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)

HATs (histone acetyltransferases) contribute to the regulation of gene expression, and loss or dysregulation of these activities may link to tumorigenesis. Here, we demonstrate that expression levels of HATs, p300 and CBP [CREB (cAMP-response-element-binding protein)-binding protein] were decreased during chemical hepatocarcinogenesis, whereas expression of MOZ (monocytic leukaemia zinc-finger protein; MYST3)--a member of the MYST [MOZ, Ybf2/Sas3, Sas2 and TIP60 (Tat-interacting protein, 60 kDa)] acetyltransferase family--was induced. Although the MOZ gene frequently is rearranged in leukaemia, we were unable to detect MOZ rearrangement in livers with hyperplastic nodules. We examined the effect of MOZ on hepatocarcinogenic-specific gene expression. GSTP (glutathione S-transferase placental form) is a Phase II detoxification enzyme and a well-known tumour marker that is specifically elevated during hepatocarcinogenesis. GSTP gene activation is regulated mainly by the GPE1 (GSTP enhancer 1) enhancer element, which is recognized by the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2)-MafK heterodimer. We found that MOZ enhances GSTP promoter activity through GPE1 and acts as a co-activator of the Nrf2-MafK heterodimer. Further, exogenous MOZ induced GSTP expression in rat hepatoma H4IIE cells. These results suggest that during early hepatocarcinogenesis, aberrantly expressed MOZ may induce GSTP expression through the Nrf2-mediated pathway.
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PMID:Histone acetyltransferase MOZ acts as a co-activator of Nrf2-MafK and induces tumour marker gene expression during hepatocarcinogenesis. 1708 29

As a component of the apoptosome, a caspase-activating complex, Apaf-1 plays a central role in the mitochondrial caspase activation pathway of apoptosis. We report here the identification of a novel Apaf-1 interacting protein, hepatocellular carcinoma antigen 66 (HCA66) that is able to modulate selectively Apaf-1-dependent apoptosis through its direct association with the CED4 domain of Apaf-1. Expression of HCA66 was able to potentiate Apaf-1, but not receptor-mediated apoptosis, by increasing downstream caspase activity following cytochrome c release from the mitochondria. Conversely, cells depleted of HCA66 were severely impaired for apoptosome-dependent apoptosis. Interestingly, expression of the Apaf-1-interacting domain of HCA66 had the opposite effect of the full-length protein, interfering with the Apaf-1 apoptotic pathway. Using a cell-free system, we showed that reduction of HCA66 expression was associated with a diminished amount of caspase-9 in the apoptosome, resulting in a lower ability of the apoptosome to activate caspase-3. HCA66 maps to chromosome 17q11.2 and is among the genes heterozygously deleted in neurofibromatosis type 1 (NF1) microdeletion syndrome patients. These patients often have a distinct phenotype compared to other NF1 patients, including a more severe tumour burden. Our results suggest that reduced expression of HCA66, owing to haploinsufficiency of HCA66 gene, could render NF1 microdeleted patients-derived cells less susceptible to apoptosis.
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PMID:Positive regulation of apoptosis by HCA66, a new Apaf-1 interacting protein, and its putative role in the physiopathology of NF1 microdeletion syndrome patients. 1738 Jan 55

Virus infection triggers IFN immune defenses in infected cells in part through viral nucleic acid interactions, but the pathways by which dsDNA and DNA viruses trigger innate defenses are only partially understood. Here we present evidence that both retinoic acid-induced gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS) are required for dsDNA-induced IFN-beta promoter activation in a human hepatoma cell line (Huh-7), and that activation is efficiently blocked by the hepatitis C virus NS3/4A protease, which is known to block dsRNA signaling by cleaving MAVS. These findings suggest that dsDNA and dsRNA share a common pathway to trigger the innate antiviral defense response in human cells, although dsDNA appears to trigger that pathway upstream of the dsRNA-interacting protein RIG-I.
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PMID:Double-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cells. 1751 27

HCCA2 (hepatocellular carcinoma-associated gene 2) was initially identified as a HCC (hepatocellular carcinoma)-specific protein and subsequently, a long splice variant of HCCA2 was identified as a co-activator of transcription factor YY1 (Yin Yang 1). To investigate the role of HCCA2 in HCC genesis and progression, we screened a human fetal liver cDNA library and identified a novel HCCA2-interacting protein, MAD2L2 (MAD2 mitotic arrest deficient-like 2 (yeast)). The interaction between HCCA2 and MAD2L2 was confirmed by in vitro and in vivo binding assays and the interaction domain was mapped to the N-terminus of HCCA2 by sequential deletion. HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells. Furthermore, overexpression of HCCA2 led to cell cycle arrest at G0/G1 phase and therefore inhibited cell proliferation. Our research suggests that HCCA2 may play a novel role in cell cycle regulation.
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PMID:Hepatocellular carcinoma-associated gene 2 interacts with MAD2L2. 1754 14

Hepatitis C virus (HCV) infection represents a major public health problem throughout the world. The establishment of viral replicons has enhanced our understanding of the mechanism underlying HCV replication. However, the specific virus-host cell interactions involved in HCV RNA replication are not well understood. In the present study, we isolated several human hepatoma Huh-7-derived subclones with a range of HCV RNA replication efficiencies by end-point dilution. Of these, the clones HuhTe4 and HuhTe6 were observed to proliferate at the same rate; however, HuhTe6 supported a significantly greater degree of viral RNA replication. Using cDNA microarray analysis, a total of 36 genes (0.4%) demonstrated variable expression, with a >or=2-fold difference in expression noted between HuhTe4 and HuhTe6. Among genes that are implicated in a variety of functional categories, a subset of these differentially-expressed genes has a role in signal transduction and cell communication, including thioredoxin-interacting protein, Rab6B, sorting nexin 16 and UDP-galactose:ceramide glycosyltransferase. The genes identified in this study should be examined further to determine their roles in HCV RNA replication. The Huh-7 subclones identified in this study provide a tool for identifying novel host factors involved in viral replication.
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PMID:Transcriptomic comparison of human hepatoma Huh-7 cell clones with different hepatitis C virus replication efficiencies. 1764 25

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

Previously, we identified YueF as a novel Hepatitis B virus X protein (HBx)-interacting protein. Herein, we studied the functions of YueF and HBx in hepatocarcinogenesis. YueF was expressed at high levels in normal human hepatic cells and tissues, but scarcely found in hepatoma cells or other tumor tissues. Over-expression of YueF, or YueF and HBx could induce cell apoptosis and enhance p53 expression in hepatoma cells, whereas over-expression of HBx alone behaved contrarily. These results indicate that YueF has tumor suppressor activity and affects the functions of HBx in cell apoptosis and p53 expression in hepatoma cells.
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PMID:Putative tumor suppressor YueF affects the functions of hepatitis B virus X protein in hepatoma cell apoptosis and p53 expression. 1800 Jul 58

The glucocorticoid receptor (GR) forms part of a multiprotein complex consisting of chaperones and proteins active in glucocorticoid signaling and other pathways. By immunoaffinity purification of GR, followed by Edman sequencing and Western blotting, we identified the FMS-like tyrosine kinase 3 (Flt3) as a GR-interacting protein in rat liver and hepatoma cells. Flt3 interacts with both non-liganded and liganded GR. The DNA-binding domain of GR is sufficient for Flt3 interaction as shown by GST-pull down experiments. Studies of the effects of Flt3 and its ligand FL in glucocorticoid-driven reporter-gene assays in Cos7 cells, show that co-transfection with Flt3 and FL potentiates glucocorticoid effects. Treatment with FL had no effect on GR location and Dex induced translocation of GR was unaffected by FL. In summary, GR and Flt3 interact, affecting GR signaling. This novel cross-talk between GR and a hematopoietic growth factor might also imply glucocorticoid effects on Flt3-mediated signaling.
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PMID:FMS-like tyrosine kinase 3 interacts with the glucocorticoid receptor complex and affects glucocorticoid dependent signaling. 1826 79

The major hereditary breast cancer susceptibility gene BRCA2 is associated with familial breast and ovarian cancer. BRCA2 plays a role in DNA repair, transcription, cell cycle regulation, maintenance of genomic stability in response to DNA damage, centrosome regulation, and cytokinesis. To further understand the function of BRCA2, we used a yeast two-hybrid method and identified a novel BRCA2-interacting protein, BJ-HCC-20A, which is reported to be a potential cancer-testis antigen. We confirmed the interaction between endogenous BJ-HCC-20A and BRCA2 in mammalian cells, and showed that BJ-HCC-20A interacts with a portion of the highly conserved region of BRCA2 in various mammals, and M phase-specific phosphorylation of the binding region of BRCA2 modulates BJ-HCC-20A binding. Overexpression of BJ-HCC-20A increases cell growth, and downregulation of endogenous BJ-HCC-20A expression using small interfering RNA suppresses cell growth and leads to the induction of apoptosis. Importantly, the BJ-HCC-20A mRNA level is downregulated by adriamycin (ADR)-induced DNA damage and depletion of BJ-HCC-20A expression by small interfering RNA promotes the reduction of BRCA2 expression and enhances cell apoptosis in response to DNA damage. Additionally, the recovery of BJ-HCC-20A expression in ADR-induced DNA damage inhibits ADR-induced apoptosis. The data suggest that BJ-HCC-20A promotes cell growth and may regulate the induction of cell apoptosis in response to DNA damage in cooperation with BRCA2 in an M phase-dependent manner. Therefore, we speculate that targeting BJ-HCC-20A may aid in the treatment of breast tumors.
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PMID:Novel BRCA2-interacting protein BJ-HCC-20A inhibits the induction of apoptosis in response to DNA damage. 1830 34

ADAM12 belongs to a disintegrin-like and metalloproteinase-containing protein family that possesses multidomain structures composed of a pro-domain, a metalloprotease, disintegrin-like, cysteine-rich, epidermal growth factor-like, and transmembrane domains, and a cytoplasmic tail. Overexpression of several ADAMs has been reported in human cancer, and we recently described the involvement of ADAM12 in liver injury (Le Pabic, H., Bonnier, D., Wewer, U. M., Coutand, A., Musso, O., Baffet, G., Clement, B., and Theret, N. (2003) Hepatology 37, 1056-1066). In this study, we used a yeast two-hybrid screening of a cDNA library from human hepatocellular carcinoma to analyze binding partners of ADAM12. We identify RACK1, a receptor for activated protein kinase C (PKC), as a new ADAM12 interacting protein. RACK1 is up-regulated in patients with hepatocellular carcinoma and is highly expressed by activated hepatic stellate cells. We demonstrate the involvement of RACK1 in mediating the PKC-dependent translocation of ADAM12 to membranes of activated hepatic stellate cells. In particular, treatment of cells with phorbol esters enhances ADAM12 immunostaining in the membrane fractions and the co-immunoprecipitation of ternary complexes containing RACK1, ADAM12, and PKC. By using RNA interference, we demonstrate that inhibition of RACK1 expression diminishes the phorbol 12-myristate 13-acetate-dependent translocation of ADAM12 to membranes of hepatic stellate cells. Finally, hepatic stellate cells cultured on coated type I collagen induces relocalization of ADAM12 in the membrane, suggesting that this major matrix component in liver cancer and fibrogenesis might stimulate ADAM12 translocation to the cell membrane where its shedding activity takes place.
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PMID:RACK1, a new ADAM12 interacting protein. Contribution to liver fibrogenesis. 1862 36


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