Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte apoptosis is increased in patients with nonalcoholic steatohepatitis and correlates with disease severity. Long-chain saturated fatty acids, such as palmitate and stearate, induce apoptosis in liver cells. The present study examined insulin-mediated protection against saturated fatty acid-induced apoptosis in the rat hepatoma cell line, H4IIE, and primary rat hepatocytes. Cells were provided a control media (no fatty acids) or the same media containing 250 micromol/liter of albumin-bound oleate or palmitate for 16 h. Insulin concentrations were 0, 1, 10, or 100 nmol/liter (n=4-6/treatment). Palmitate, but not oleate, activated caspase-3 and induced DNA fragmentation in the absence of insulin. Insulin reduced palmitate-mediated activation of caspase-3 and DNA fragmentation in a dose-dependent manner. Phosphatidylinositol 3-kinase inhibitors abolished these effects of insulin. Insulin-mediated inhibition of palmitate-induced apoptosis was not due to an augmentation in the unfolded protein response or increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate, but not oleate, increased c-Jun NH2 terminal kinase activity in the absence of insulin. Insulin or SP600125, a chemical inhibitor of c-Jun NH2 terminal kinase, blocked palmitate-mediated activation of c-Jun NH2 terminal kinase and reduced apoptosis. These data suggest that insulin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in insulin-deficient and/or -resistant states.
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PMID:Insulin protects liver cells from saturated fatty acid-induced apoptosis via inhibition of c-Jun NH2 terminal kinase activity. 1743 Oct 9

RNA interference (RNAi) induced by small interfering RNA (siRNA) can trigger sequence-specific gene silencing in mammalian cells. It has been proposed that siRNA can be developed as a novel strategy for cancer therapy. However effective delivery of therapeutically active siRNAs into the target tissue/cells in vivo is still a major obstacle for successful application. Oncolytic adenoviral vector mediated RNAi provides the potential advantages of minimizing the harm of normal cells, regenerating siRNAs within the tumor microenvironment and inspiring an additive antitumor outcome through viral oncolysis. Hepatocellular carcinoma (HCC) displays a high resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cell death, partially due to high expression levels of the X-linked Inhibitor-of-Apoptosis protein (XIAP). Here, we utilized an oncolytic adenovirus (ZD55) for expressing short hairpin RNA (shRNA), a precursor of siRNA, to knockdown XIAP. To increase sensitivity of HCC cells to TRAIL, we have used ZD55 to deliver both XIAP-shRNA and TRAIL into HCC cells. The results showed that the combination of ZD55-XIAP-shRNA and ZD55-TRAIL resulted in significant reduction of XIAP expression and potent antitumor activity both in HCC cells and in animal model with tumor. This pilot study offers a promise of using oncolytic adenovirus to deliver siRNA targeting overexpressed oncogenes and a novel strategy for cancer therapy by regulating the equilibrium between the proapoptotic and antiapoptotic factors.
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PMID:Synergistic antitumor activity of XIAP-shRNA and TRAIL expressed by oncolytic adenoviruses in experimental HCC. 1793 93

TIP30 (Tat-interacting protein 30), a newly found proapoptotic factor, appears to be involved in multiple functions including metabolic suppression, apoptosis induction, and diminishing angiogenic properties. In the present study, we reported that mitochondrial events were required for apoptosis induced by TIP30 in hepatocellular carcinoma cells (HCC cells). Translocation of Bax was essential for TIP30-induced apoptosis, whereas overexpression of the anti-apoptotic protein Bcl-xL delayed both second mitochondria-derived activator of caspases (Smac/DIABLO) release and onset of apoptosis. Furthermore, TIP30-induced apoptosis was dependent on caspase activity because the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (z-VAD-fmk) blocked DNA fragmentation. Release of Smac/DIABLO from the mitochondria through the TIP30-P53-Bax cascade was required to remove the inhibitory effect of XIAP (X-linked Inhibitor of Apoptosis) and allowed apoptosis to proceed. Our results showed for the first time that Bax-dependent release of Smac/DIABLO, cytochrome c and AIF from the mitochondria mediated the contribution of the mitochondrial pathway to TIP30-mediated apoptosis. Our data suggested that adenovirus-mediated overexpression of TIP30 was capable of inducing therapeutic programmed cell death in vitro by activating the mitochondrial pathway of apoptosis. On the basis of these studies, elucidating the mechanism by which TIP30 induces cell death might establish it as an anticancer approach.
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PMID:Tip30-induced apoptosis requires translocation of Bax and involves mitochondrial release of cytochrome c and Smac/DIABLO in hepatocellular carcinoma cells. 1799 90

Interleukin (IL)-18 plays an important role in the pathogenesis of several liver diseases as well as Fas-mediated apoptosis. However, the effects of IL-18 on Fas-mediated liver injury have not been well elucidated. Therefore, we examined the effects of IL-18 on Fas-mediated apoptosis in in vitro and in vivo experiments. We found that recombinant IL-18 protected mouse hepatocellular carcinoma cell lines, BNL5, from Fas-mediated apoptosis in a dose-dependent manner with up-regulation of both nuclear factor (NF) kappaB and X-linked inhibitors of apoptosis (XIAP). IL-18 transgenic (Tg) mice were also protected from Fas-mediated liver injury and this was further confirmed by histological study and TUNEL staining. In IL-18 Tg mice, up-regulation of XIAP and down-regulation of caspase 3 were observed after injection of anti-Fas, which was consistent with the in vitro findings. These results suggest that IL-18 suppresses Fas-mediated apoptosis of hepatocytes by up-regulation of NFkappaB and XIAP, following inhibition of caspase-3 activity. This observation raises the possibility that IL-18 could be a therapeutic strategy for Fas-mediated liver injury as a negative regulator of XIAP.
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PMID:Protective role of interleukin-18 against Fas-mediated liver injury. 1857 74

Hepatic apoptosis is elevated in patients with non-alcoholic steatohepatitis and is correlated with the severity of the disease. Long-chain saturated fatty acids, such as palmitate, induce apoptosis in liver cells. The present study examined adiponectin-mediated protection against saturated fatty acid-induced apoptosis in the human hepatoma cell line, HepG2. Cells were cultured in a control media (i.e. without fatty acids) or the same media containing 250 micromol L(-1) of albumin-bound oleate or palmitate for 24 h. The adiponectin concentrations used were: 0, 1, 10 or 100 microg mL(-1) (n = 4-6 per treatment). Palmitate and thapsigargin, but not oleate, activated caspase-3 and decreased cell viability in the absence of adiponectin. Adiponectin reduced palmitate- and thapsigargin-induced activation of caspase-3 and cell death in a dose-dependent manner. Phosphatidylinositol 3-kinase and AMP-activated protein kinase inhibitors abolished the effects of adiponectin. Adiponectin-induced inhibition of palmitate- and thapsigargin-induced apoptosis was not the result of an augmentation in the unfolded protein response or the increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate and thapsigargin, but not oleate, increased c-Jun NH(2) terminal kinase phosphorylation in the absence of adiponectin. Adiponectin blocked palmitate- and thapsigargin-induced activation of c-Jun NH(2) terminal kinase and reduced apoptosis. These data suggest that adiponectin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in adiponectin-deficient individuals.
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PMID:Full-length adiponectin protects hepatocytes from palmitate-induced apoptosis via inhibition of c-Jun NH2 terminal kinase. 1929 Aug 87

Glypicans are heparan sulfate proteoglycans that are bound to the cell surface by glycosylphosphatidylinositol. While six members of the glypican family are known in mammals, our study focused on glypican 3 (GPC3). Loss-of-function mutations of GPC3 result in the Simpson-Golabi-Behmel syndrome, an X-linked disorder characterized by pre- and postnatal liver and other organ overgrowth. GPC3 is overexpressed in human hepatocellular carcinoma; however, its role in normal liver regeneration and hepatocyte proliferation is unknown. Here we investigated the role of GPC3 in hepatocyte proliferation. GPC3 mRNA and protein levels begin to increase 2 days after hepatectomy with peak expression levels by day 5. In hepatocyte cultures, GPC3 reaches a plateau when hepatocyte proliferation decreases. In vitro studies using Morpholino oligonucleotides showed that blocking GPC3 expression promoted hepatocyte growth. Yeast two-hybrid assays revealed that GPC3 interacts with CD81, a member of the tetraspanin family that is reported to be involved in hepatitis C virus infection and cell proliferation. We found that CD81 levels also increased 2 days after partial hepatectomy and toward the end of regeneration. Immunofluorescence showed that CD81 and GPC3 colocalize by 2 and 6 days after hepatectomy. Co-immunoprecipitation validated the interaction of GPC3 and CD81. Our results indicate that GPC3 may be a negative regulator of liver regeneration and hepatocyte proliferation, and that this regulation may involve CD81.
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PMID:Investigation of the role of glypican 3 in liver regeneration and hepatocyte proliferation. 1957 24

Oleanolic acid (OA) and ursolic acid (UA) are commonly found in plants and herbs and have been reported to possess hepatoprotective, anti-inflammatory and anticancer activities. In the present study, the effects of OA and UA on induction of apoptosis in human hepatocellular carcinoma HuH7 cells and the related mechanisms were investigated. The results demonstrate that OA and UA could inhibit the growth of HuH7 cells with IC(50) values of 100 and 75 microM, respectively. Cell cycle analysis using flow cytometry indicated that the fraction of HuH7 cells in sub-G1 phase progressively increased with increasing concentrations of OA or UA from 20 to 80 microM. Treatment with OA and UA for 8 h induced a dramatic loss of the mitochondria membrane potential and interfered with the ratio of expression levels of pro- and antiapoptotic Bcl-2 family members in HuH7 cells. OA and UA-induced apoptosis involving the release of mitochondria cytochrome c into the cytosol and subsequently induced the activation of caspase-9 and caspase-3, followed by cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, HuH7 cells treated with OA and UA suppressed the activity of NF-kappaB and modulated the mRNA expression of X-linked inhibitor of apoptotic protein (XIAP) as compared with untreated cells. These results demonstrate that OA and UA induce apoptosis in HuH7 cells through a mitochondria-mediated pathway and downregulation of XIAP.
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PMID:Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP. 2041 21

Cirrhosis is a premalignant condition leading to hepatocellular carcinoma. Cirrhotic nodules are surrounded by a rim of CK 7/CK19-positive biliary cells termed ductular reaction. Half of all regenerative cirrhotic nodules are thought to be monoclonal by studying the pattern of inactivation of the X-linked human androgen receptor gene (HUMARA). Using a new technique for lineage tracing in human liver based on the identification in the mitochondrial DNA of mutations in the cytochrome c oxidase (CCO) gene, the authors discovered that 20% of regenerative nodules were monoclonal; in addition they showed that hepatic progenitor cells within abutting CCO-deficient cells of the ductular reaction had the same mutations as the adjacent regenerative nodule, indicating a common cell origin. It is the first direct evidence that regenerative nodules in cirrhosis can be derived from hepatic progenitor cells.
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PMID:Human cirrhosis: monoclonal regenerative nodules derived from hepatic progenitor cells abutting ductular reaction. 2043 May 57

Hepatocellular carcinoma (HCC) remains a common malignant cancer worldwide. There is an urgent need to identify new molecular targets for the development of novel therapeutic approaches. Herein, we review the structure, function and biology of glypican-3 (GPC3) and its role in human cancer with a focus on its potential as a therapeutic target for immunotherapy. GPC3 is a cell-surface protein that is over-expressed in HCC. Loss-of-function mutations of GPC3 cause Simpson-Golabi-Behmel syndrome (SGBS), a rare X-linked overgrowth condition. GPC3 binds Wnt and Hedgehog (Hh) signalling proteins. GPC3 is also able to bind basic growth factors such as fibroblast growth factor 2 through its heparan sulphate glycan chains. GPC3 is a promising candidate for liver cancer therapy given that it shows high expression in HCC. An anti-GPC3 monoclonal antibody has shown anti-cancer activity in mice and its humanised IgG molecule is currently undergoing clinical evaluation in patients with HCC. There is also evidence that soluble GPC3 may be a useful serum biomarker for HCC.
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PMID:Glypican-3: a new target for cancer immunotherapy. 2111 73

Subcompartments of the plasma membrane are believed to be critical for lymphocyte responses, but few genetic tools are available to test their function. Here we describe a previously unknown X-linked B cell-deficiency syndrome in mice caused by mutations in Atp11c, which encodes a member of the P4 ATPase family thought to serve as 'flippases' that concentrate aminophospholipids in the cytoplasmic leaflet of cell membranes. Defective ATP11C resulted in a lower rate of phosphatidylserine translocation in pro-B cells and much lower pre-B cell and B cell numbers despite expression of pre-rearranged immunoglobulin transgenes or enforced expression of the prosurvival protein Bcl-2 to prevent apoptosis and abolished pre-B cell population expansion in response to a transgene encoding interleukin 7. The only other abnormalities we noted were anemia, hyperbilirubinemia and hepatocellular carcinoma. Our results identify an intimate connection between phospholipid transport and B lymphocyte function.
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PMID:ATP11C is critical for the internalization of phosphatidylserine and differentiation of B lymphocytes. 2182 67


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