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)

Chronic liver inflammation and hepatic regeneration by infection with hepatitis B (HBV) or C virus (HBC) seem to be important risk factors for hepatocellular carcinoma (HCC). Regarding the hepatocarcinogenesis of HBV DNA integration, it has been variously hypothesized that mechanisms such as the alteration of host chromosomal DNA and transcriptional trans-acting activity of the X gene are activated. On the other hand, integration of HCV virus into chromosomal DNA has not been reported. It is suggested that HCV could replicate more efficiently in noncancerous than in cancerous tissues. Therefore, it might affect some oncogenes or cause an inactivation of tumor suppressor genes in the early stage of HCC. Genetic alterations such as a point mutation and loss of heterozygosity are considered to be late events occurring after tumorigenesis. Regeneration of liver cells through chronic hepatitis increases the incidence of genetic alterations in hepatic cells and/or HCCs in both HBV- and HCV-infected patients.
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PMID:Pathogenesis of hepatocellular carcinoma: a review from the viewpoint of molecular analysis. 872 3

Substantial evidence indicates that several common viruses are clearly or probable causal factors in the etiology of specific malignancies. These viruses either normally establish latency or can become persistent infections. Oncogenesis is probably linked to an enhanced level of viral activation in the infected host, reflecting heavy viral dose or compromised immune control. The major virus-malignancy systems include hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) and adult T-cell leukemia/lymphoma (ATL); Epstein-Barr virus (EBV) and endemic Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's disease; and human papilloma virus (HPV) and cervical cancer. Of these, a vaccine is available only for HBV. These malignancies tend to occur in early to mid-life and account for a substantial amount of morbidity and person-years lost. They are also likely to occur as "opportunistic malignancies" among individuals infected with human immunodeficiency virus type-1, particularly among those who experience prolonged survival.
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PMID:Overview: viral agents and cancer. 874 95

Helicobacter hepaticus has been associated with naturally occurring hepatitis in certain inbred strains of mice, and in A/JCr mice it has been linked to the development of hepatic adenomas and adenocarcinomas. H. hepaticus was orally inoculated into 30 axenic, outbred female mice, and the mice were studied longitudinally to fulfill Koch's postulates and to ascertain the pathogenic potential of the organism under defined germfree conditions. Ten cage contact mice were also housed in the same germfree isolator to study transmission patterns, and 10 germfree mice were maintained in separate isolators as controls. Mice serially euthanized from 3 weeks through 24 months postinoculation (p.i.) were surveyed by culture and PCR for H. hepaticus in liver and intestinal tissues. Tissues were analyzed for histopathological changes, and sera were assayed for the presence of immunoglobulin G antibody to H. hepaticus and changes in the liver enzyme alanine aminotransferase. Inoculated mice and cage contact mice were persistently infected with H. hepaticus as identified by culture and PCR, in both the intestine and, less frequently, the liver, for the duration of the 2-year study. Animals developed persistent chronic hepatitis, and in some animals enterocolitis was noted. Hepatocellular carcinoma was diagnosed in one H. hepaticus-infected mouse. The level of H. hepaticus serum antibody was highest in experimentally infected mice at 12 to 18 months p.i.; this corresponded in general to the time interval when the highest levels of alanine aminotransferase were recorded. Although cage contact mice became persistently infected with H. hepaticus, lesions were less severe and the levels of serological biomarkers utilized in the study were lower. The H. hepaticus-infected mouse will provide an ideal model to study putative bacterial virulence determinants and how they interact with the host to induce chronic inflammation and tumorigenesis.
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PMID:Persistent hepatitis and enterocolitis in germfree mice infected with Helicobacter hepaticus. 875 16

Insulin-like growth factors initiate tyrosyl phosphorylation of the insulin receptor substrate I (IRS-I) protein and activate multiple signaling pathways essential for liver growth. This gene has been found to be up-regulated in human hepatocellular carcinomas (HCCs), and overexpression of IRS-1 in NIH 3T3 cells leads to malignant transformation with activation of the mitogen-activated protein kinase cascade. To explore another possible role of IRS-I in hepatocarcinogenesis, we examined the capability of transforming growth factor beta1 (TGF-beta1), a known negative regulator of hepatocyte growth, to induce programmed cell death in the context of IRS-I overexpression. Hep3B HCC cells were stably transfected with a retroviral vector containing the IRS-I gene. The overexpressed IRS-I protein was highly tyrosyl phosphorylated following insulin/insulin- like growth factor I stimulation and led to constitutive activation of downstream signal transduction molecules such as phosphatidylinositol-3 kinase and mitogen-activated protein kinase. Although parental Hep3B cells were sensitive to apoptosis, the Hep3B-IRS-I-transfected cells acquired resistance to TGF-beta1-induced programmed cell death. Our investigations suggest that IRS-I-mediated signals may act as survival factors and protect against TGF-beta1-induced apoptosis in HCC; this phenomenon may contribute to hepatic oncogenesis.
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PMID:Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. 875 99

Phthalate esters such as di(2-ethylhexyl)phthalate (DEHP) either promote or inhibit rat liver tumorigenesis depending on the carcinogenesis protocol. In this study, we examined the expression of two histochemical markers, the tumor associated isozyme of aldehyde dehydrogenase (ALDH-3) and the oncoprotein p21 Ras, in the livers of male F344 rats. The rats were initiated with DEN and further treated with either DEHP (a known inhibitor of hepatocarcinogenesis), phenobarbital (PB, a known promoter of hepatocarcinogenesis), or a combination of DEHP and PB. The studies were designed to examine the expression of these markers in both normal appearing liver and hepatic hyperplastic and neoplastic lesions and to correlate the early expression of the markers at 26 weeks in the normal appearing liver to later tumor incidence at 52 weeks. The expression of each marker was detected by immunohistochemical methods on formalin-fixed paraffin embedded sections of normal appearing liver or liver lesions. We found that ALDH-3 and p21 expression were significantly enhanced in rats receiving PB after DEN initiation at 26 weeks and that the incidence of hepatocellular carcinomas was likewise increased compared to control or DEN only treated animals. DEN initiation followed by a combination of PB and either 0.1 or 0.5% DEHP significantly reduced ALDH-3 but not p21 Ras expression at 26 weeks compared to DEN plus PB only. These treatment regimens also reduced the incidence of hepatocellular carcinomas at 52 weeks. DEN followed by any of the three doses of DEHP without PB resulted in ALDH-3 expression similar to DEN alone. However, p21 Ras expression was significantly increased after these treatments. For all treatment groups, both the early (26 weeks) expression of p21 Ras and ALDH-3 correlated with hepatocellular carcinoma incidence at 52 weeks. However, the correlation between hepatocellular carcinoma and ALDH-3 expression was better than p21 Ras or the other markers we have studied. We concluded that ALDH-3 expression is significantly downregulated after DEHP treatment, and that expression of the isozyme correlated with later hepatocarcinoma incidence and may indicate a significant relationship between ALDH-3 expression and hepatocarcinogenesis during DEHP treatment.
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PMID:Hepatocyte expression of tumor associated aldehyde dehydrogenase (ALDH-3) and p21 Ras following diethylnitrosamine (DEN) initiation and chronic exposure to di(2-ethylhexyl)phthalate (DHEP). 876 21

Integrated hepatitis B virus (HBV) DNA is found in the great majority of human hepatocellular carcinomas, suggesting that these viral integrations may be implicated in liver oncogenesis. Besides the insertional mutagenesis characterized in a few selected cases and the contribution of viral transactivators to cell transformation to malignancy, HBV has been shown to generate gross chromosomal rearrangements potentially involved in carcinogenesis. Here, we report a t(3;8) chromosomal translocation present in a hepatocellular carcinoma developed in noncirrhotic liver tissue. One side of the translocation, in 8p23, is shown to be in the vicinity of the carboxypeptidase N gene, a locus that is heavily transcribed in liver tissue and frequently deleted in hepatocellular carcinomas and other epithelial tumors. The other side of the translocation, in 3q27-29, is widely implicated in several types of translocations occurring in different malignancies, such as large-cell lymphomas. The present data strongly support a model in which HBV-induced chromosomal rearrangements play a key role during multistep liver oncogenesis.
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PMID:A t(3;8) chromosomal translocation associated with hepatitis B virus intergration involves the carboxypeptidase N locus. 879 83

The majority of hepatocellular carcinomas (HCCs) from hepatitis B virus (HBV)-endemic areas contain integrated viral sequences. To better understand the role of HBV DNA insertion in tumorigenesis, we examined the integration site of a HCC harboring a single insert. Cellular DNAs flanking the viral sequences were mapped to chromosomes 17 and 8, indicating a translocation had occurred at the site of viral integration. Regional mapping of chromosome 17 demonstrated that HBV had integrated in 17p12-pter, a region that harbors the p53 tumor suppressor gene. Many studies have shown that chromosome 17p allele loss occurs frequently in HCCs from certain geographical areas. To investigate the chromosome 8 allele status in Chinese HCCs, a panel of 37 matched normal and HCC DNAs from Qidong, China was analyzed for tumor-specific allele loss with RFLP probes from both arms of chromosome 8. Tumor-specific loss of heterozygosity was highest on the short arm with 71.4% (10/14) and 85.0% (17/20) of the informative patients missing an allele for 8p23 (YNM3) or 8p21 (NEFL), respectively. Allele loss from the long arm of chromosome 8 was also observed with 30.0% (6/20) and 33.3% (7/21) of the samples informative for 8q22 (CA2) and 8q24 (MCT128.2), respectively. The high allele loss on 8p correlates with recent studies of other human cancers and is interpreted to indicate that a tumor suppressor gene(s) whose loss is important for carcinogenesis lies within this region. These findings also support a model in which HBV insertions associated with gross chromosomal changes can identify genomic regions where alteration is important for development of some HCCs.
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PMID:Frequent loss of chromosome 8p in hepatitis B virus-positive hepatocellular carcinomas from China. 889 69

The possibility to identify epitopes presented by tumor cells to cytotoxic T lymphocytes (CTL) has given rise to new fields in tumor immunology. The tumor suppressor gene product p53 is a good candidate antigen because it is involved in the tumorigenesis of many cancers. It accumulates in an inactivated form due to mutation or formation of heterodimers with an oncogene product. Epitopes from the mutant or wild-type p53 proteins are thought to be presented by tumor cells and to induce a tumor-specific CTL response. To identify such epitopes, mouse wild-type p53 peptides encompassing the H-2 Db anchoring motif were tested for their association with the Db molecule. Positive peptides were assayed for their ability to induce CTL in C57BL/6 mice. CTL specific for one wild-type p53 peptide, p232-240, were isolated and found to lyse hepatocarcinoma cell lines established from mice transgenic for simian virus 40 large T antigen which overexpress p53. These results show that the p232-240 epitope from wild-type p53 is naturally processed and presented in H-2b tumor cells.
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PMID:A wild-type p53 cytotoxic T cell epitope is presented by mouse hepatocarcinoma cells. 892 49

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections lead to cirrhosis and increase the risk for the development of hepatocellular carcinoma (HCC). Angiogenesis is an essential step in oncogenesis and contributes to tumor progression in adult organs; however, to what extent angiogenesis occurs in the liver during chronic viral hepatitis has not been studied. Ninety-nine matched patients affected by chronic hepatitis due to either HBV or HCV were studied together with 13 controls (5 patients were affected by familial hyperbilirubinemia with normal liver histology; 6 patients with stage II primary biliary cirrhosis; and 2 patients with pseudo inflammatory tumor). Microvessel density was assessed in liver biopsies by immunostaining using two different antibodies against endothelial cell antigens, QB-END/10 and Factor VIII. In addition, the liver homogenates and sera of HCV- or HBV-positive patients and controls were tested for their capacity to stimulate the migration and proliferation of freshly isolated human endothelial cells in vitro. Evidence of angiogenesis was significantly more frequent in HCV-positive patients compared with HBV-infected subjects or controls (74% vs. 39% vs. 8%) (chi2 = 20.78; P < .0001) (HCV+ vs. HBV+ vs. controls). The degree of microvessel density was also higher in HCV- than in HBV-positive patients or controls (chi2 = 12.28; P < .005). In addition, HCV-positive sera and liver homogenates stimulated a higher migration and proliferation of human endothelial cells in vitro compared with HBV-positive or control sera and liver homogenates. These observations indicate that angiogenesis is particularly linked to HCV infection, suggesting a possible contribution to HCV-related liver oncogenesis.
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PMID:Chronic viral hepatitis induced by hepatitis C but not hepatitis B virus infection correlates with increased liver angiogenesis. 898 96

The insulin-like growth factor 2 (IGF2) gene is regulated in a complex manner, involving developmentally regulated use of four different promoters as well as transcriptional repression of the maternal allele due to genomic imprinting. It has been well documented that liver is an exceptional organ in which overall transcription from the four IGF2 promoters is markedly imbalanced towards preferential paternal expression only in fetal life, this being relaxed during the postnatal period, resulting in biallelic expression thereafter. We previously reported a marked allelic-expression imbalance in the overall transcription of IGF2 in hepatocellular carcinoma (HCC), leading to preferential expression nonrandomly from the paternal allele. The study presented here, using 18 HCC specimens taken directly from patients, showed that this molecular change often reflects promoters switching from the adult P1 promoter to the fetal P2, P3, and P4 promoters. Interestingly, however, we found that restoration of allele-specific expression of the P1 promoter nonrandomly from the paternal allele was also frequent in HCC suggesting retention of an imprint for paternal expression from the P1 promoter of IGF2 in adult normal liver and altered availability of its modifying factor or factors in HCC. Further studies of the molecular mechanisms involved in the fluctuation of promoter usage and genomic imprinting of IGF2 are warranted to gain an insight into the biology of the liver in terms of development and oncogenesis.
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PMID:Altered transcriptional regulation of the insulin-like growth factor 2 gene in human hepatocellular carcinoma. 914 13


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