Abstract:
BACKGROUND & AIMS:Aberrant activation of the RAS pathway is ubiquitous in human hepatocarcinogenesis, but the molecular mechanisms leading to RAS induction in the absence of RAS mutations remain under-investigated. We defined the role of Ras GTPase activating proteins (GAPs) in the constitutive activity of Ras signaling during human hepatocarcinogenesis. METHODS:The mutation status of RAS genes and RAS effectors was assessed in a collection of human hepatocellular carcinomas (HCC). Levels of RAS GAPs (RASA1-4, RASAL1, nGAP, SYNGAP1, DAB2IP, and NF1) and the RASAL1 upstream inducer PITX1 were determined by real-time RT-PCR and immunoblotting. The promoter and genomic status of RASAL1, DAB2IP, NF1, and PITX1 were assessed by methylation assays and microsatellite analysis. Effects of RASAL1, DAB2IP, and PITX1 on HCC growth were evaluated by transfection and siRNA analyses of HCC cell lines. RESULTS:In the absence of Ras mutations, downregulation of at least one RAS GAP (RASAL1, DAB2IP, or NF1) was found in all HCC samples. Low levels of DAB2IP and PITX1 were detected mostly in a HCC subclass from patients with poor survival, indicating that these proteins control tumor aggressiveness. In HCC cells, reactivation of RASAL1, DAB2IP, and PITX1 inhibited proliferation and induced apoptosis, whereas their silencing increased proliferation and resistance to apoptosis. CONCLUSIONS:Selective suppression of RASAL1, DAB2IP, or NF1 RAS GAPs results in unrestrained activation of Ras signaling in the presence of wild-type RAS in HCC.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Calvisi DF,Ladu S,Conner EA,Seo D,Hsieh JT,Factor VM,Thorgeirsson SSdoi
10.1016/j.jhep.2010.06.036subject
Has Abstractpub_date
2011-02-01 00:00:00pages
311-9issue
2eissn
0168-8278issn
1600-0641pii
S0168-8278(10)00786-5journal_volume
54pub_type
杂志文章abstract:BACKGROUND/AIM:The aim of this study was to assess the pathology and pathogenic mechanisms involved in the occlusion of transjugular intrahepatic portosystemic stent-shunts. METHODS:Thirty-four patients with transjugular intrahepatic portosystemic stent-shunt who had at least two portographic assessments of shunt func...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/s0168-8278(96)80026-2
更新日期:1996-02-01 00:00:00
abstract:BACKGROUND/AIMS:A simple and reproducible hepatic immunohistochemical staining (IHS) for hepatitis C virus (HCV) is not available. We aimed to validate hepatic IHS with monoclonal antibody (Mab) IG222, directed against the HCV-envelope 2 (E2) protein. METHODS:A three-step indirect immunoperoxidase method was used for ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(02)00389-6
更新日期:2003-02-01 00:00:00
abstract::The nucleocapsid antigens (HBc and HBe) are present on the membranes of HBV-infected hepatocytes from HBV carriers. In autologous cytotoxicity experiments we demonstrate that cytotoxic T cells sensitised to the nucleocapsid proteins of hepatitis B are present in HBe antigen-positive HBV carriers with chronic hepatitis...
journal_title:Journal of hepatology
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更新日期:1987-02-01 00:00:00
abstract:BACKGROUND & AIMS:Virus-specific T cells capable of controlling HBV and eliminating hepatocellular carcinoma (HCC) expressing HBV antigens are deleted or dysfunctional in patients with chronic HBV or HBV-related HCC. The goal of this study was to determine if T cell receptor (TCR) gene transfer can reconstitute HBV-spe...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2010.10.025
更新日期:2011-07-01 00:00:00
abstract:BACKGROUND/AIMS:In these studies, we tested the hypothesis that increased lipid intake would exacerbate the severity of nutritional steatohepatitis. METHODS:C57Bl/6J mice were fed methionine-and-choline deficient (MCD) diets containing 20% (high) or 5% (low) fat by weight for 3 weeks and compared to lipid-matched cont...
journal_title:Journal of hepatology
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更新日期:2008-09-01 00:00:00
abstract:BACKGROUND/AIMS:The pathogenesis of the inflammatory lesion in primary sclerosing cholangitis is unknown. The clinical picture is characterized by i.a. episodes of fever, the cause of which also remains speculative. Previous studies of bacterial isolates in the liver or bile ducts in primary sclerosing cholangitis have...
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pub_type: 杂志文章
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更新日期:1998-03-01 00:00:00
abstract:BACKGROUND:NGM282, an engineered analogue of the gut hormone FGF19, improves hepatic steatosis and fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH). However, NGM282 increases serum cholesterol levels by inhibiting CYP7A1, which encodes the rate-limiting enzyme in the conversion of cholesterol t...
journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究
doi:10.1016/j.jhep.2018.11.032
更新日期:2019-04-01 00:00:00
abstract:BACKGROUND/AIMS:Interleukin-12 (IL-12), a cytokine with antitumor activity, was examined for the suppressive effect on hepatocellular carcinoma (HCC) in mouse model, and its mechanism of antitumor activity was analyzed. METHODS:Mice implanted with MIH-2 HCC cells were treated with recombinant mouse IL-12 (500 ng/mouse...
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更新日期:2006-11-01 00:00:00
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更新日期:2018-08-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2020-07-01 00:00:00
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pub_type: 杂志文章
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更新日期:2003-04-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1995-04-01 00:00:00
abstract:BACKGROUND & AIMS:FibroTest™ (FT) and Transient Elastography (TE) have been validated as non-invasive markers of METAVIR fibrosis stages from F0 to F4 using biopsy, and as prognostic markers of liver related mortality in patients with chronic hepatitis C. The aim was to extend the validation of FT and TE as markers of ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2013.11.016
更新日期:2014-04-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:1994-09-01 00:00:00
abstract::In situ hybridization with oligonucleotide probes has been used to localise hepatitis A virus RNA genomic sequences in formalin-fixed and routinely processed human liver biopsies from three patients. Using radiolabelled Sulphur-35 antisense probes, viral genomic sequences were found in all three cases, but signal inte...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(94)80012-x
更新日期:1994-03-01 00:00:00
abstract::The integrated results of a worldwide clinical research program studying interferon-alpha 2a (IFN-alpha 2a) (Roferon-A, F. Hoffmann-La Roche Ltd, Basel, Switzerland) for the treatment of chronic hepatitis C in 1831 patients are reviewed in this paper. According to a multivariate analysis of the data available from thi...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1995-01-01 00:00:00
abstract:BACKGROUND/AIMS:To evaluate the clinical, biochemical and histological implications of a concomitant HGV infection in "HCV-related" chronic liver disease. METHODS:Eighty-three HCV-RNA positive patients with chronic liver disease were tested for GBV-C/HGV coinfection by heminested PCR. RESULTS:Twenty-two (26.5%) patie...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(97)80448-5
更新日期:1997-06-01 00:00:00
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journal_title:Journal of hepatology
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更新日期:2000-01-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.05.033
更新日期:2009-11-01 00:00:00
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pub_type: 杂志文章
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更新日期:1993-01-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0168-8278(97)80428-x
更新日期:1997-03-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2009-08-01 00:00:00
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pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2009-05-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:1999-11-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(03)00160-0
更新日期:2003-07-01 00:00:00
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pub_type: 杂志文章
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更新日期:1991-05-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2013.04.011
更新日期:2013-08-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(92)90015-h
更新日期:1992-05-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2020.07.014
更新日期:2020-12-01 00:00:00
abstract::To evaluate the efficacy of recombinant interferon alpha-2b in the treatment of patients with acute post-transfusion hepatitis C, a randomized controlled trial was conducted in 33 acute post-transfusion hepatitis C patients; 16 patients received 3 million units of subcutaneously injected recombinant interferon alpha-2...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1994-11-01 00:00:00