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)

IkappaB kinase (IKK) catalytic subunits play a key role in cytokinemediated nuclear factor (NF)-kappaB signaling, and a loss of NF-kappaB function appears to inhibit inflammation and oncogenesis. Manumycin A is a potent and selective farnesyltransferase inhibitor with antitumor activity. We found that manumycin A caused a rapid and potent inhibition of IKK activity induced by tumor necrosis factor alpha in a number of cell types. Most unexpectedly, other classes of farnesyltransferase inhibitors had no inhibitory effect. To identify the molecular mechanisms of manumycin A action, cultured human HepG2 hepatoma cells were transiently transfected with various IKKalpha and IKKbeta constructs, and a striking difference in manumycin A sensitivity was observed. Furthermore, cells expressing wild-type IKKbeta and IKKbeta mutated in the activation loop at Cys-179 exhibited covalent homotypic dimerization of IKKbeta in response to manumycin A, whereas substitution of Cys-662 and -716 conferred protection against dimer formation. Direct inhibition of IKK activity and formation of stable IKKbeta dimers were observed in the presence of manumycin A that could be blocked by dithiothreitol. IKK interaction with the adaptor protein IKKgamma/NEMO was disrupted in manumycin A-treated cells. Most importantly, administration of manumycin A to mice xenografted with murine B16F10 tumors caused potent IKK-suppressive effects. Thus, manumycin A with its epoxyquinoid moieties plays an important regulatory function in IKK signaling through pathways distinct from its role as a protein farnesylation inhibitor.
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PMID:Binding of manumycin A inhibits IkappaB kinase beta activity. 1631 58

Hepatitis B virus (HBV) infections play an important role in the development of cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of HBV-related HCC, however, has not been fully described. Evidence suggests that the HBV X protein (HBx) plays a crucial role in the pathogenesis of HCC. The high occurrence of anti-HBx antibody in the serum of HCC patients indicates that it could be a prognostic marker of HBV infection and HCC. HBx stimulates and influences signal transduction pathways within cells. HBx also binds to such protein targets as p53, proteasome subunits, and UV-damaged DNA binding proteins. It also interacts with the cyclic AMP-responsive element binding protein, ATF-2, NFkappaB, and basal transcription factors. HBx is primarily localized to the cytoplasm, where it interacts with and stimulates protein kinases, including protein kinase C, Janus kinase/STAT, IKK, PI-3-K, stress-activated protein kinase/Jun N-terminal kinase, and protein kinase B/Akt. It is also found in the mitochondrion, where it influences the Bcl-2 family. This review examines the role of HBx in the life cycle of HBV as well as the various signal transduction pathways involved in the pathogenesis of HBV-induced hepatocarcinogenesis.
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PMID:Effects of hepatitis B virus X protein on the development of liver cancer. 1645 63

TNF-alpha activates several intracellular pathways to regulate inflammation, cell death, and proliferation. In the liver, TNF-alpha is not only a mediator of hepatotoxicity but also contributes to the restoration of functional liver mass by driving hepatocyte proliferation and liver regeneration. This review summarizes recent advances in TNF-alpha signaling mechanisms that demonstrate how the IKK, ROS, and JNK pathways interact with each other to regulate hepatocyte apoptosis and proliferation. Activation of these pathways is causatively linked to liver injury induced by concanavalin A, TNF-alpha, and ischemia-reperfusion and to liver regeneration and hepatocarcinogenesis. In light of recent findings, pharmacological inhibitors of JNK and IKK and antioxidants may be promising new tools for the treatment of hepatitis, ischemia-reperfusion injury, and hepatocellular carcinoma.
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PMID:Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. 1653 70

The IkappaB kinase (IKK) subunit NEMO/IKKgamma is essential for activation of the transcription factor NF-kappaB, which regulates cellular responses to inflammation. The function of NEMO in the adult liver remains elusive. Here we show that ablation of NEMO in liver parenchymal cells caused the spontaneous development of hepatocellular carcinoma in mice. Tumor development was preceded by chronic liver disease resembling human nonalcoholic steatohepatitis (NASH). Antioxidant treatment and genetic ablation of FADD demonstrated that death receptor-mediated and oxidative stress-dependent death of NEMO-deficient hepatocytes triggered disease pathogenesis in this model. These results reveal that NEMO-mediated NF-kappaB activation in hepatocytes has an essential physiological function to prevent the spontaneous development of steatohepatitis and hepatocellular carcinoma, identifying NEMO as a tumor suppressor in the liver.
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PMID:Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. 1729 19

Activation-induced cytidine deaminase (AID) is involved in somatic DNA alterations of the immunoglobulin gene for amplification of immune diversity. The fact that constitutive expression of AID in mice causes tumors in various organs, including lymphoid tissues and lungs, suggests the important role of the aberrant editing activity of AID on various tumor-related genes for carcinogenesis. AID expression, however, is restricted to activated B cells under physiological conditions. We demonstrate here that ectopic AID expression is induced in response to tumor necrosis factor-alpha stimulation in cultured human hepatocytes. The proinflammatory cytokine-mediated expression of AID is achieved by IkappaB kinase-dependent nuclear factor (NF)-kappaB signaling pathways. Hepatitis C virus, one of the leading causes of hepatocellular carcinoma (HCC), enhanced AID expression via NF-kappaB activation through expression of viral core protein. The aberrant expression of AID in hepatoma-derived cells resulted in accumulation of genetic alterations in the c-myc and pim1 genes, suggesting that inappropriate expression of AID acts as a DNA mutator that enhances the genetic susceptibility to mutagenesis in human hepatocytes. Our current findings indicate that the inappropriate expression of AID is induced by proinflammatory cytokine stimulation and may provide the link between hepatic inflammation and the development of HCC.
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PMID:Expression of activation-induced cytidine deaminase in human hepatocytes via NF-kappaB signaling. 1740 78

The Insulin Receptor Substrate (IRS) proteins are key players in insulin signal transduction and are the best studied targets of the insulin receptor. Ser/Thr phosphorylation of IRS proteins negatively modulates insulin signaling; therefore, the identification of IRS kinases and their target Ser phosphorylation sites is of physiological importance. Here we show that in Fao rat hepatoma cells, the IkappaB kinase beta (IKKbeta) is an IRS-1 kinase activated by selected inducers of insulin resistance, including sphingomyelinase, ceramide, and free fatty acids. Moreover, IKKbeta shares a repertoire of seven potential target sites on IRS-1 with protein kinase C zeta (PKCzeta), an IRS-1 kinase activated both by insulin and by inducers of insulin resistance. We further show that mutation of these seven sites (Ser-265, Ser-302, Ser-325, Ser-336, Ser-358, Ser-407, and Ser-408) confers protection from the action of IKKbeta and PKCzeta when they are overexpressed in Fao cells or primary hepatocytes. This enables the mutated IRS proteins to better propagate insulin signaling. These findings suggest that insulin-stimulated IRS kinases such as PKCzeta overlap with IRS kinases triggered by inducers of insulin resistance, such as IKKbeta, to phosphorylate IRS-1 on common Ser sites.
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PMID:Common inhibitory serine sites phosphorylated by IRS-1 kinases, triggered by insulin and inducers of insulin resistance. 2975 19

Deletion of NEMOLambdaKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, Roskams T, Trautwein C, Pasparakis M. The IkappaB kinase (IKK) subunit NEMOLambdaKKgamma is essential for activation of the transcription factor NF-kappaB, which regulates cellular responses to inflammation. The function of NEMO in the adult liver remains elusive. Here we show that ablation of NEMO in liver parenchymal cells caused the spontaneous development of hepatocellular carcinoma in mice. Tumor development was preceded by chronic liver disease resembling human non-alcoholic steatohepatitis (NASH). Antioxidant treatment and genetic ablation of FADD demonstrated that death receptor-mediated and oxidative stress-dependent death of NEMO-deficient hepatocytes triggered disease pathogenesis in this model. These results reveal that NEMO-mediated NF-kappaB activation in hepatocytes has an essential physiological function to prevent the spontaneous development of steatohepatitis and hepatocellular carcinoma, identifying NEMO as a tumor suppressor in the liver. [Abstract reproduced by permission of Cancer Cell 2007;11:119-132].
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PMID:The role of NF-kappaB in hepatocarcinogenesis: promoter or suppressor? 1756 88

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, beta-Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16(INK4A) and p53 and TGF-beta/SMAD signaling. Oncosuppressor genes, including p16(INK4A), E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16(INK4A) inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.
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PMID:Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma. 1847 8

Advanced glycation end products (AGEs) could be implicated in insulin resistance. However, the molecular mechanisms underlying this are not fully understood. Since pigment epithelium-derived factor (PEDF) blocks the AGE-signaling pathways, we examined here whether and how PEDF improves insulin resistance in AGE-exposed hepatoma cells, Hep3B cells. Proteins were extracted from Hep3B cells, immunoprecipitated with or without insulin receptor substrate-1 (IRS-1) antibodies, and subjected to Western blot analysis. Glycogen synthesis was measured using [ (14)C]-d-glucose. AGE induced Rac-1 activation and increased phosphorylation of IRS-1 at serine-307 residues, JNK, c-JUN, and IkappaB kinase in association with decreased IkappaB levels in Hep3B cells. PEDF or overexpression of dominant negative Rac-1 blocked these effects of AGE on Hep3B cells. Further, AGEs decreased tyrosine phosphorylation of IRS-1, and subsequently reduced the association of p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by PEDF. Our present study suggests that PEDF could improve the AGE-elicited insulin resistance in Hep3B cells by inhibiting JNK- and IkappaB kinase-dependent serine phosphorylation of IRS-1 via suppression of Rac-1 activation. PEDF may play a protective role against hepatic insulin resistance in diabetes.
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PMID:Pigment epithelium-derived factor (PEDF) ameliorates advanced glycation end product (AGE)-induced hepatic insulin resistance in vitro by suppressing Rac-1 activation. 1879 73

The NF-kappaB signaling pathway has particular relevance to several liver diseases including hepatitis (liver infection by Helicobacter, viral hepatitis induced by HBV and HCV), liver fibrosis and cirrhosis and hepatocellular carcinoma. Furthermore, the NF-kappaB signaling pathway is a potential target for development of hepatoprotective agents. Several types of drugs including: selective estrogen receptor modulators (SERMs), antioxidants, proteasome inhibitors, IKK inhibitors and nucleic acid-based decoys have been shown to interfere with NF-kappaB activity at different levels and may be useful for the treatment of liver diseases. However, NF-kappaB also plays an important hepatoprotective function that needs to be taken into consideration during development of new therapeutic regimens.
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PMID:NF-kappaB signaling, liver disease and hepatoprotective agents. 1893 90


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