Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis B virus (HBV) transgenic mice (official designation, Tg [Alb-1 HBV] Bri 44) invariably develop macroscopically evident tumors within the 20th month of life. Sustained proliferative activity seems to play an important role in the development of these lesions. We previously showed that ursodeoxycholate (UDC) stimulates hepatocyte proliferation in various experimental settings. Herein, we tested the assumption that biological factors able to further increase liver cell proliferation, such as UDC, could accelerate tumor development in this animal model. For this study, 22 eight-week-old male transgenic mice were divided into 2 groups; 11 animals received a standard diet, and 11 received a UDC-enriched diet. The 2 groups were further divided into 2 subgroups of 5 and 6 animals each and were sacrificed at 3 and 15 months of age, respectively. These different times were chosen to exclude diet-related toxicity (in 3-month-old mice) and evaluate tumor growth (in 15-month-old mice). In addition, hepatocyte proliferation was assessed in all animals. In 3-month-old mice receiving UDC, cholestatic and cytolytic indices as well as liver histology were comparable to those in controls. At 15 months, all UDC-treated mice showed large multinodular tumors whereas only 33% of controls developed smaller uninodular neoplasms. Hepatocyte proliferation was increased in all animals receiving UDC compared with controls. In conclusion, the increase in serum UDC (undetectable in mice fed a standard diet), in the absence of any toxic effect on the liver, suggests the involvement of this bile salt in the stimulation of hepatocyte proliferation and tumor growth.
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PMID:Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice. 1266 81

Evidence indicates that cyclooxygenase (COX)-2-derived prostaglandins (PGs) contribute to tumor growth by inducing angiogenesis. We investigated the role of COX-2 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). COX-2 and vascular endothelial growth factor (VEGF) expressions were examined by immunohistochemistry in 24 HBV-associated HCC. Tumor micro-vessel density (MVD) was assessed using CD34 immunohistochemistry. Hep3B HCC cell line, which carries integrated HBV genome, was stably transfected with human COX-2 cDNA. COX-2 and VEGF expressions were determined by Western blot while PG level was determined by ELISA. The effects of PGs on VEGF expression were also investigated. Expression of COX-2 and VEGF in HCC cells were observed in 19 (79%) and 16 (67%) cases, respectively. Well-differentiated HCC expressed COX-2 more strongly than less-differentiated HCC (p<0.001). COX-2 expression was found to correlate with VEGF expression and MVD (p=0.003 and 0.004, respectively). COX-2 overexpressing Hep3B clone had higher VEGF expression as compared to non-COX-2 expressing clone and parental cells. Treatment of the COX-2 overexpressing cells with a COX-2-selective inhibitor, NS-398 (10 microM), decreased PGE2 level and attenuated VEGF expression. Addition of PGE2 (10 microM) and the stable analog of PGI2, carbaprostacyclin (5 microM), to Hep3B cells also increased VEGF expression. Up-regulation of COX-2 correlates with VEGF expression and tumor angiogenesis in HBV-associated HCC. Moreover, COX-2 up-regulates VEGF expression in HCC cells, possibly via PGs production. Selective inhibition of COX-2 may block HCC associated angiogenesis and thus provides a rational approach for treatment of this malignancy.
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PMID:Cyclooxygenase-2 pathway correlates with vascular endothelial growth factor expression and tumor angiogenesis in hepatitis B virus-associated hepatocellular carcinoma. 1501 Aug 22

The Cancer Etiology Branch of the National Cancer Institute hosted a workshop, "Validation of a causal relationship: criteria to establish etiology," to determine whether recent technological advances now make it possible to delineate improved or novel criteria for the rapid establishment for cancer causation. The workshop was held in Washington, D.C., December 11-12, 2003, and participants were among the international leaders in the fields of epidemiology, chemistry, biochemistry, microbiology, virology, environmental and chemical carcinogenesis, immunology, pathology, molecular pathology, genetics, oncology, and surgical oncology. There was a general consensus that the rapid identification of human carcinogens and their removal (when possible) or the establishment of specific preventive and therapeutic measures was the most desirable and effective way to have a rapid and positive impact in the fight against cancer. From a clinical perspective, it may be as important to target initiators, cocarcinogens and promoters, if by removing any one of them tumor growth can be prevented. Future studies should focus on interactions among and between different biological, chemical, and physical agents. Analyses of single agents can at times miss their carcinogenic potential when such agents are carcinogenic only in subgroups of individuals because of their genetic background, diet, exposure to other carcinogens, or microbial infection. Epidemiology, molecular pathology (including chemistry, biochemistry, molecular biology, molecular virology, molecular genetics, epigenetics, genomics, proteomics, and other molecular-based approaches), and animal and tissue culture experiments should all be seen as important integrating evidence in the determination of human carcinogenicity. Concerning the respective roles of epidemiology and molecular pathology, it was noted that epidemiology allows the determination of the overall effect of a given carcinogen in the human population (e.g., hepatitis B virus and hepatocellular carcinoma) but cannot prove causality in the individual tumor patient. Molecular pathology cannot determine the overall impact of a carcinogen in the population but can at times prove causality in the individual tumor patient [such as the detection of high-risk human papillomavirus (HPV) in a cervical carcinoma biopsy]. This is possible when molecular techniques have shown that the agent is required for transformation or malignant growth of human cells (such as antisense HPV strategies showing the requirement for the expression of HPV proteins for tumor cell growth) and when there is supportive experimental animal evidence. Ideally, epidemiology and molecular pathology information together with experimental evidence in animals should be available for the most reliable identification of human carcinogens. All sets of data are not always available, and a rapid identification of human carcinogens is in the best public health interest. Swift validation of a causal relationship when followed by a rapid deployment of preventive and therapeutic approaches should lead to a favorable public health impact (such as hepatitis B virus vaccination to prevent hepatocellular carcinoma).
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PMID:Modern criteria to establish human cancer etiology. 1528 63

The X protein (HBx) of hepatitis B virus (HBV) plays important roles in hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) during viral infection. In this study, we demonstrated that co-transfection of mouse embryo fibroblasts (STO) with HBx and activated Ras triggered apoptotic cell death, while HBx or activated Ras individually failed to induce apoptosis. In addition, STO cells were able to form colonies on soft agar after transfected with HBx or Ras, and cells co-transfected with both genes failed to transform. Moreover, nude mice injected with STO cells carrying either HBx or Ras could develop tumor, but tumor growth was inhibited by the injection of both STO cells harboring HBx and carrying Ras. These results suggested that HBx plays a role as a tumor inducer and stimulates neoplastic transformation of normal cells, but shifts its function to the induction of apoptosis in association with Ras.
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PMID:Functional switch of viral protein HBx on cell apoptosis, transformation, and tumorigenesis in association with oncoprotein Ras. 1656 76

Hepatocellular carcinoma (HCC) accounts for more than 80% of all primary liver cancers and is one of the most common malignancies worldwide. Most patients with HCC also suffer from concomitant cirrhosis, which is the major clinical risk factor for hepatic cancer and results from alcoholism, infection with the hepatitis B or hepatitis C virus, and other causes. HCC is often diagnosed at an advanced stage, when established treatment options provide limited benefit. Effective treatment for HCC includes liver resection and liver transplantation. Under most clinical circumstances, those options provide a high rate of complete response and are thought to improve survival. Partial hepatectomy is the therapy of choice in patients with HCC and a noncirrhotic liver. Usually, liver transplantation is not indicated for such patients, although in individual cases, transplantation may be considered. For most cirrhotic patients who fulfill the Milan criteria, liver transplantation is the ultimate treatment option. Liver transplantation restores liver function and ensures the removal of all hepatic foci of tumor as well as tissue with a high oncogenic potential for early tumor recurrence. Because of the present lack of available organs, living-donor liver transplantation (LDLT) is an increasingly popular alternative. LDLT enables recipients to avoid a long pretransplantation waiting time and increases the number of livers available for transplantation. It is also the most effective approach to reducing the dropout rate. Strategies to reduce tumor growth in patients who are awaiting liver transplantation are important to ensure that those individuals continue to fulfill the Milan criteria for transplantation. For that purpose, using ablative techniques or chemoembolization to control local tumor growth is useful.
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PMID:Liver resection and transplantation in the management of hepatocellular carcinoma: a review. 1723 57

The X protein of hepatitis B virus (HBx) is often expressed in human hepatocellular carcinoma (HCC) but its role on tumor growth is not fully clarified. In this study, RNA interference was employed to knockdown HBx expression in Hep3B HCC cells, which naturally express carboxyl-end truncated form of HBx frequently found in HCC tissues. Specific knockdown of HBx strongly inhibited cell growth and tumorigenicity in xenograft model. HBx repression induced apoptosis in Hep3B cells and significantly increased cell sensitivity to cisplatin-induced apoptosis. These results suggest that RNA interference-mediated HBx suppression exerts potent anti-proliferative and chemosensitizing effects in human HCC.
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PMID:RNA interference targeting HBx suppresses tumor growth and enhances cisplatin chemosensitivity in human hepatocellular carcinoma. 1729 61

Tissue-targeted delivery of small interfering RNA (siRNA) must be achieved before RNA interference (RNAi) technology can be used in practical therapeutic approaches. In this study, the potential of apolipoprotein A-I (apo A-I) for the systemic delivery of nucleic acids to the liver is demonstrated using real-time in vivo imaging. As a proof of concept, synthetic siRNAs against hepatitis B virus (HBV) were formulated into complexes of apo A-I and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (DTC-Apo) and injected intravenously (i.v.) into a mouse model carrying replicating HBV. We show that administration of these nanoparticles can significantly reduce viral protein expression by receptor-mediated endocytosis. The advantages of the apo A-I-mediated siRNA delivery method are its liver specificity, its effectiveness at low doses (< or = 2 mg/kg) in only a single treatment, and its persistent antiviral effect up to 8 days. The liver-targeted gene silencing was also shown by in vivo images, in which bioluminescent signals emitted from the liver were efficiently reduced after i.v. administration of luciferase-specific siRNA and DTC-Apo lipoplex. Thus, our unique approach to siRNA delivery creates a foundation for the development of a new class of promising therapeutics against hepatitis viruses or hepatocyte genes related to tumor growth.
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PMID:Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I. 1744 Apr 41

Live attenuated bacteria have great potential for use in vaccine development due to several unique advantages, including stable antigen expression, effective antigen presentation, convenient and inexpensive delivery, and low cost of vaccine production. In this study, we expressed hepatitis B virus x gene (HBx) on mouse melanoma cells as the target antigen and constructed Salmonella-based HBx vaccines by two strategies, i.e., recombinant eukaryotic plasmid encoding HBx and a recombinant prokaryotic plasmid encoding Type III secretion system effector-HBx fusion protein. Both HBx constructs elicited significant levels of CTL reaction and IFN-gamma secreting T cells. When mice were challenged with melanoma cells expressing HBx, tumor growth rates in immunized animals were significantly slower than controls. Tumor sizes and tumor weight indices of immunized mice were also significantly lower than controls. We conclude that both strategies described in this study may lead to novel approaches of tumor vaccines.
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PMID:Two oral HBx vaccines delivered by live attenuated Salmonella: both eliciting effective anti-tumor immunity. 1822 55

Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1 alpha (HIF-1 alpha) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1 alpha, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1 alpha. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1 alpha. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBx-transgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1 alpha, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.
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PMID:Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. 1826 40

Boehmeria nivea extract (BNE) is widely used in southern Taiwan as a folk medicine for hepato-protection and hepatitis treatment. In previous studies, we demonstrated that BNE could reduce the supernatant hepatitis B virus (HBV) DNA in HBV-producing HepG2 2.2.15 cells. In the present study, we established an animal model of HBV viremia and used it to validate the efficacy of BNE in vivo. In this animal model, serum HBV DNA and HBsAg were elevated in accordance with tumor growth. To evaluate the anti-HBV activity of BNE, HBV-viremia mice were built up after one subcutaneous inoculation of HepG2 2.2.15 tumor cells in severe combined immunodeficiency mice over 13 days. The levels of serum HBV DNA were elevated around 10(5)-10(6) copies per milliliter. Both oral and intraperitoneal administration of BNE were effective at inhibiting the production of HBsAg and HBV DNA, whereas tumor growth was not affected by all test articles. Intraperitoneal administration of BNE appeared to have greater potential to inhibit serum HBV DNA levels compared with oral administration under the same dosage. Notably, reduced natural killer cell activity was also observed after high dosage of BNE administration, and this correlated with reduced serum HBV DNA. In conclusion, BNE exhibited potential anti-HBV activity in an animal model of HBV viremia.
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PMID:The Anti-hepatitis B Virus Activity of Boehmeria nivea Extract in HBV-viremia SCID Mice. 1895 4


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