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 possibility that hepatitis C virus core gene product (HCV-core) acts as a transactivator in insulin-like growth factor II (IGF-II) gene transcription was tested. HCV-core protein increases endogenous IGF-II expression from promoter 4 (P4) of the IGF-II gene through two cis-acting elements: Sp1 and Egr1 binding sites. Sp1 and Egr1 both bind to IGF-II P4 and functionally cooperate in mediating the maximal activity of IGF-II P4. HCV-core protein induced the binding of Sp1 and Egr1 on its binding sites on IGF-II P4. In addition, Sp1 and Egr1 were stimulated to phosphorylate by HCV-core, and its DNA binding activity was up-regulated upon HCV-core transfection. Transfection with HCV-core in HepG2 cells stimulated the membrane translocation of protein kinase C (PKC) and the treatment of HCV-core transfected cells with calphostin C, a PKC inhibitor, blocked induction of Sp1 and Egr1 DNA binding activity, and eventually transcriptional transactivations of the IGF-II gene. Increasing the DNA binding activity of the phosphorylated form of Sp1 and Egr1 might be an important mechanism for regulating IGF-II gene expression and for promoting cell division during hepatic carcinogenesis. These results indicate that HCV-core functions as a positive regulator of IGF-II transcription through the PKC pathway and that Sp1 and Egr1 are direct targets of the transcriptional regulation of the IGF-II gene which plays an important role in hepatitis C virus pathogenesis during the formation of hepatocellular carcinoma (HCC).
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PMID:Hepatitis C virus core protein transactivates insulin-like growth factor II gene transcription through acting concurrently on Egr1 and Sp1 sites. 1133 42

The mechanism of hepatocarcinogenesis in hepatitis C virus (HCV) infection is still undefined. One possibility is the involvement of oxidative stress, which can produce genetic mutations as well as gross chromosomal alterations and contribute to cancer development. We recently showed that after a long period, the core protein of HCV induces hepatocellular carcinoma (HCC) in transgenic mice with marked hepatic steatosis but without inflammation, indicating a direct involvement of HCV in hepatocarcinogenesis. To elucidate the biochemical events before the development of HCC, we examined several parameters of oxidative stress and redox homeostasis in a mouse model of HCV-associated HCC. For young mice ages 3-12 months, there was no significant difference in the levels of hydroperoxides of phosphatidylcholine (PCOOH) and phosphatidylethanolamine in liver tissue homogenates between transgenic and nontransgenic control mice. In contrast, the PCOOH level was increased by 180% in old core gene transgenic mice > 16 months old. Concurrently, there was a significant increase in the catalase activity, and there were decreases in the levels of total and reduced glutathione in the same mice. A direct in situ determination by chemiluminescence revealed an increase in hydroperoxide products by 170% even in young transgenic mice, suggesting that hydroperoxides were overproduced but immediately removed by an activated scavenger system in young mice. Electron microscopy revealed lipofuscin granules, secondary lysosomes carrying various cytoplasmic organelles, and disruption of the double membrane structure of mitochondria, and PCR analysis disclosed a deletion in mitochondrial DNA. Interestingly, alcohol caused a marked increase in the PCOOH level in transgenic mice, suggesting synergism between alcohol and HCV in hepatocarcinogenesis. The HCV core protein thus alters the oxidant/antioxidant state in the liver in the absence of inflammation and may thereby contribute to or facilitate, at least in part, the development of HCC in HCV infection.
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PMID:Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. 1138 61

Hepatocellular carcinoma remains widely prevalent in tropical Africa and south-east Asia and is largely related to chronic hepatitis B virus (HBV) infection. Primary prevention by vaccination of infants at or near birth is effective but any reduction in tumour incidence cannot be expected for decades to come yet, even in those countries in which the necessary resources exist, as millions of adults remain chronically infected. Meanwhile, the incidence is rising in Japan, Mediterranean countries of Europe, Middle East and North Africa and in the USA, largely due to chronic hepatitis C virus (HCV) infection introduced by the indiscriminate use of unscreened blood and blood products in the recent past. Much has been learned from molecular biological studies on hepatocarcinogenesis incriminating the HBX gene of HBV, the core protein of HCV and a unique guanine to thymine transversion at codon 249 has been observed in cases due to aflatoxin exposure. The subject of precancerous lesions, notably adenomatous/dysplastic nodules and large-cell/small-cell change continues to be a source of much debate and the distinction of nodular lesions in cirrhosis from early carcinoma remains uncertain. Spontaneous regression of hepatocellular carcinoma is rare but it is probably immunologically mediated and treatment by activated T-lymphocytes may reduce recurrence rates after surgery. The positive identification of hepatocellular carcinoma by a liver-specific antibody has greatly facilitated the diagnosis in difficult cases.
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PMID:Hepatocellular carcinoma: an overview. 1149 26

Overwhelming lines of epidemiological evidence have indicated that chronic infection with hepatitis C virus(HCV) poses a major risk toward development of hepatocellular carcinoma(HCC). In the pathogenesis of HCC associated with HCV, it remains controversial whether these hepatitis viruses play a direct role or merely serve for an indirect role. By virtue of transgenic mouse established by us, it has become evident hat the core protein of HCV has an oncogenic potential. The findings in our studies indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with chronic hepatitis may play a role, as well. Combined, our results suggest that there would be a mechanism for the development of HCC in persistent infection with hepatitis C virus that is distinct from those for the other cancers. Similar to the pathogenesis of other malignancies represented by colorectal cancer, the accumulation of a set of genetic aberrations may also be necessary for a multi-stage development of HCC. However, HCV core protein, to which an oncogenic potential is ascribed, may allow some of the multiple stages skipped in hepatocarcinogenesis. Unlike for the other cancers, therefore, infection with HCV may be capable of eliciting HCC in the absence of a complete set of genetic aberrations. Such a scenario would explain unusually high incidence and multicentric nature of HCC developing in chronic hepatitis C.
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PMID:[HCV core gene transgenic mouse as a model for viral hepatocarcinogenesis]. 1149 35

Hepatitis C virus (HCV) often causes a prolonged and persistent infection, and an association between hepatocellular carcinoma (HCC) and HCV infection has been noted. The pathogenesis of liver damage is at least in part related to virus-mediated factors. Understanding the molecular basis of pathogenesis is a major challenge in gaining insight into HCV-associated disease progression. Recent experimental evidence using HCV cloned genomic regions suggests that the core protein has numerous functional activities. These include its likely role in encapsidation of viral RNA, a regulatory effect on cellular and unrelated viral promoters, interactions with a number of cellular proteins, an modulatory role in programmed cell death or apoptosis under certain conditions, involvement in cell growth promotion and immortalization, induction of HCC in transgenic mice, and a possible immunoregulatory role. These intriguing properties suggest that the core protein, in concert with cellular factors, may contribute to pathogenesis during persistent HCV infection.
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PMID:Hepatitis C virus core protein: intriguing properties and functional relevance. 1152 Jun 7

Hepatocellular carcinoma (HCC) is a disease that is extremely difficult to manage and is markedly increasing in incidence. Malignant transformation generally occurs in the setting of liver dysfunction related to a number of different diseases, including viral hepatitis, alcoholic liver disease, and aflatoxin exposure. Short of surgical or ablative approaches, no standard therapy exists for HCC and the prognosis is poor. Perhaps our best hope is that further elucidation of the specific molecular features underlying the disease will translate into innovative, and potentially disease-specific strategies to manage this difficult cancer. Exposure to aflatoxin is associated with a specific mutation in the tumor-suppressor gene p53. The exact molecular events underlying hepatocarcinogenesis in the setting of viral infection have yet to be elucidated, although there is evidence to suggest that virus-encoded proteins contribute to malignant transformation. Both hepatitis B X antigen and hepatitis C core protein appear to interact with a variety of cellular proteins leading to alterations in signal transduction and transcriptional activity. These events presumably cooperate to facilitate malignant progression by promoting extended hepatocyte survival, evasion of the immune response, and acquisition of mutations through genomic instability.
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PMID:Molecular mechanisms underlying the development of hepatocellular carcinoma. 1168 45

Hepadnaviral replication requires the concerted action of the polymerase and core proteins to ensure selective packaging of the RNA pregenome into nucleocapsids. Virus assembly is initiated by cis-preferential binding of polymerase to the encapsidation signal straightepsilon, present on pregenomic RNA. Using the duck hepatitis B virus (DHBV) model, we analyzed how core protein is recruited to the RNA/polymerase preassembly complex. Two sets of trans-complementation assays were performed in cotransfected hepatoma cells. First, a replication-competent DHBV construct was tested for its ability to rescue replication of genomes bearing mutations within the core region. Self-packaging of wild-type pregenomes was more efficient than cross-packaging of core-deficient pregenomes, and this bias was strongly enhanced if mutant pregenomes coded for self-assembly-competent, but packaging-deficient, core proteins. Second, the site of wild-type core protein translation, i.e., pregenomic RNA (cis) or separate messenger RNA (trans), was analyzed for its effect on the phenotype of a previously described dominant-negative (DN) DHBV core protein mutant. This mutant forms chimeric nucleocapsids with wild-type core proteins and blocks reverse transcription within most, but not all, mixed particles. Strikingly, suppression of viral DNA synthesis by the mutant increased 100-fold when wild-type core protein was provided in trans. Our results suggest that recruitment of core protein to the DHBV preassembly complex occurs in a cis-preferential manner. This mechanism may account for the leakiness of DN DHBV core protein mutants targeting reverse transcription.
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PMID:Cis-preferential recruitment of duck hepatitis B virus core protein to the RNA/polymerase preassembly complex. 1178 78

Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence and chronic hepatitis. HCV-induced chronic hepatitis is a major risk factor for the development of hepatocellular carcinoma. The high incidence of HCV persistence suggests that this virus has evolved one or more mechanisms to evade and possibly suppress host immune responses. To understand the mechanism(s) involved in the establishment of HCV persistence, we have identified an HCV core protein as an immunomodulatory molecule to suppress host immune response. We have further determined a molecular mechanism of HCV core-mediated immune suppression by searching for a potential host protein(s) capable of associating with the HCV core protein. Interestingly, the Clq complement receptor, gC1qR, can bind to the HCV core. Clq is a ligand of gClqR and is involved in the early defense against viral infection as well as regulation of adaptive immune response. Similar to Clq, the HCV core can inhibit human T-lymphocyte proliferative response through its interaction with the gC1qR. It implicates that HCV core/gClqR-induced immune suppression may play a critical role in the establishment of persistent infection.
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PMID:Hepatitis C virus: immunosuppression by complement regulatory pathway. 1179 59

Overwhelming lines of epidemiological evidence have indicated that chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). In the pathogenesis of HCC associated with HBV or HCV, it remains controversial whether these hepatitis viruses play a direct role or merely an indirect role. By virtue of transgenic mice established by us, it has become evident that the product of the HBV X gene (HBx protein) and the core protein of HCV have an oncogenic potential, although the pathways through which these two viral proteins operate may differ. The findings in our studies indicate that HBV and HCV are directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with chronic hepatitis may play a role as well. Combined, our results suggest that there might be a mechanism in the development of HCC in persistent infection with hepatitis viruses that is distinct from that in other cancers. Similarly to the pathogenesis of other malignancies represented by colorectal cancer, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HBx protein and HCV core protein, to which an oncogenic potential is attributed, may allow some of the multiple stages skipped in hepatocarcinogenesis. Unlike for the other cancers, therefore, infection with HBV or HCV may be capable of inducing HCC in the absence of a complete set of genetic aberrations. Such a scenario would explain an unusually high incidence and multicentric nature of HCC developing in chronic hepatitis B or C.
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PMID:Molecular mechanism of viral hepatocarcinogenesis. 1186 82

Human hepatitis B virus (HBV) variants containing in-frame core internal deletion (CID) have been demonstrated to contain all the functional features of defective interfering (DI) particles (Yuan, T. T.-T., M.-H. Lin, D. S. Chen, and C. Shih, 1998, J. Virol. 72, 578-584). Here, we report that out-of-frame HBV CID variants exhibit defective interfering property similar to in-frame CID variants characterized previously. This result raises the possibility that it may be the deleted pregenomic RNA product, rather than the deleted core protein product, that is responsible for interference. Furthermore, a genomic deletion elsewhere does not cause interference since preS2 deletion variants exhibit no influence on wild-type HBV replication. Consistent with the natural occurrence of HBV CID variants, we recently identified CID variants of woodchuck hepatitis virus (WHV) in natural infection. However, unlike HBV CID variants, functional characterization of WHV CID variants using a human hepatoma cell line has not revealed any interference in tissue culture. In summary, defective interference is a general phenomenon for both in-frame and out-of-frame HBV CID variants.
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PMID:Out-of-frame versus in-frame core internal deletion variants of human and woodchuck hepatitis B viruses. 1187 6


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