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 aim of this study was to investigate whether there was a particular hepatitis B virus (HBV) X protein (HBx) mutant associated with Taiwanese patients with hepatocellular carcinoma (HCC). Initially, the entire coding region of HBx gene from the serum samples of 14 Taiwanese patients were sequenced. A novel mutant, HBx-A31, was preferentially found in patients with HCC. Sera from 67 patients with HCC and 100 patients with chronic hepatitis B were thus subjected for codon 31 analysis using a dual amplification created restriction site method. HBx-A31 was detected more frequently in patients with HCC (52% versus 12%; P<0.001) and in patients with liver cirrhosis (44% versus 6%; P<0.001). Site directed mutagenesis experiment revealed that HBx-A31 was less effective in transactivating HBV enhancer I-X promoter complex, less efficient in supporting HBV replication, and less potent in enhancing TNF-alpha induced increment of CPP32/caspase 3 activities in HepG2 cells. In conclusion, a prevalent HBx mutant was identified in Taiwanese patients with hepatocellular carcinoma. Development of this mutant might represent a strategy of the virus to escape immune surveillance and thus contribute to the process of multiple-step hepatocarcinogenesis.
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PMID:Identification and characterization of a prevalent hepatitis B virus X protein mutant in Taiwanese patients with hepatocellular carcinoma. 1107 37

Type I interferon (IFN) receptor consists of two chains (Hu-IFN-alphaR1 and Hu-IFN-alphaR2), and Hu-IFN-alphaR2 takes a soluble, short, or long form (Hu-IFN-alphaR2a, Hu-IFN-alphaR2b, or Hu-IFN-alphaR2c, respectively). We examined Hu-IFN-alphaR2 expression in hepatocellular carcinoma (HCC) tissues and their corresponding non-cancerous (non-HCC) tissues. Immunohistochemically, Hu-IFN-alphaR2 expression was positive in 53 (77%) of 69 HCC tissues and in 61 (88%) of 69 non-HCC tissues. Hu-IFN-alphaR2 protein in tissue homogenates of HCC and non-HCC tissues obtained from 29 patients was measured by using ELISA kits, and the amount was 12.7+/-10.9 pg/mg protein in HCC tissue and 10.5+/-5.0 pg/mg protein in non-HCC tissue. Number of specimens in which Hu-IFN-alphaR2 level was 3 pg/mg protein or lower, or 20 pg/mg protein or higher, was one each for non-HCC, while it was 7 (24%) and 6 (21%) for HCC. RT-PCR analysis was done in 7 of the 29 HCC cases. It revealed both Hu-IFN-alphaR2a and Hu-IFN-alphaR2c were expressed in all HCC tissues and in 6 of the 7 non-HCC tissues, and Hu-IFN-alphaR2b was expressed in all HCC tissues and in 4 of the 7 non-HCC tissues. Because immunostaining intensity of Hu-IFN-alphaR2 tended to be higher in the areas with active inflammation, effects of inflammatory cytokines (IL-1alpha, IL-1beta, and TNF-alpha) on Hu-IFN-alphaR2 expression were examined on 11 HCC cell lines. As a result, TNF-alpha up-regulated Hu-IFN-alphaR2 expression in 7 of the 11 cell lines. In 3 of the 7 cell lines, up-regulation of Hu-IFN-alphaR2 on cell surface, as well as of the soluble form of Hu-IFN-alphaR2, was induced not only by TNF-alpha, but also by IL-1alpha or IL-1beta. In conclusion, both HCC and non-HCC tissues frequently express Hu-IFN-alphaR2c that is necessary for Type I IFN response. Hu-IFN-alphaR2 expression in HCC tissues is often attenuated or enhanced, and may be regulated by inflammatory cytokines.
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PMID:Expression of Hu-IFN-alphaR2 chain of type I interferon receptor in human hepatocellular carcinoma and non-cancerous tissues. 1107 20

RC-RNase purified from Rana catesbeiana (bullfrog) oocytes is a pyrimidine-guanine sequence-specific ribonuclease. RC-RNase is derived from the RNase superfamily genes exerting distinct ribonucleolytic activity and possesses cytotoxicity to tumor cells, but rarely to primary cells. In this study, we utilized RC-RNase to function with antiproliferative cytokines. The combination with TNF-alpha or TNF-beta would not aggravate cell death. However, the combination with IFN-gamma could induce synergistic cytotoxicity verified by XTT assays toward three hepatoma cell lines bearing different differentiation stages. The distinct cytotoxicity from RC-RNase or RC-RNase/IFN-gamma on different hepatoma cells was correlated with the differentiation extent but not the proliferation rate of the cells. Despite the synergistic cytotoxicity and severe mitochondrial disruptions in the RC-RNase/IFN-gamma-treated cells, we scarcely detected any significant feature of apoptosis or necrosis by FACS analysis on annexin-V/propidium iodide staining. The mechanisms of cell death triggered by RC-RNase or RC-RNase/IFN-gamma require further investigation.
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PMID:Synergistic cytotoxicity of Rana catesbeiana ribonuclease and IFN-gamma on hepatoma cells. 1116 59

NF-kappaB activation is triggered by the degradation of inhibitory proteins, such as I(kappa)B-alpha. I(kappa)B-alpha levels are only transiently lowered since one gene activated by NF-kappaB is I(kappa)B-alpha. We found that I(kappa)B-alpha was replenished rapidly in a human colon cell line (HT-29), even in the presence of degradation-inducing phosphorylation (at serine-32). This finding lead us to hypothesize that posttranscriptional mechanisms were also in place to facilitate I(kappa)B-alpha replenishment. Expression of I(kappa)B-alpha from the constitutive, non-NF-kappaB regulated cytomegalovirus promoter in HT-29 cells showed that TNF-alpha or IL-1beta treatment increased I(kappa)B-alpha levels in the absence of transcriptional activation. The TNF-alpha-induced increase in transgenic I(kappa)B-alpha appeared to result from the stabilization of newly synthesized I(kappa)B-alpha, since this increase was effectively preempted by a proteasome inhibitor (MG132) or by I(kappa)B-alpha stabilization through the deletion C-terminal destabilizing elements (without additive or synergistic effects). Analysis of a hepatoma cell line (Hepa 1-4C7) indicated that the I(kappa)B-alpha stabilization may be constitutive in these cells. NF-kappaB stimuli therefore appear to trigger negative feedback pathways in some cells that terminate a NF-kappaB response by increasing the stability of newly synthesized I(kappa)B-alpha.
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PMID:Cytokine-induced stabilization of newly synthesized I(kappa)B-alpha. 1135 57

The mRNA for the alpha1-acid glycoprotein (AAG) was expressed not only in hepatoma cells, but also in non-hepatic cancer cells. The expression of the AAG mRNA in HT-29 human colon carcinoma cells is induced by cytokines, IL-6, IL-1, and TNF-alpha, in a manner characteristic of the acute phase response, and the expression of AAG mRNA was up-regulated in differentiated HT-29 cells.
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PMID:Induction of alpha1-acid glycoprotein mRNA by cytokines and differentiation in human colon carcinoma cell. 1135 96

The multidrug resistance protein Mdr1b in rats is up-regulated during liver regeneration after partial hepatectomy or after endotoxin treatment. We hypothesize that up-regulation of Mdr1b in these models is TNF-alpha-dependent. The mechanism of Mdr1b activation by TNF-alpha is unknown as TNF-alpha can signal through various pathways, including NF-kappaB and p53, transcription factors for which binding sites in the Mdr1b promoter have been identified. We aimed to elucidate the mechanism of up-regulation of Mdr1b by TNF-alpha. We selectively used constructs expressing dominant negative Fas-associated death domain protein (FADD), TNF receptor associated factor-2 (TRAF2) or IkappaB to inhibit pathways downstream of the TNF receptor. Further, the proteasome inhibitor MG-132 was used, which prevents the breakdown of IkappaB. We show a critical role for NF-kappaB in activation of Mdr1b gene expression both in primary rat hepatocytes and in rat hepatoma H-4-II-E cells. Because p53 is up-regulated by TNF-alpha in an NF-kappaB-dependent manner and the Mdr1b promoter contains a p53 binding site, we used liver cells expressing a dominant negative p53 to show that TNF-alpha up-regulation of Mdr1b is independent of functional p53. Using transient transfection assays, we show that Mdr1b up-regulation correlates with activation of the promoter. Mutation of the NF-kappaB site in the Mdr1b promoter prevents its induction by TNF-alpha. In conclusion our results show that activation of the rat Mdr1b gene by TNF-alpha is a result of NF-kappaB signaling and independent of p53.
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PMID:Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells is independent of p53 but requires NF-kappaB signaling. 1139 31

Human hepatocytes usually are resistant to TNF-alpha cytotoxicity. In mouse or rat hepatocytes, repression of NF-kappaB activation is sufficient to induce TNF-alpha-mediated apoptosis. However, in both Huh-7 human hepatoma cells and Hc human normal hepatocytes, when infected with an adenovirus expressing a mutated form of IkappaBalpha (Ad5IkappaB), which almost completely blocks NF-kappaB activation, >80% of the cells survived 24 h after TNF-alpha stimulation. Here, we report that TNF-alpha activates other antiapoptotic factors, such as sphingosine kinase (SphK), phosphatidylinositol 3-kinase (PI3K), and Akt kinase. Pretreatment of cells with N,N-dimethylsphingosine (DMS), an inhibitor of SphK, or LY 294002, an inhibitor of PI3K that acts upstream of Akt, increased the number of apoptotic cells induced by TNF-alpha in Ad5IkappaB-infected Huh-7 and Hc cells. TNF-alpha-induced activations of PI3K and Akt were inhibited by DMS. In contrast, exogenous sphingosine 1-phosphate, a product of SphK, was found to activate Akt and partially rescued the cells from TNF-alpha-induced apoptosis. Although Akt has been reported to activate NF-kappaB, DMS and LY 294002 failed to prevent TNF-alpha-induced NF-kappaB activation, suggesting that the antiapoptotic effects of SphK and Akt are independent of NF-kappaB. Furthermore, apoptosis mediated by Fas ligand (FasL) involving Akt activation also was potentiated by DMS pretreatment in Hc cells. Sphingosine 1-phosphate administration partially protected cells from FasL-mediated apoptosis. These results indicate that not only NF-kappaB but also SphK and PI3K/Akt are involved in the signaling pathway(s) for protection of human hepatocytes from the apoptotic action of TNF-alpha and probably FasL.
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PMID:TNF-alpha-induced sphingosine 1-phosphate inhibits apoptosis through a phosphatidylinositol 3-kinase/Akt pathway in human hepatocytes. 1141 46

Tumour necrosis factor (TNF)-alpha contributes to the pathogenesis of many inflammatory diseases. Recombinant soluble TNF receptor fusion proteins (sTNFR:Ig) are potent TNF antagonists, both in vitro and in vivo. The concentration of serum amyloid A (SAA) increases by up to 1000-fold during inflammation, largely owing to cytokine-driven transcriptional upregulation. A reporter plasmid, comprising the proximal 0.7 kb of the human SAA2 promoter fused to a luciferase gene, was used in transient transfection experiments in human HepG2 hepatoma cells to assess the quantitative and qualitative TNF antagonist properties of a construct in which sTNFR:Ig synthesis is under the control of a chimera of the SAA2 promoter and a tat/HIV element. The SAA2-tat/HIV-sTNFR:Ig construct retained the fine-tuned cytokine responsiveness of the SAA2 promoter, while exhibiting the quantitatively enhanced level of protein expression conferred by the tat/HIV element. It produced a biologically significant TNF inhibition that was at least as strong as that achieved using a CMV promoter-driven sTNFR:Ig construct. There was a dose- and time-dependent relationship between the pro-inflammatory cytokine used, and the generation of TNF antagonist activity by SAA2-tat/HIV-sTNFR:Ig. Although sTNFR:Ig protein can be induced by either TNF-alpha or interleukin (IL)-1beta, its antagonist activity is limited to the former cytokine. The SAA2-tat/HIV-sTNFR:Ig construct, and derivatives thereof, may therefore be ideally suited to gene therapy applications that require the local production of potent and specific immune modifiers only when there is active pathology. It may consequently be of particular use in the future treatment of diseases such as rheumatoid arthritis.
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PMID:In vitro evaluation of an enhanced human serum amyloid A (SAA2) promoter-regulated soluble TNF receptor fusion protein for anti-inflammatory gene therapy. 1142 7

NF-kappaB regulates liver cell death during development, regeneration, and neoplastic transformation. For example, we showed that oncogenic Ras- or Raf-mediated transformation of rat liver epithelial cells (RLEs) led to altered NF-kappaB regulation through IKK complex activation, which rendered these cells more resistant to TGF-beta1-induced apoptosis. Thus, based on these findings, we sought to determine whether NF-kappaB could also be involved in tumor growth of liver cells in vivo. Hepatocellular carcinomas (HCCs) derived from bitransgenic mice harboring TGF-alpha and c-myc transgenes targeted specifically to the liver were compared with HCCs from c-myc single transgenic mice. Tumors from bitransgenic mice are characterized by a higher frequency of appearance, lower apoptotic index, and a higher rate of cell proliferation. Here we show that NF-kappaB is activated in HCCs of double TGF-alpha/c-myc transgenic mice, but not of c-myc single transgenic mice, suggesting that TGF-alpha mediates induction of NF-kappaB. Activation of the IKK complex was observed in the HCCs of double TGF-alpha/c-myc transgenic mice, implicating this pathway in NF-kappaB induction. Lastly, activation of the Akt/protein kinase B (PKB), which has recently been implicated in NF-kappaB activation by PDGF, TNF-alpha, and Ras, was also observed. Importantly, human HCC cell lines similarly displayed NF-kappaB activation. Thus, these studies elucidate an anti-apoptotic mechanism by a TGF-alpha-Akt/PKB-IKK pathway, which likely contributes to survival and proliferation, thereby accelerating c-myc-induced liver neoplastic development in vivo.
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PMID:Roles of Akt/PKB and IKK complex in constitutive induction of NF-kappaB in hepatocellular carcinomas of transforming growth factor alpha/c-myc transgenic mice. 1143 31

Pancreatic cancer cells are usually resistant to apoptosis mediated by intrinsic or extrinsic factors. BAG-3 (Bis, CAIR), which was identified as a BAG-1-related protein, is a novel modulator of cellular anti-apoptotic activity that functions through its interaction with Bcl-2. In this study we analyzed BAG-3 expression in human pancreatic cancer tissues and cell lines. BAG-3 mRNA was expressed at moderate to high levels in all pancreatic cancer samples, but at low levels in normal pancreas tissues. In situ hybridization and immunohistochemistry analysis revealed that BAG-3 was present in the cancer cells within the pancreatic tumor mass. When BAG-3 mRNA was analyzed in other gastrointestinal cancers (hepatocellular carcinoma; esophageal, stomach and colon cancer), no difference was found from their corresponding normal controls. In pancreatic cancer cells, BAG-3 mRNA expression levels were strongly induced after heat stress, but not in response to members of the tumor necrosis factor (TNF)-alpha family (TNF-alpha, TRAIL, FasL). These findings indicate that in pancreatic cancer, in contrast to other gastrointestinal malignancies, increased levels of BAG-3 might function to block apoptosis. This characteristic of pancreatic cancer might contribute to its more aggressive growth behavior and poor responsiveness to treatment in vivo.
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PMID:The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. 1151 73


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