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

Cancer is a disease arising from both genetic and epigenetic modifications of DNA that contribute to changes in gene expression in the cell. Genetic modifications include loss or amplification of DNA, loss of heterozygosity (LOH) as well as gene mutations. Epigenetic changes in cancer are generally thought to be brought about by alterations in DNA and histone modifications that lead to the silencing of tumour suppressor genes and the activation of oncogenic genes. Other consequences that result from epigenetic changes, such as inappropriate expression or repression of some genes in the wrong cellular context, can also result in the alteration of control and physiological systems such that a normal cell becomes tumorigenic. Excessive levels of the enzymes that act as epigenetic modifiers have been reported as markers of aggressive breast cancer and are associated with metastatic progression. It is likely that this is a common contributor to the recurrence and spread of the disease. The emphasis on genetic changes, for example in genome-wide association studies and increasingly in whole genome sequencing analyses of tumours, has resulted in the importance of epigenetic changes having less attention until recently. Epigenetic alterations at both the DNA and histone level are increasingly being recognised as playing a role in tumourigenesis. Recent studies have found that distinct subgroups of poor-prognosis tumours lack genetic alterations but are epigenetically deregulated, pointing to the important role that epigenetic modifications and/or their modifiers may play in cancer. In this review, we highlight the multitude of epigenetic changes that can occur and will discuss how deregulation of epigenetic modifiers contributes to cancer progression. We also discuss the off-target effects that epigenetic modifiers may have, notably the effects that histone modifiers have on non-histone proteins that can modulate protein expression and activity, as well as the role of hypoxia in epigenetic regulation.
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PMID:Epigenetic regulation in cancer progression. 2594 94

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.
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PMID:STAT3 regulated ARF expression suppresses prostate cancer metastasis. 2649 36

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG(FS) in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG(FS) abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG(FS) can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAG(FS) expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response.
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PMID:Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. 2623 63

microRNAs (miRNAs) are a family of short, non-coding RNA molecules that drive a complex network of post-transcriptional gene regulation by enhancing target mRNA decay and/or inhibiting protein synthesis from mRNA transcripts. They regulate genes involved in key aspects of normal cell growth, development and the maintenance of body homeostasis and have been closely linked to the development and progression of human disease, in particular cancer. Over recent years there has been much interest regarding their potential as biomarkers and as therapeutic agents or targets. microRNA-7 (miR-7) is a 23 nucleotide (nt) miRNA known primarily to act as a tumour suppressor. miR-7 directly inhibits a number of oncogenic targets and impedes various aspects of cancer progression in vitro and in vivo, however, some studies have also implicated miR-7 in oncogenic roles. This review summarises the role of miR-7 in cancer, its potential in miRNA-based replacement therapy and its capacity as both a diagnostic and prognostic biomarker.
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PMID:Clinical Potential of microRNA-7 in Cancer. 2630 64

Although oral cancers are generally preceded by a well-established pre-cancerous stage, there is a lack of well-defined clinical and morphological criteria to detect and signal progression from pre-cancer to malignant tumours. We conducted a critical review to summarize the evidence regarding aberrant DNA methylation patterns as a potential diagnostic biomarker predicting progression. We identified all relevant human studies published in English prior to 30th April 2015 that examined DNA methylation (%) in oral pre-cancer by searching PubMed, Web-of-Science and Embase databases using combined key-searches. Twenty-one studies (18-cross-sectional; 3-longitudinal) were eligible for inclusion in the review, with sample sizes ranging from 4 to 156 affected cases. Eligible studies examined promoter region hyper-methylation of tumour suppressor genes in pathways including cell-cycle-control (n=15), DNA-repair (n=7), cell-cycle-signalling (n=4) and apoptosis (n=3). Hyper-methylated loci reported in three or more studies included p16, p14, MGMT and DAPK. Two longitudinal studies reported greater p16 hyper-methylation in pre-cancerous lesions transformed to malignancy compared to lesions that regressed (57-63.6% versus 8-32.1%; p<0.01). The one study that explored epigenome-wide methylation patterns reported three novel hyper-methylated loci (TRHDE; ZNF454; KCNAB3). The majority of reviewed studies were small, cross-sectional studies with poorly defined control groups and lacking validation. Whilst limitations in sample size and study design preclude definitive conclusions, current evidence suggests a potential utility of DNA methylation patterns as a diagnostic biomarker for oral pre-cancer progression. Robust studies such as large epigenome-wide methylation explorations of oral pre-cancer with longitudinal tracking are needed to validate the currently reported signals and identify new risk-loci and the biological pathways of disease progression.
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PMID:DNA methylation markers for oral pre-cancer progression: A critical review. 2745 Aug 69

Carcinogenesis as well as cancer progression result from genetic and epigenetic changes of the genome that leads to dysregulation of transcriptional activity of genes. Epigenetic mechanisms in cancer cells comprise (i) post-translation histone modification (i.e., deacetylation and methylation); (ii) DNA global hypomethylation; (iii) promoter hypermethylation of tumour suppressor genes and genes important for cell cycle regulation, cell differentiation and apoptosis; and (iv) posttranscriptional regulation of gene expression by noncoding microRNA. These epigenetic aberrations can be readily reversible and responsive to both synthetic agents and natural components of diet. A source of one of such diet components are cruciferous vegetables, which contain high levels of a number of glucosinolates and deliver, after enzymatic hydrolysis, sulforaphane and other bioactive isothiocyanates, that are involved in effective up-regulation of transcriptional activity of certain genes and also in restoration of active chromatin structure. Thus a consumption of cruciferous vegetables, treated as a source of isothiocyanates, seems to be potentially useful as an effective cancer preventive factor or as a source of nutrients improving efficacy of standard chemotherapies. In this review an attempt is made to elucidate the role of sulforaphane in regulation of gene promoter activity through a direct down-regulation of histone deacetylase activity and alteration of gene promoter methylation in indirect ways, but the sulforaphane influence on non-coding micro-RNA will not be a subject of this review.
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PMID:The Role of Sulforaphane in Epigenetic Mechanisms, Including Interdependence between Histone Modification and DNA Methylation. 2670 71

Lemur tyrosine kinase-3 (LMTK3) plays an important role in cancer progression and is associated with breast, lung, gastric and colorectal cancer. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that typically repress target genes at post-transcriptional level and have an important role in tumorigenesis. By performing a miRNA expression profile, we identified a subset of miRNAs modulated by LMTK3. We show that LMTK3 induces miR-34a, miR-196-a2 and miR-182 levels by interacting with DEAD-box RNA helicase p68 (DDX5). LMTK3 binds via DDX5 to the pri-miRNA of these three mature miRNAs, thereby sequestrating them from further processing. Ectopic expression of miR-34a and miR-182 in LMTK3-overexpressing cell lines (MCF7-LMTK3 and MDA-MB-231-LMTK3) inhibits breast cancer proliferation, invasion and migration. Interestingly, miR-34a and miR-182 directly bind to the 3'UTR of LMTK3 mRNA and consequently inhibit both its stability and translation, acting as tumour suppressor-like miRNAs. In aggregate, we show that LMTK3 is involved in miRNA biogenesis through modulation of the Microprocessor complex, inducing miRNAs that target LMTK3 itself.
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PMID:LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5. 2673 63

The junctional adhesion molecule (JAMs) family belongs to the immunoglobulin subfamily involved in the formation of tight junctions (TJ) in both endothelial and epithelial cells. Aberrant expression of JAM-2 is associated with cancer progression but little work has been carried out in discovering how this affects changes in cell behaviour. The present study aimed to examine the expression of JAM-2 in human colon cancer specimens and cell lines and its role in the development of colon cancer. JAM-2 expression in human colon cancer specimens (normal, n=75; cancer, n=94) and cell lines was analysed using quantitative real-time PCR and conventional RT-PCR. Colon cancer cells were stably transfected with a mammalian expression vector to overexpress JAM-2-Flag. The effect on growth, adhesion and migration following overexpression of JAM-2 was then investigated using in vitro models. TJ function was assessed using a trans-epithelial resistance assay (TER, with an EVOM voltammeter). JAM-2 was lowly expressed in colon cancer cells such as RKO, HT115. JAM-2 overexpression in RKO cells (RKO-JAM-2) and HT115 cells (HT115-JAM-2) showed retarded adhesion (P<0.05). An in vivo tumour model showed that RKO-JAM-2 had significantly reduced growth (P<0.05), invasion (P<0.05) and migration (P<0.05) as well as in HT115-JAM-2, except on proliferation and migration. Expression of JAM-2 resulted in a significant increase in TER and decrease in permeability of polarized monolayers (P<0.05). Further analysis of JAM-2 transcript levels against clinical aspects demonstrated that the decreasing JAM-2 expression correlated to disease progression, metastasis and poor survival. Taken together, JAM-2 may function as a putative tumour suppressor in the progression and metastasis of colorectal cancer.
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PMID:Effect of junctional adhesion molecule-2 expression on cell growth, invasion and migration in human colorectal cancer. 2678 73

Sarcomas represent a complex group of malignant neoplasms of mesenchymal origin and their heterogeneity poses a serious diagnostic and therapeutic challenge. There is therefore a need to elucidate the molecular mechanisms underpinning the pathogenesis of the more than 70 distinguishable sarcoma subtypes. The transcription factor TBX3, a critical developmental regulator, is overexpressed in several cancers of epithelial origin where it contributes to tumorigenesis by different molecular mechanisms. However, the status and role of TBX3 in sarcomas have not been reported. Here we show that a diverse subset of soft tissue and bone sarcoma cell lines and patient-derived sarcoma tissues express high levels of TBX3. We further explore the significance of this overexpression using a small interferring RNA approach and demonstrate that TBX3 promotes the migratory ability of chondrosarcoma, rhabdomyosarcoma and liposarcoma cells but inhibits fibrosarcoma cell migration. This suggested that TBX3 may play a key role in the development of different sarcoma subtypes by functioning as either an oncoprotein or as a brake to prevent tumour progression. To further explore this, TBX3 knockdown and overexpression cell culture models were established using chondrosarcoma and fibrosarcoma cells as representatives of each scenario, and the resulting cells were characterized with regard to key features of tumorigenesis. Results from in vitro and in vivo assays reveal that, while TBX3 promotes substrate-dependent and -independent cell proliferation, migration and tumour formation in chondrosarcoma cells, it discourages fibrosarcoma formation. Our findings provide novel evidence linking TBX3 to cancers of mesenchymal origin. Furthermore, we show that TBX3 may be a biomarker for the diagnosis of histologically dynamic sarcoma subtypes and that it impacts directly on their oncogenic phenotype. Indeed, we reveal that TBX3 may exhibit oncogene or tumour suppressor activity in sarcomas, which suggests that its role in cancer progression may rely on cellular context.
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PMID:The T-box transcription factor 3 is a promising biomarker and a key regulator of the oncogenic phenotype of a diverse range of sarcoma subtypes. 2690 Sep 51

DNA hypermethylation at the promoter of tumour-suppressor genes is tightly correlated with their transcriptional repression and recognized as the hallmark of majority of cancers. Epigenetic silencing of tumour suppressor genes impairs their cellular functions and activates a cascade of events driving cell transformation and cancer progression. Here, we examine site-specific and spatiotemporal alteration in DNA methylation at a target region in BRCA1 gene promoter, a model tumour suppressor gene. We have developed a programmable CRISPR-Cas9 based demethylase tool containing the deactivated Cas9 (dCas9) fused to the catalytic domain (CD) of Ten-Eleven Translocation (TET) dioxygenase1 (TET1CD). The fusion protein selectively demethylates targeted regions within BRCA1 promoter as directed by the designed single-guide RNAs (sgRNA), leading to the transcriptional up-regulation of the gene. We also noticed the increment in 5-hydroxymethylation content (5-hmC) at the target DNA site undergoing the most profound demethylation. It confirms the catalytic activity of TET1 in TET1-dCas9 fusion proteins-mediated demethylation at these target sequences. The modular design of the fusion constructs presented here allows for the selective substitution of other chromatin or DNA modifying enzymes and for loci-specific targeting to uncover epigenetic regulatory pathways at gene promoters and other selected genomic regions.
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PMID:CRISPR-dCas9 mediated TET1 targeting for selective DNA demethylation at BRCA1 promoter. 2735 40


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