glycoforms. Insulin, T4 and high concentrations of E2 decreased the secretion of CBG by HepG2 cells (p<0.05). Ethanol, the solvent used for E2, T and DMZ, also significantly attenuated CBG secretion. 2D-PAGE resolved 13-14 glycoforms of CBG produced by HepG2 cells. Insulin caused a reduction in the synthesis of more acidic, while T4 and DMZ decreased the production of more basic CBG glycoforms. Stimulation with E2 resulted in the synthesis of additional isoforms of increased acidity, which may represent a type of CBG only seen during pregnancy in vivo. Possible physiological implications of these findings are discussed.
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PMID:Hormonal effects on the secretion and glycoform profile of corticosteroid-binding globulin. 1702 48


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