Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For most patients with advanced or multifocal hepatocellular carcinoma (HCC) or with metastatic malignant liver disease treatment options are limited, resulting in a poor prognosis. Novel therapeutic strategies such as gene therapy are therefore urgently required. Gene therapeutic approaches use gene delivery systems (vectors) to introduce DNA constructs as therapeutic agents into living cells. Antitumour strategies include the reintroduction of tumour suppressor genes into tumour cells, the expression of foreign enzymes to render tumours susceptible to treatment with chemotherapeutic agents and the enhancement of tumour immunogenicity by expressing immunomodulatory genes or by genetic vaccination with tumour antigens. Furthermore, gene therapy may be also used for anti-angiogenesis to reduce tumour growth and metastatic potential. Other novel approaches aim at the development of genetically altered replication competent viruses, which selectively replicate in tumour cells inducing cell lysis. Although most clinical trials of antitumour gene therapy so far have failed to induce strong therapeutic effects, further improvement of antitumour gene therapy may finally result in potent clinical treatment options for patients with malignant liver tumours.
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PMID:Gene therapy for malignant liver disease. 1184 16

WFDC1 is a recently isolated human gene identified as a tumour suppressor gene candidate. It is not known whether alterations in this gene are associated with human cancers. The WFDC1 gene maps in human chromosome 16q24, an area of frequent loss of heterozygosity (LOH) in several tumour types, in particular in hepatocellular carcinoma (HCC). We investigated its role in 46 European HCC by means of the detection of LOH at the WFDC1 locus. We describe here an assay for the detection of loss of heterozygosity at this locus using two dinucleotide repeat polymorphisms identified in WFDC1 introns, with a combined informativity of 86%. LOH was observed in 4/40 informative HCC samples. We further investigated the role of WFDC1 as a tumour suppressor gene candidate in five hepatocellular cell lines and in tumours exhibiting LOH by means of mutation, promoter methylation and gene expression analysis. In HCC samples showing LOH, no mutation of the remaining allele was observed. No significant up or down gene expression was observed in tumour samples comparatively to normal liver and gene expression did not seem related to promoter methylation. These results suggest a minor role, if any, of WFDC1 in hepatocarcinogenesis. However, this approach might be useful for investigating the role of this candidate tumour suppressor gene in other tumour types.
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PMID:Analysis of alterations of WFDC1, a new putative tumour suppressor gene, in hepatocellular carcinoma. 1203 31

EDD (E3 isolated by differential display), located at chromosome 8q22.3, is the human orthologue of the Drosophila melanogaster tumour suppressor gene 'hyperplastic discs' and encodes a HECT domain E3 ubiquitin protein-ligase. To investigate the possible involvement of EDD in human cancer, several cancers from diverse tissue sites were analysed for allelic gain or loss (allelic imbalance, AI) at the EDD locus using an EDD-specific microsatellite, CEDD, and other polymorphic microsatellites mapped in the vicinity of the 8q22.3 locus. Of 143 cancers studied, 38 had AI at CEDD (42% of 90 informative cases). In 14 of these cases, discrete regions of imbalance encompassing 8q22.3 were present, while the remainder had more extensive 8q aberrations. AI of CEDD was most frequent in ovarian cancer (22/47 informative cases, 47%), particularly in the serous subtype (16/22, 73%), but was rare in benign and borderline ovarian tumours. AI was also common in breast cancer (31%), hepatocellular carcinoma (46%), squamous cell carcinoma of the tongue (50%) and metastatic melanoma (18%). AI is likely to represent amplification of the EDD gene locus rather than loss of heterozygosity, as quantitative RT-PCR and immunohistochemistry showed that EDD mRNA and protein are frequently overexpressed in breast and ovarian cancers, while among breast cancer cell lines EDD overexpression and increased gene copy number were correlated. These results demonstrate that AI at the EDD locus is common in a diversity of carcinomas and that the EDD gene is frequently overexpressed in breast and ovarian cancer, implying a potential role in cancer progression.
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PMID:EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer. 1290 90

Mutations of p53 tumour suppressor gene often occur in hepatocellular carcinoma and, in particular, codon 249 hot-spot mutation is displayed by hepatocellular carcinomas occurring in hepatitis B virus-endemic areas with high dietary aflatoxin intake. This study was done to determine the frequency of p53 codon 249 mutation in hepato-cellular carcinoma in Nigerian patients with this tumour. Tumour samples were obtained from 18 Nigerian patients (all from the Southwest of the country) with histologically confirmed hepatocellular carcinoma by autopsy (n = 14), surgical resection (n = 3) and ante-mortem liver biopsy (n = 1). Fourteen of them had co-existing cirrhosis. Amplification of exon 7 of p53 gene from DNA samples of hepatocellular carcinoma tissue was undertaken by nested polymerase chain reaction followed by restriction enzyme analysis. One out of the 18 tumour samples tested (5.5%) demonstrated codon 249 mutation. This study suggests that, in Nigeria, especially the south-western region, aflatoxins appear to play a limited role in hepatocarcinogenesis.
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PMID:P53 codon 249 mutation in hepatocellular carcinomas from Nigeria. 1451 Jan 67

Only a small percentage of primary and secondary liver tumours is suitable for surgical resection. Gene therapy represents a novel strategy that seems to be effective both, in vitro and in vivo. The use of tumour suppressor gene p53 therapy, suicide gene therapy, immune gene therapy and therapy with replication-competent oncolytic adenoviruses in liver tumours already entered the first clinical trials. In patients with hepatocellular carcinoma, the first clinical trials in phase I and II showed good tolerance and low toxicity to gene therapy. However, the clinical benefit for the patients treated either with wild type p53 or E1B deleted adenoviruses were marginal.
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PMID:[Gene therapy of liver tumors: results of the first clinical studies]. 1460 42

The tumour suppressor gene, LKB1/STK11, has been mapped to chromosome 19p13, a region showing frequent allelic loss in various human cancers, including hepatocellular carcinoma (HCC). Additionally, LKB1 physically associates with p53 and regulates p53-dependent apoptotic pathways. To investigate whether genetic alterations of LKB1 could be involved in the tumorigenesis of HCC, we analysed the genetic alterations of the LKB1 and p53 genes in seven dysplastic nodules and 80 HCCs. We found one LKB1 missense mutation, CCG-->CTG (Pro-->Leu) at codon 281 within the kinase domain. We also found allelic loss in six of 27 (22%) informative HCC cases and all of them were HBV-positive cases. In addition, we detected seven missense, one nonsense and one silent mutations (nine of 80, 11%) of p53 in HCCs only. These results suggest that genetic alterations of the LKB1 or p53 genes may play an important role in tumour development or progression of a sub-set of HCCs, and may also provide alternative mechanisms to protect the HCC cell from p53-dependent apoptosis.
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PMID:Genetic analysis of the LKB1/STK11 gene in hepatocellular carcinomas. 1468 97

Missense mutations in the DNA-binding core domain of the tumour suppressor protein p53 are frequent in cancer. Many of them result in loss of native structure. The mutation R249S is one of the six most common cancer-associated p53 mutations ("hot-spots"). As it is highly frequent in hepatocellular carcinoma, its rescue is an important therapeutic target. We have used NMR techniques to study the structural effects of the R249S mutation. The overall fold of the core domain is retained in R249S, and it does not take up a denatured "mutant conformation". However, the beta-sandwich had increased flexibility and, according to changes in chemical shift, there was local distortion throughout the DNA-binding interface. It is likely that the R249S mutation resulted in an ensemble of native and native-like conformations in a dynamic equilibrium. The peptide FL-CDB3 that was designed to rescue mutants of p53 by binding specifically to its native structure was found to revert the chemical shifts of R249S back towards the wild-type values and so reverse the structural effects of mutation. We discuss the implications for a rescue strategy and also for the analysis of antibody-binding data.
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PMID:Structural distortion of p53 by the mutation R249S and its rescue by a designed peptide: implications for "mutant conformation". 1474 Dec 14

Hepatocellular carcinoma (HCC) is the most important primary hepatic cancer and is a common cancer type worldwide. Many aetiological factors have been related to HCC development, such as liver cirrhosis, hepatitis viruses and alcohol consumption. Inactivation of the p53 tumour suppressor gene is one of the most common abnormalities in many tumours, including HCC. p53 is of crucial importance for the regulation of the cell cycle and the maintenance of genomic integrity. In HCC, hepatitis B and C virus (HBV and HCV) effect carcinogenic pathways, independently leading to anomalies in p53 function. Several authors have reported that some HCV proteins, such as the core, NS5A and NS3 proteins, interact with p53 and prevent its correct function. The mechanisms of action of these HCV proteins in relation to p53 are not completely clear, but they might cause its cytoplasmic retention or accumulation in the perinuclear region where the protein is not functional. The identification of the interactions between p53 and HCV proteins is of great importance for therapeutic strategies aimed at reducing the chronicity and/or carcinogenicity of the virus.
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PMID:Hepatocellular carcinoma: molecular interactions between hepatitis C virus and p53 in hepatocarcinogenesis. 1498 3

Among genetic alterations, the activation of proto-oncogenes and inactivation of tumour suppressor genes in affected cells are considered to be the core molecular events that provide a selective growth advantage and clonal expansion during the multistep process of carcinogenesis. The TP53 tumour suppressor gene is mutated in about half of all human cancer cases. The p53 protein modulates multiple cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle arrest, senescence and apoptosis. Mutations in the TP53 gene can abrogate these functions, leading to genetic instability and progression to cancer. The molecular archaeology of the TP53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of each type of cancer. The spectrum of somatic mutations in the TP53 gene, of which 75% are missense mutations, implicates environmental carcinogens and endogenous processes in the etiology of human cancer. The presence of a characteristic TP53 mutation can also manifest a molecular link between exposure to a particular carcinogen and a specific type of human cancer, e.g. exposure to aflatoxin B1 (AFB1) and codon 249 mutations in hepatocellular carcinoma; exposure to ultraviolet (UV) light and C:C-->T:T tandem mutations in skin cancer; and cigarette smoking and the prevalence of G-->T transversions in lung cancer. Although exogenous carcinogens have been shown to target p53 selectively, evidence supporting the endogenous insult of TP53 from oxyradicals and nitrogen-oxyradicals is also accumulating. TP53 mutations can be a biomarker of carcinogen effect. Determining the characteristic TP53 mutation load in non-tumorous tissue, using a highly sensitive mutation assay, can indicate exposure to a specific carcinogen and may also help in identifying individuals at an increased risk of cancer.
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PMID:TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. 1505

Hepatocellular carcinoma (HCC) is one of the most common malignancies in Southeast Asia. Although inactivation of pRb2/p130 has been reported in a variety of human cancers, its function in HCC has not been established. In this study we report that loss of expression of pRb2/p130 was detected by immunohistochemistry and western blotting in 15.2% (7 of 46) HCCs examined. High levels of pRb2/p130 expression were found in 84.8% (39 of 46) HCCs studied. Western blot analysis revealed that HCC had 3.5-fold higher pRb2/p130 than adjacent benign liver (ABL) tissues. 71.7% (33 of 46) of HCCs examined exhibited both nuclear and cytoplasmic staining for pRb2/p130. Cytoplasmic staining was found in 93.5% (43 of 46) of ABL tissues. Overproduction of pRb2/p130 in HepG2 cells led to growth suppression, cell cycle arrest in G0/G1, altered cell morphology, inhibition of in vitro colony formation and reduction in tumourigenicity in SCID mice. This demonstration suggests a role of pRb2/p130 as a tumour suppressor protein in HCC and the loss of this protein may lead to the development or progression of HCC. Overexpression of pRb2/p130 in HCC was, therefore, suggested to be a programmed protective response of the organism to uncontrolled proliferation.
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PMID:Overexpression of tumour suppressor retinoblastoma 2 protein (pRb2/p130) in hepatocellular carcinoma. 1505 24


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