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)

The FHIT gene is located at a chromosomal site (3p14.2) which is commonly affected by translocations and deletions in human neoplasia. Although FHIT alterations at the DNA and RNA level are frequent in many types of tumours, the biological and clinical significance of these changes is not clear. In this study we aimed at correlating loss of Fhit protein expression with a large number of molecular genetic and clinical parameters in a well-characterized cohort of non-small-cell lung cancers (NSCLCs). Paraffin sections of 99 non-small-cell carcinomas were reacted with an anti-Fhit polyclonal antibody in a standard immunohistochemical reaction. Abnormal cases were characterized by complete loss of cytoplasmic Fhit staining. The Fhit staining results were then correlated with previously obtained clinical and molecular data. Fifty-two of 99 tumours lacked cytoplasmic Fhit staining, with preserved reactivity in adjacent normal cells. Lack of Fhit staining correlated with: loss of heterozygosity (LOH) at the FHIT 3p14.2 locus, but not at other loci on 3p; squamous histology; LOH at 17p13 and 5q but not with LOH at multiple other suspected tumour suppressor gene loci; and was inversely correlated with codon 12 mutations in K-ras. Fhit expression was not correlated overall with a variety of clinical parameters including survival and was not associated with abnormalities of immunohistochemical expression of p53, RB, and p16. All of these findings are consistent with loss of Fhit protein expression being as frequent an abnormality in lung cancer pathogenesis as are p53 and p16 protein abnormalities and that such loss occurs independently of the commitment to the metastatic state and of most other molecular abnormalities.
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PMID:Loss of Fhit expression in non-small-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features. 1073 5

Recent studies have demonstrated that angiogenesis and suppressed cell-mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein-Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-alpha, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-alpha have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease.
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PMID:The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease. 1074 Dec 73

Allelic loss at the short arm of chromosome 3 is one of the most common and earliest events in the pathogenesis of lung cancer, and is observed in more than 90% of small-cell lung cancers (SCLCs) and in 50-80% of non-small-cell lung cancers (NSCLCs). Frequent and early loss of heterozygosity and the presence of homozygous deletions suggested a critical role of the region 3p21.3 in tumorigenesis and a region of common homozygous deletion in 3p21.3 was narrowed to 120 kb (ref. 5). Several putative tumour-suppressor genes located at 3p21 have been characterized, but none of these genes appear to be altered in lung cancer. Here we describe the cloning and characterization of a human RAS effector homologue (RASSF1) located in the 120-kb region of minimal homozygous deletion. We identified three transcripts, A, B and C, derived from alternative splicing and promoter usage. The major transcripts A and C were expressed in all normal tissues. Transcript A was missing in all SCLC cell lines analysed and in several other cancer cell lines. Loss of expression was correlated with methylation of the CpG-island promoter sequence of RASSF1A. The promoter was highly methylated in 24 of 60 (40%) primary lung tumours, and 4 of 41 tumours analysed carried missense mutations. Re-expression of transcript A in lung carcinoma cells reduced colony formation, suppressed anchorage-independent growth and inhibited tumour formation in nude mice. These characteristics indicate a potential role for RASSF1A as a lung tumour suppressor gene.
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PMID:Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. 1088 81

Mutations of the tumour suppressor gene p53 lead to accumulation of the mutated p53 protein and subsequent production of antoantibodies against p53 proteins, which are also detected in lung cancer. Lung cancer is frequently associated with idiopathic pulmonary fibrosis (IPF). Therefore, we hypothesized that there might be a relationship between the p53 mutation and high prevalence of lung cancer in IPF. To test this hypothesis, we measured serum p53 antibody levels by an ELISA in various lung diseases including lung cancer (n=98), IPF (n=46; with lung cancer, n=14 and without lung cancer, n=32), pulmonary emphysema (PE, n=23) and healthy controls (HC, n=93). The median values of the serum anti-p53 antibody in each group were 8.78, 9.18, 8.08 and 4.95 for patients with lung cancer, IPF with lung cancer, IPF without lung cancer and PE, respectively, and 2.2 for the healthy control group. The groups of IPF (with and without lung cancer) showed a similar level of median values to the lung cancer group and a tendency for a higher level than the PE group. When the cut-off value was set at 7.7 according to the 95% specificity level for normal control, the incidence of positive anti-p53 antibody was significantly higher in lung cancer (61.2%), IPF with lung cancer (57.1%) and IPF without lung cancer (53.1%) than PE (21.7%). These results suggest that p53 mutations occur frequently and substantially in IPF, resulting in a high prevalence of lung cancer.
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PMID:Serum anti-p53 autoantibodies from patients with idiopathic pulmonary fibrosis associated with lung cancer. 1112 96

About 30% of human tumours carry ras gene mutations. Of the three genes in this family (composed of K-ras, N-ras and H-ras), K-ras is the most frequently mutated member in human tumours, including adenocarcinomas of the pancreas ( approximately 70-90% incidence), colon ( approximately 50%) and lung ( approximately 25-50%). To construct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncogenic alleles of K-ras that can be activated only on a spontaneous recombination event in the whole animal. Here we show that mice carrying these mutations were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the effects of germline mutations in the tumour suppressor gene p53, which is known to be mutated along with K-ras in human tumours. This approach has several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.
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PMID:Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. 1132 55

The candidate tumour suppressor gene, LUCA-15, maps to the lung cancer tumour suppressor locus 3p21.3. Overexpression of an alternative RNA splice variant of LUCA-15 has been shown to retard human Jurkat T cell proliferation and to accelerate CD95-mediated apoptosis. An antisense cDNA to the 3'-UTR of this splice variant was able to suppress CD95-mediated apoptosis. Here, we report that overexpression of LUCA-15 itself suppresses CD95-mediated apoptosis in Jurkat cells. This suppression occurs prior to the final execution stage of the CD95 signalling pathway, and is associated with up-regulation of the apoptosis inhibitory protein Bcl-2. LUCA-15 overexpression is also able to inhibit apoptosis induced by the protein kinase inhibitor staurosporine, but is not able to significantly suppress apoptosis mediated by the topoisomerase II inhibitor etoposide. These findings suggest that LUCA-15 is a selective inhibitor of cell death, and confirm the importance of the LUCA-15 genetic locus in the control of apoptosis.
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PMID:LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells. 1142 Jun 83

Lung cancer is a leading cause of cancer death worldwide; however, despite major advances in cancer treatment during the past two decades, the prognostic outcome of lung cancer patients has improved only minimally. This is largely due to the inadequacy of the traditional screening approach, which detects only well-established overt cancers and fails to identify precursor lesions in premalignant conditions of the bronchial tree. In recent years this situation has fundamentally changed with the identification of molecular abnormalities characteristic of premalignant changes; these concern tumour suppressor genes, loss of heterozygosity at crucial sites and activation of oncogenes. After considering the morphological modifications that occur in premalignant lesions of the bronchial tree, we analyse the alterations occurring in a series of relevant genes: p53 and its functional regulation by MDM2 and p14ARF, p16INK4, p15INK4b, FHIT, as well as LOH at important sites such as 3p, 8p, 9p and 5q. Activation of oncogenes is considered for K-ras, the cyclin D1, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), and finally the c-myc oncogene. The expression of c-myc is influenced strongly by the presence of growth factors (GFs), among which EGF is of prime importance, as well as its receptor coded for by the c-erbB-2 oncogene. Basic knowledge at the molecular level has extremely important clinical implications with regard to early diagnosis, risk assessment and prevention, and therapeutic targets. The novel techniques for early diagnosis and screening of premalignant lung lesions, such as fluorescence bronchoscopy, endobronchial ultrasound, spiral computed tomography combined with precise spatial localization techniques, should basically change the approach to the problems raised by this disease and allow for an increased discovery rate of incipient lesions. Sequential applications will lead to the identification of individuals/populations at high risk, while the availability of accurate 'intermediate end points' will enable the effects of preventive trials to be monitored. Finally, the same molecular abnormalities may serve as 'starting points' for innovative treatments designed to restore the altered functions to normality. Recent developments in our knowledge and understanding of the molecular genetic abnormalities in premalignant lung lesions open an era of hope.
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PMID:Molecular genetic abnormalities in premalignant lung lesions: biological and clinical implications. 1143 8

In 1997, the International Agency for Research on Cancer (IARC) upgraded its evaluation of crystalline silica to a Group 1 human carcinogen. Criticism against such decision is based on the lack of consistency in experimental results across animal species, violation of an important principle for causality, such as the replication of findings under different circumstances of exposure, and the lack of a clear dose-response curve. The most recent epidemiological literature on the silica-silicosis-lung cancer link replicates the inconsistent findings that have been characterising 50 years of scientific debate in the occupational arena. Exposure circumstances capable of modifying the silica-lung cancer association include chronic bronchitis, composition of the dust mixing, particularly concerning co-occurrence of other known or probable lung carcinogens, total respirable dust, concentration of silica in respirable dust, type of crystalline silica and particle surface characteristics. The hypothesis of a silicosis-mediated pathway points toward an unspecific mechanism shared with other fibrotic conditions, for which silica might be just one of the triggers. In envisaging a multivariate multistep model of lung cancer among silica-exposed workers, silica might be considered as a "passive components of the sufficient cause", i.e., one of the associated risk factors, concurrent or subsequent to the "active component(s) of the sufficient cause" (including, for instance, smoking, asbestos, radon-daughters, arsenic, hexavalent chromium, nickel, polycyclic aromatic hydrocarbons (PAH), and diesel exhausts among the external risk factors; and DNA repair enzymes polymorphism and spontaneous inactivation of tumour suppressor genes among the internal risk factors), which adds up in modulating the tumoral development in not easily predictable directions. If silica acts as a human lung carcinogen depending on certain occupational exposure circumstances, perhaps those circumstances and not silica itself should be classified for their human carcinogenicity potential.
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PMID:Multifactorial aetiology of lung cancer among silica-exposed workers. 1160 27

Dysregulation of CpG-methylation is a common feature of many human cancers and tumour suppressor genes can be silenced by hypermethylation. Recently, 2 methyl-CpG-binding domain proteins have been linked to gene inactivation by their ability to recruit co-repressors and HDAC-activity to methylated gene promoters. Here, we have analysed mRNA expression of these genes, MeCP2 and MBD2, in a wide variety of primary human tumours. In solid tumours, expression levels of MBD2 (57/71) and MeCP2 (64/71) were significantly reduced in the majority of primary tumours as detected by quantitative real-time RT-PCR. Western blot analyses of MeCP2 in matched tumour-normal samples of patients with non-small-cell lung cancer (NSCLC) indicated reduced protein in a significant percentage of patients. In acute myelogenous leukaemia (n = 26), expression levels were only slightly reduced and did not differ between samples analysed at diagnosis or at the time of relapse. In early-stage NSCLC (n = 70) expression of MeCP2 and MBD2 was significantly lower in squamous cell carcinoma than in adenocarcinoma or large cell carcinoma (P = 0.03 and P = 0.01). To further elucidate the mechanisms of gene regulation, we analysed MeCP2 and MBD2 regulation during haematopoietic differentiation. No significant changes in MeCP2 or MBD2 expression were found when NB4 cells were differentiated toward granulocytes suggesting that neither differentiation nor cell cycle status were relevant for the reduced expression of these genes in human cancer. In conclusion, the significant loss of MeCP2 and MBD2 expression in human cancers suggests a potential role of this phenomenon in the development of solid human tumours.
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PMID:Loss of expression of HDAC-recruiting methyl-CpG-binding domain proteins in human cancer. 1171 Aug 31

The human homologue of the Drosophila Roundabout gene DUTT1 (Deleted in U Twenty Twenty) or ROBO1 (Locus Link ID 6091), a member of the NCAM family of receptors, was recently cloned from the lung cancer tumour suppressor gene region 2 (LCTSGR2 or U2020 region) at 3p12. DUTT1 maps within a region of overlapping homozygous deletions characterized in both small cell lung cancer lines (SCLC) and in a breast cancer line. In this report we (a) defined the genomic organization of the DUTT1 gene, (b) performed mutation and expression analysis of DUTT1 in lung, breast and kidney cancers, (c) identified tumour specific promoter region methylation of DUTT1 in human cancers. The gene was found to contain 29 exons and spans at least 240 kb of genomic sequence. The 5' region contains a CpG island, and the poly(A)(+) tail has an atypical 5'-GATAAA-3' signal. We analysed DUTT1 for mutations in lung, breast and kidney cancers, no inactivating mutations were detected by PCR-SSCP. However, seven germline missense changes were found and characterized. DUTT1 expression was not detectable in one out of 18 breast tumour lines analysed by RT-PCR. Bisulfite sequencing of the promoter region of DUTT1 gene in the HTB-19 breast tumour cell line (not expressing DUTT1) showed complete hypermethylation of CpG sites within the promoter region of the DUTT1 gene (-244 to +27 relative to the translation start site). The expression of DUTT1 gene was reactivated in HTB-19 after treatment with the demethylating agent 5-aza-2'-deoxycytidine. The same region was also found to be hypermethylated in six out of 32 (19%) primary invasive breast carcinomas and eight out of 44 (18%) primary clear cell renal cell carcinomas (CC-RCC) and in one out of 26 (4%) primary NSCLC tumours. Furthermore 80% of breast and 75% of CC-RCC tumours showing DUTT1 methylation had allelic losses for 3p12 markers hence obeying Knudson's two hit hypothesis. Our findings suggest that DUTT1 warrants further analysis as a candidate for the tumour suppressor gene (TSG) at 3p12, a region defined by hemi and homozygous deletions and functional analysis.
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PMID:Tumour specific promoter region methylation of the human homologue of the Drosophila Roundabout gene DUTT1 (ROBO1) in human cancers. 1208 32


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