Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) have the ability to degrade basement membranes and may thus play an important role in extracellular matrix turnover in liver fibrosis and carcinogenesis. Serum levels of MMPs have been suggested as diagnostic markers in these processes. We measured serum MMP-2 and MMP-9 by ELISA in 91 patients with chronic liver disease, including 25 patients with hepatocellular carcinoma (HCC), and in 60 controls. MMP-2 was significantly higher in patients with chronic liver disease compared to controls, and increased with Child-Pugh class. There was a significant correlation between MMP-2 and liver function (bilirubin, albumin, and prothrombin time), and a strong opposite correlation between MMP-9 and these parameters. MMP-2 levels in patients with HCC were significantly higher than in controls, but comparable to patients with chronic liver disease without this malignancy. MMP-9 yielded no significant differences between patients with or without HCC and controls. Serum MMP-2 and to a lesser extent MMP-9 correlate with the severity of liver disease and may reflect changes in extracellular matrix remodeling. Due to a considerable overlap in patients with chronic liver disease with or without HCC, MMP-2 and MMP-9 can not be used as a diagnostic marker for HCC.
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PMID:Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma. 1266 27

Diallylphthalate is widely used as a crosslinking agent for unsaturated polyesters. Diallylphthalate or diallylphthalate polyester blends are used primarily as plasticizers and carriers for adding catalysts and pigments to polyesters and in molding, electrical parts, laminating compounds, and impregnation of metal castings. Rubber compounds, epoxy formulations, and polyurethane foams may also contain diallylphthalate. Precise figures are not currently available, although annual production of diallylphthalate in the United States is known to exceed 5,000 pounds, and an estimated 57,000 pounds were imported into the United States in 1982. Toxicology and carcinogenesis studies of diallylphthalate (approximately 99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 0 (vehicle control), 50, or 100 mg/kg 5 days per week for 103 weeks. The diallylphthalate doses used in the 2-year studies were chosen on the basis of 13-week studies, wherein doses of 200 or 400 mg/kg caused death, reductions in body weight gains, or periportal hepatocellular necrosis and fibrosis in both sexes. Mean body weights and survival of male and female rats administered diallylphthalate were essentially the same as those of the vehicle controls throughout the 2-year studies, although hepatotoxicity was produced in both sexes by the 100 mg/kg dose. Based on the results of the prechronic studies and the effects on the liver in the 2-year studies, the doses used in the 2-year studies were considered to be adequate for carcinogenicity testing. Male and female rats receiving the 100 mg/kg dose of diallylphthalate in the 2-year studies developed chronic liver diseases characterized by periportal fibrosis, periportal accumulation of pigment, and severe bile duct hyperplasia. Pigment accumulation also occurred at the 50 mg/kg dose in both sexes. Diallylphthalate administration increased the occurrence of mononuclear cell leukemia in female rats (P<0.05 by trend tests), and the increase in the 100 mg/kg dose female rats was greater (P</=0.05) than in the vehicle controls by pairwise comparisons (vehicle control, 15/50, 30%; low dose, 15/43, 35%; high dose, 25/49, 51%). An increased occurrence of mononuclear cell leukemia was not observed in male rats receiving diallylphthalate. A previous NTP carcinogenesis study (NTP TR 242) reported an increased incidence of lymphomas in male B6C3F1 mice receiving diallylphthalate by gavage for 2 years at doses of 0, 150, or 300 mg/kg. This increase was considered to be equivocally related to diallylphthalate administration. The incidences of hyperplasia and inflammatory lesions of the forestomach were increased in a dose-related fashion in both sexes of mice in that study, and uncommon forestomach papillomas were observed in 0%, 2%, and 4% of both sexes of mice. Because of the numerical increase in forestomach papillomas, the concomitant presence of forestomach hyperplasia, and the rarity of forestomach papillomas in vehicle control (corn oil gavage) B6C3F1 mice, the development of these proliferative lesions of the forestomach in mice may have been related to diallylphthalate administration. In the current study in rats, a squamous cell carcinoma was found in one high dose male rat. Diallylphthalate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by a 9,000 x g supernatant fraction from the livers of Aroclor 1254-treated male Sprague-Dawley rats or Syrian hamsters. Diallylphthalate did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these carcinogenicity studies on diallylphthalate. No data discrepancies were found that influenced the final interpretations. Under the conditions of this study, the administration of diallylphthalate by gavage in corn oil to male and female F344/N rats for 2 years caused chronic liver disease characterized by periportal fibrosis and pigment accumulation and an increasetal fibrosis and pigment accumulation and an increased severity of bile duct hyperplasia. The incidence of mononuclear cell leukemia was significantly increased in female rats receiving 100 mg/kg. Because of the variability in the incidence of this neoplasm in aged Fisher 344 rats and the difficulty in definitively diagnosing this lesion in Fisher 344 rats, this increase was considered to be equivocal evidence of carcinogenicity of diallylphthalate in female rats. There was no evidence of carcinogenicity in male rats. Synonym: DAP
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PMID:NTP Toxicology and Carcinogenesis Studies of Diallylphthalate (CAS No. 131-17-9) in F344/N Rats (Gavage Studies). 1274 96

We have reported previously that acyclic retinoid, a synthetic retinoid X receptor alpha (RXRalpha)-ligand, suppresses the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. On the other hand, HCCs become refractory to physiological concentrations of the natural RXRalpha-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXRalpha. Here, we show that acyclic retinoid restores the function of RXRalpha in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXRalpha. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXRalpha phosphorylation. Although 9cRA also suppressed Ras activity, it simultaneously down-regulated mitogen-activated protein kinase phosphatase-1, an enzyme that inactivates Erk, thereby leaving the phosphorylation status of Erk unchanged. A combination of 9cRA (a potent ligand) and acyclic retinoid (a weak ligand preventing phosphorylation) resulted in a marked cooperation in transactivation via the RXR-response element and in inhibiting the proliferation of HuH7 cells. These events provide a novel molecular basis for the antitumor activity of acyclic retinoid against HCC.
Carcinogenesis 2003 Aug
PMID:Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. 1280 34

Studies of autoantibodies in systemic rheumatic diseases have provided abundant evidence suggesting that autoimmune responses are antigen-driven and that autoantibodies often can be viewed as reporters of the immune system revealing the identity of antigens which might be playing roles in the pathophysiology of the disease process. Recent data from our laboratory suggest a similar mechanistic process may be involved in humoral immune responses in certain cancers such as hepatocellular carcinoma (HCC). HCC is unique in that one can follow a cohort of patients with chronic liver disease who will likely progress to develop malignancy over a period of 10 or more years. It has been observed that during transition from chronic liver disease to HCC, novel autoantibodies can appear which are not detected prior to pre-malignant conditions. The hypothesis is that these novel antibody responses may be stimulated by cellular proteins which are involved in carcinogenesis. By immunoscreening an expression library to isolate cDNA clones of autoantigens, a RNA-binding autoantigen p62 has been identified in HCC recently and autoantibodies to p62 were found in 21% of a cohort of HCC patients. p62 is a cytoplasmic protein which binds to mRNA encoding insulin-like growth factor II (IGF-II), a growth factor which is known to be overexpressed in HCC and is tumorigenic in transgenic animals. The expression of p62 is developmentally regulated, and expressed in fetal, but not in adult liver. Our recent observations showing that p62 was aberrantly expressed in 30% of unselected HCC suggest that it could play a role in HCC and other tumors by upregulating expression of growth factor IGF-II in the milieu of other oncogenic factors.
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PMID:Autoantibodies to IGF-II mRNA binding protein p62 and overexpression of p62 in human hepatocellular carcinoma. 1284 8

The immune response to hepatitis viruses is believed to be involved in the development of chronic hepatitis; however, its pathogenetic potential has not been clearly defined. The current study, using a transgenic mouse model of chronic hepatitis B, was designed to determine the relative contributions of the immune cell subsets to the progression of liver disease that induces hepatocellular carcinogenesis. Hepatitis B virus transgenic mice were adoptively transferred with CD4+ and CD8+ T cell-enriched or -depleted and B cell-depleted splenocytes obtained from hepatitis B surface antigen-primed, syngeneic nontransgenic donors. The resultant liver disease, hepatocyte apoptosis, regeneration, and tumor development were assessed and compared with the manifestations in mice that had received unfractionated spleen cells. Transfer of CD8(+)-enriched splenocytes caused prolonged disease kinetics, and a marked increase in the extent of hepatocyte apoptosis and regeneration. In 12 of 14 mice the transfer resulted in multiple hepatocellular carcinomas (HCCs) comparable with the manifestations seen in the mice transferred with total splenocytes. In contrast, mice that had received CD4(+)-enriched cells demonstrated lower levels of liver disease and developed fewer incidences of HCC (4 of 17). The experiment also revealed that all of the groups of mice complicated with HCC developed comparable mean numbers and sizes of tumors. B-cell depletion had no effect on disease kinetics in this model. Taken together, these results demonstrate that the pathogenetic events induced by CD8+ T-cell subset are primarily responsible for the induction of chronic liver disease that increases tumor incidence, suggesting their potential in triggering the process of hepatocarcinogenesis.
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PMID:Different procarcinogenic potentials of lymphocyte subsets in a transgenic mouse model of chronic hepatitis B. 1512 77

Streptococcus bovis is one of the nonenterococcal species included among the streptococci group D. It is part of the normal bowel flora in humans and animals, but it is also responsible for infectious diseases (10-15% of all cases of bacterial endocarditis). Many cases of bacteremia and metastatic abscesses (spleen, liver, soft tissues, bone, meninges, endocardium) caused by S. bovis were reported as associated with digestive tract diseases, mainly colonic disease, and, in particular colonic neoplasms, or chronic liver diseases. A role in carcinogenesis has been suggested for this microorganism. The authors report two cases of S. bovis sepsis, one associated with colonic neoplasm and the other with liver cirrhosis and gastric carcinoma. Discussion is focused on probable mechanisms that favor gastric colonization and systemic diffusion of S. bovis from the gut in patients with gastrointestinal neoplasms or chronic liver disease and provides clinical recommendations for patients with S. bovis infections.
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PMID:Non-life-threatening sepsis: report of two cases. 1516 50

Chemokine production by cancer cells constitutes a duality. Leukocyte recruitment under the pressure of chemokines may be beneficial for the host or for the tumor. Recently, the chemokine fractalkine and its receptor CX3CR1 have been shown to be expressed in hepatocytes in vivo and in a human hepatocarcinoma cell line in vitro. Therefore, the aim of this study was to analyze the expression of CX3CR1 in hepatocellular carcinoma (HCC) in vivo and to investigate the prevalence of the genetic CX3CR1 polymorphism V249I in HCC patients since this polymorphism has been associated with reduced number of fractalkine binding sites, reduced cell-cell adhesion and decreased signaling and chemotaxis. Genotyping was performed in 183 patients with histologically proven HCC and 99 healthy controls by RFLP-analysis. The frequency of the individual genotypes was similar in HCC patients and controls. The V249I polymorphism revealed no association with tumor grade and stage, the presence of extrahepatic metastasis or the degree of fibrosis in non-tumorous tissue. In addition to genotyping, CX3CR1 mRNA expression was analyzed by quantitative PCR in 9 HCC specimens and in 6 cases in corresponding non-tumorous liver tissues. CX3CR1 mRNA expression levels in HCC showed high variation between individual patients. Similarly, expression in HCC compared to non-tumorous liver varied, from strong downregulation to remarkable upregulation. CX3CR1 mRNA expression levels showed no correlation to the V249I polymorphism. In summary, these results suggest that the patho-physiological role of individual chemokines in carcinogenesis may vary and that the functional CX3CR1 polymorphism V249I is no genetic risk factor for HCC. However, additional independent studies in HCC patients with different ethnic background will be needed to confirm the present study and to elucidate the functional role of CX3CR1 and its polymorphism V249I in chronic liver disease and hepatocarcinogenesis.
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PMID:Lack of association between the functional CX3CR1 polymorphism V249I and hepatocellular carcinoma. 1580 64

Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid-defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P-positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH.
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PMID:Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. 1700 38

Hepatocellular carcinoma (HCC) is a fatal disease and hepatitis B and C viruses (HBV and HCV) are considered as major causative factors for the development of HCC. We have conducted gene expression profiling studies to search for potential target genes responsible for HCV-mediated HCC. Adenoviruses encoding core (HCV structural protein), NS3 and NS5A [HCV non-structural (NS) proteins] were generated and infected individually or together in freshly isolated primary human hepatocytes. An adenovirus harboring the oncogenic HBV protein, HBx, was included for comparison. A microarray platform of over 22,000 human oligos was analyzed to seek out significant differentially expressed genes among these viral proteins. We also compared these gene expression profiles with those obtained from HCV-infected liver samples from chronic liver disease (CLD) patients and HCV-related HCC. We found that HCV-related proteins largely induce unique genes when compared with HBx. In particular, interferon-inducible gene 27 (IFI27) was highly expressed in HCV or core-infected hepatocytes and HCV-related CLD or HCC, but was not significantly expressed in HBx-infected hepatocytes or HBV-related CLD or HCC, indicating that IFI27 may play a role in HCV-mediated HCC. In conclusion, our results suggest that HBV and HCV promote HCC development mainly through different mechanisms.
Carcinogenesis 2007 Jul
PMID:Induction of a unique gene expression profile in primary human hepatocytes by hepatitis C virus core, NS3 and NS5A proteins. 1740 95

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the most severe complication of chronic liver disease. The annual number of new cases worldwide is approximately 550,000, representing more than 5% of human cancers and is the third leading cause of cancer-related deaths. The stages of the malignancy as well as the severity of the underlying liver disease are essential factors in planning the therapeutic approach. Curative treatment options are represented mainly by surgery (ie, resection or transplantation), but most patients are not candidates for a curative option, and only palliative treatment could be given to these patients. Among palliative treatments, only chemoembolization has been proven to be effective, but other options are currently being investigated. Major risk factors for HCC are well known and are dependent on the geographic area. In Europe, the United States, and Japan, the main risk factors are liver cirrhosis, hepatitis B and C virus, alcohol, and tobacco; in contrast, in Africa and Asia, these factors are hepatitis B and C virus, tobacco use, and aflatoxin exposure. Cirrhosis from any cause is a predisposing factor for HCC and could be considered as a premalignant condition. The present concept of carcinogenesis in HCC is a multistage process. This article describes the natural history of HCC and discusses the various treatment options available at present.
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PMID:Natural history of hepatocellular carcinoma and current treatment options. 1824 38


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