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)

Since its discovery as a protein associated with the cytoplasmic region of E-cadherin, beta-catenin has been shown to perform two apparently unrelated functions: it has a crucial role in cell-cell adhesion in addition to a signaling role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta-catenin accumulation and transcriptional activation of specific target genes during development. It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death. The APC/beta-catenin pathway is highly regulated and includes players such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF. c-MYC and cyclin D1 were recently identified as a key transcriptional targets of this pathway and additional targets are likely to emerge. Published 1999 John Wiley & Sons, Inc.
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PMID:beta-catenin signaling and cancer. 1058 Sep 87

The Wnt signaling pathway is essential for development and organogenesis. Wnt signaling stabilizes beta-catenin, which accumulates in the cytoplasm, binds to 1-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes. Mutations in CTNNB1 (encoding beta-catenin) or APC (adenomatous polyposis coli) have been reported in human neoplasms including colon cancers and hepatocellular carcinomas (HCCs). Because HCC5 tend to show accumulation of beta-catenin more often than mutations in CTNNB1, we looked for mutations in AXIN1, encoding a key factor for Wnt signaling, in 6 HCC cell lines and 100 primary HCC5. Among the 4 cell lines and 87 HCC5 in which we did not detect CTNNB1 mutations, we identified AXIN1 mutations in 3 cell lines and 6 mutations in 5 of the primary HCCs. In cell lines containing mutations in either gene, we observed increased DNA binding of TCF associated with beta-catenin in nuclei. Adenovirus mediated gene transfer of wild-type AXINI induced apoptosis in hepatocellular and colorectal cancer cells that had accumulated beta-catenin as a consequence of either APC, CTNNB1 or AXIN1 mutation, suggesting that axin may be an effective therapeutic molecule for suppressing growth of hepatocellular and colorectal cancers.
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PMID:AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. 1070 Jan 76

Hepatocellular carcinoma (HCC) is one of the human cancers clearly linked to viral infections. Although the major viral and environmental risk factors for HCC development have been unravelled, the oncogenic pathways leading to malignant transformation of liver cells have long remained obscure. Recent outcomes have been provided by extensive allelotype studies which resulted in a comprehensive overview of the main genetic abnormalities in HCC, including DNA copy gains and losses. The differential involvement of the p53 tumor-suppressor gene in tumors associated with various risk factors has been largely clarified. Evidence for a crucial role of the reactivation of the Wnt/beta-catenin pathway, through mutations in the beta-catenin and axin genes in 30-40% of liver tumors, represents a major breakthrough. It has also been shown that the Rb pathway is frequently disrupted by methylation-dependent silencing of the p16INK4A gene and stimulation of Rb degradation by a proteosomal subunit. Presently, the identification of candidate oncogenes and tumor suppressors in the most frequently altered chromosomal regions is a major challenge. Great insights will come from integrating the signals from different pathways operating at preneoplastic and neoplastic stages. This search might, in time, permit an accurate evaluation of the major targets for therapeutic treatments.
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PMID:Genetics of hepatocellular carcinoma. 1093 68

beta-Catenin plays a key role in the Wnt signaling pathway, and mutations of CTNNB1, the gene that encodes beta-catenin, have been identified in about one-fourth of human hepatocellular carcinomas from regions of low aflatoxin B1 exposure. In this study 62 hepatocellular carcinomas (HCCs) from people highly exposed to aflatoxin B1 in Guangxi, People's Republic of China, were laser-capture microdissected and examined for CTNNB1 mutations. In addition, 41 of the HCCs were evaluated for the presence of the beta-catenin protein by immunohistochemical methods. Twenty of the HCCs showed positive results for beta-catenin, with strong membrane staining, while adjacent non-neoplastic liver tissue lacked or showed only weak membrane staining. One HCC, in which a CTNNB1 mutation was not detected, showed nuclear staining for the beta-catenin protein. Mutations of CTNNB1 were identified in five HCCs. These consisted of four point mutations in the glycogen serine kinase-3beta phosphorylation region of codons 32-45 and one deletion of codons 32-38. These mutations were similar to those previously reported for human HCC, although at a lower frequency. A signature mutation profile associated with aflatoxin B1 exposure could not be identified. The immunohistochemical findings indicate a role for accumulation of beta-catenin and possibly increased Wnt signaling in aflatoxin B1-associated HCC. The low frequency of CTNNB1 mutations, however, suggests that mutation of another Wnt signaling component, such as the Wnt scaffolding protein axin or the adenomatous polyposis coli protein, both of which modulate beta-catenin stability, also may be involved in aflatoxin-associated HCC. Published 2001 Wiley-Liss, Inc.
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PMID:CTNNB1 mutations and beta-catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1. 1142 83

Axin, an important regulator of beta-catenin, is frequently mutated in human hepatocellular carcinomas (HCCs), and transduction of the wild-type Axin gene (AXIN1) induces apoptosis in HCC cells as well as in colon cancer cells. To investigate the detailed biological function of Axin, we searched on a cDNA microarray for genes whose expression was altered by transfer of wild-type AXIN1 into colon-cancer cell line LoVo. Among the genes showing altered expression, we focused on one, termed AXUD1 (AXIN1 up-regulated), that revealed enhanced expression in response to exogenously expressed AXIN1 but not to LacZ, a control gene. The AXUD1 gene consists of five exons and encodes a transcript with an open reading frame of 1767 bp. A 3.2-kb transcript of AXUD1 was expressed in all human tissues examined, most abundantly in lung, placenta, skeletal muscle, pancreas and leukocyte. By radiation-hybrid mapping we assigned its chromosomal location at 3p22, a region where frequent loss of heterozygosity has been reported in lung, renal, prostate, breast and cervical cancers. AXUD1 was frequently down-regulated in lung, kidney, liver and colon cancers compared with their corresponding normal tissues, suggesting that AXUD1 may have a tumor-suppressor function in those organs.
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PMID:Identification of AXUD1, a novel human gene induced by AXIN1 and its reduced expression in human carcinomas of the lung, liver, colon and kidney. 1152 92

Aberrant activation of Wnt signaling caused by mutations in adenomatous polyposis coli (APC) or beta-catenin is a critical event in the development of human colorectal tumors. Wnt signaling stabilizes beta-catenin, which in turn associates with TCF/LEF family transcription factors, ultimately altering the expression of Wnt target genes. We have recently identified ICAT, a beta-catenin-interacting protein that interferes with the interaction between beta-catenin and TCF-4, thereby negatively regulating Wnt signaling. In the present study, we generated a recombinant adenovirus encoding ICAT and examined its effect on the growth of tumor cells. We found that Icat inhibits proliferation of colorectal tumor cells mutated in APC or beta-catenin and hepatocellular carcinoma cells mutated in AXIN: By contrast, Icat did not inhibit growth of either normal or tumor cells containing the wild-type APC, beta-catenin, and Axin genes. Icat also inhibited the anchorage-independent growth of colorectal tumor cells and tumorigenic growth of colorectal tumor xenografts. Furthermore, we found that Icat inhibits both dephosphorylation of Cdc2 and nuclear translocation of cyclin B1 and induces G(2) arrest followed by cell death in colorectal tumor cells. These results suggest that Wnt signaling is critical for the growth of colorectal tumors and some hepatocellular carcinomas and that expression of ICAT or drugs which mimic its effects may be useful in the treatment of these tumors.
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PMID:Overexpression of Icat induces G(2) arrest and cell death in tumor cell mutants for adenomatous polyposis coli, beta-catenin, or Axin. 1203 51

Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type beta-catenin and the Wnt-beta-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/beta-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.
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PMID:Viral hepatitis and liver cancer: the case of hepatitis C. 1679 25

Hepatocellular carcinoma (HCC) is a common human cancer with high mortality, and currently, there is no effective chemoprevention or systematic treatment. Recent evidence suggests that cyclooxygenase-2 (COX-2)-derived PGE(2) and Wnt/beta-catenin signaling pathways are implicated in hepatocarcinogenesis. Here, we report that omega-3 polyunsaturated fatty acids (PUFA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) inhibit HCC growth through simultaneously inhibition of COX-2 and beta-catenin. DHA and EPA treatment resulted in a dose-dependent reduction of cell viability with cleavage of poly ADP ribose polymerase, caspase-3, and caspase-9 in three human HCC cell lines (Hep3B, Huh-7, HepG2). In contrast, AA, a omega-6 PUFA, exhibited no significant effect. DHA and EPA treatment caused dephosphorylation and thus activation of GSK-3beta, leading to beta-catenin degradation in Hep3B cells. The GSK-3beta inhibitor, LiCl, partially prevented DHA-induced beta-catenin protein degradation and apoptosis. Additionally, DHA induced the formation of beta-catenin/Axin/GSK-3beta binding complex, which serves as a parallel mechanism for beta-catenin degradation. Furthermore, DHA inhibited PGE(2) signaling through downregulation of COX-2 and upregulation of the COX-2 antagonist, 15-hydroxyprostaglandin dehydrogenase. Finally, the growth of HCC in vivo was significantly reduced when mouse HCCs (Hepa1-6) were inoculated into the Fat-1 transgenic mice, which express a Caenorhabditis elegans desaturase converting omega-6 to omega-3 PUFAs endogenously. These findings provide important preclinical evidence and molecular insight for utilization of omega-3 PUFAs for the chemoprevention and treatment of human HCC.
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PMID:Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2. 1988 46

Transforming growth factor-beta cooperates with oncogenic Ras to activate nuclear beta-catenin during the epithelial to mesenchymal transition of hepatocytes, a process relevant in the progression of hepatocellular carcinoma (HCC). In this study we investigated the role of beta-catenin in the differentiation of murine, oncogene-targeted hepatocytes and in 133 human HCC patients scheduled for orthotopic liver transplantation. Transforming growth factor-beta caused dissociation of plasma membrane E-cadherin/beta-catenin complexes and accumulation of nuclear beta-catenin in Ras-transformed, but otherwise normal hepatocytes in p19(ARF)-/- mice. Both processes were inhibited by Smad7-mediated disruption of transforming growth factor-beta signaling. Overexpression of constitutively active beta-catenin resulted in high levels of CK19 and M2-PK, whereas ablation of beta-catenin by axin overexpression caused strong expression of CK8 and CK18. Therefore, nuclear beta-catenin resulted in dedifferentiation of neoplastic hepatocytes to immature progenitor cells, whereas loss of nuclear beta-catenin led to a differentiated HCC phenotype. Poorly differentiated human HCC showed cytoplasmic redistribution or even loss of E-cadherin, suggesting epithelial to mesenchymal transition. Analysis of 133 HCC patient samples revealed that 58.6% of human HCC exhibited strong nuclear beta-catenin accumulation, which correlated with clinical features such as vascular invasion and recurrence of disease after orthotopic liver transplantation. These data suggest that activation of beta-catenin signaling causes dedifferentiation to malignant, immature hepatocyte progenitors and facilitates recurrence of human HCC after orthotopic liver transplantation.
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PMID:Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence. 2000 39

HEPATOCELLULAR CARCINOMA: EpidemiologyManagement of HCC-Standard Approaches and Reports During the Past Year SurgeryLocoregional Treatment Local AblationChemoembolizationOther Local Treatment ModalitiesSystemic TreatmentClinical Trial DesignBasic Science and Biomarkers Basic and Translational SciencePrognostic and Predictive Markers Prognostic MarkersPredictive MarkersAccomplishments and Future DirectionsApplication of the AccomplishmentsFuture Directions BILIARY TRACT CANCERS: Overview of the DiseaseManagement of Biliary Tract Cancers-Current Approaches and Reports During the Past Year Surgical Resection and Adjuvant TherapySystemic Therapy for Unresectable or Metastatic Biliary Tract Cancer Cytotoxic ChemotherapyCytotoxic Chemotherapy in Combination With Targeted AgentSingle-Agent Targeted TherapyCombination of Targeted AgentsBiologyFuture Directions.
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PMID:Accomplishments in 2008 in the management of hepatobiliary cancers. 2001 62


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