Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liposarcoma, a malignancy of fat cells, is the most common soft tissue sarcoma. Though rare, poorly differentiated liposarcomas commonly metastasize to lungs and liver, leading to poor prognosis. Prevention of Extracellular matrix (ECM) degradation by inhibition of matrix metalloproteinases (MMPs) activity has been shown to be a promising therapeutic approach to inhibition of cancer progression. A nutrient mixture (NM) containing lysine, proline, ascorbic acid, and green tea extract has shown significant anticancer activity against a number of cancer cell lines. We investigated the effect of NM on liposarcoma cell line SW-872 proliferation (MTT assay), MMP secretion (gelatinase zymography), invasion through Matrigel, and apoptosis and morphology (live green caspase kit and H&E). Liposarcoma cell growth was inhibited by 36 and 61% at 500 and 1,000 microg/ml NM. Zymography demonstrated both MMP-2 and MMP-9 secretion, with PMA-enhanced MMP-9 activity. NM inhibited both MMPs with virtual total inhibition at 500 microg/ml NM. Invasion through Matrigel was inhibited at 100, 500, and 1,000 microg/ml by 44, 75, and 100%, respectively. Dose-dependent apoptosis of liposarcoma cells was evident with NM challenge, with virtually all cells exposed to 1,000 microg/ml NM in late apoptosis. H&E staining did not demonstrate any changes in morphology at lower concentrations. However, some apoptotic changes were evident at higher concentrations. In conclusion, NM significantly inhibited liposarcoma cell growth, MMP activity, and invasion and induced apoptosis in vitro-important parameters for cancer development, suggesting NM as a potential treatment strategy for liposarcoma.
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PMID:Inhibition of cell invasion and MMP production by a nutrient mixture in malignant liposarcoma cell line SW-872. 1791 88

The Polycomb Group (PcG) protein EZH2 is a critical component of a multiprotein complex that methylates Lys(27) of histone 3 (H3K27), which consequently leads to the repression of target gene expression. We have previously reported that EZH2 is overexpressed in metastatic prostate cancer and is a marker of aggressive diseases in clinically localized solid tumors. However, the global set of genes directly regulated by PcG in tumors is largely unknown, and thus how PcG mediates tumor progression remains unclear. Herein we mapped genome-wide H3K27 methylation in aggressive, disseminated human prostate cancer tissues. Integrative analysis revealed that a significant subset of these genes are also targets of PcG in embryonic stem cells, and their repression in tumors is associated with poor prognosis. By stepwise cross-validation, we developed a "Polycomb repression signature" composed of 14 direct targets of PcG in metastatic tumors. Notably, solid tumor subtypes in which this gene signature is repressed show poor clinical outcome in multiple microarray data sets of tumors including breast and prostate cancer. Taken together, our results show a fingerprint of PcG-mediated transcriptional repression in metastatic prostate cancer that is reminiscent of stem cells and associated with cancer progression. Therefore, PcG proteins play a central role in the epigenetic silencing of target genes and functionally link stem cells, metastasis, and cancer survival.
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PMID:A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. 1800 6

Matrix metalloproteinases (MMPs) are a family of extracellular proteinases whose contributions to cancer progression have been studied because of their matrix-degrading abilities and elevated expression in advanced stage tumors. Recent findings suggest a role for MMPs during the multiple stages of tumor progression including establishment and growth, migration, invasion, metastasis, and angiogenesis. MMP-9 regulation at the molecular level can be studied by measuring the effect(s) of a variety of physiological and pharmacological agents on cells. Multiple signaling molecules such as protein kinase C, pertussis toxin-sensitive guanine nucleotide-binding protein G, and protein tyrosine kinases are known to mediate the secretion of MMPs in cell lines. We previously reported an upregulation of MMP-9 in T cells of mammary tumor-bearing mice. In this study, pharmacologic inhibitors were used to dissect the signaling pathways involved in the upregulation of MMP-9 in the splenic T cells of normal and mammary tumor-bearing mice. Staurosporine, a protein kinase inhibitor, stimulated MMP-9 secretion by normal T lymphocytes, while the constitutively high levels of MMP-9 produced by tumor bearers' T cells were decreased by Genistein, a specific tyrosine kinase inhibitor, and Rottlerin, a PKC inhibitor. Using a NF-kappaB specific probe to the murine MMP-9 promoter, electromobility shift assays of nuclear proteins from normal and tumor bearers' splenic T cells revealed a pattern of higher intensity bands from the tumor bearers' nuclear extracts, indicating a greater amount of these transcription factors bound to the recognition motif. When mammary tumor bearers' T cells were cultured with the NF-kappaB inhibitors, N-p-Tosyl-L-lysine chloromethyl ketone hydrochloride and Bay 11-7082, there was a subsequent decreased production of MMP-9. These results suggest that the tumor burden may be activating various signaling pathways within splenic T lymphocytes to upregulate MMP-9 expression.
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PMID:Molecular events involved in the increased expression of matrix metalloproteinase-9 by T lymphocytes of mammary tumor-bearing mice. 1809 25

Human kallikrein 14 (KLK14) is a member of the human kallikrein gene family of serine proteases, and its protein, hK14, has recently been suggested to serve as a new ovarian and breast cancer marker. To gain insights into hK14's physiological functions, the active recombinant enzyme was obtained in an enzymatically pure state for biochemical and enzymatic characterizations. We studied its substrate specificity and behavior to various protease inhibitors, and identified candidate physiological substrates. hK14 had trypsin-like activity with a strong preference for Arg over Lys in the P1 position, and its activity was inhibited by typical serine protease inhibitors. The protease degraded casein, fibronectin, gelatin, collagen type I, collagen type IV, fibrinogen, and high-molecular-weight kininogen. Furthermore, it rapidly hydrolyzed insulin-like growth factor binding protein-3 (IGFBP-3). These findings suggest that hK14 may be implicated in tumor progression in ovarian carcinoma.
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PMID:Expression and enzymatic characterization of recombinant human kallikrein 14. 1821 83

Polycomb-group genes (PcG), identified by Drosophila genetics, are believed to maintain positional information by constituting a cellular memory system. Recently this system has been proved to be supported by epigenetic transcription regulation. PcG products comprise two distinct complexes, PcG complex 1 and 2. First PcG complex 2 silences chromatin and encodes a histone code by methylating histone H3 at lysine 27. PcG complex 1 is, then, recruited by recognizing the histone code, and ubiquitinates histone H2A and/or inhibits chromatin remodeling to maintain the silenced states of the locus. Biologically, PcG-deficient mice provided biological evidence that PcG are essential for sustaining stem cell activity. More recently PcG were reported to be correlated with cancer progression and prognosis as well as with cancer stem cell activity. PcG may thus play a crucial part in sustaining the activities of malignant as well as normal stem cells. Although PcG were initially seen to maintain stem cell activity through repression of the INK4a locus, they now appear to perform more diverse functions in supporting stem cells. This paper summarizes current information on the molecular roles of PcG in normal and malignant stem cells and discusses the implications in future cancer therapy and regenerative medicine.
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PMID:Role of Polycomb-group genes in sustaining activities of normal and malignant stem cells. 1822 10

Epigenetic gene regulation is a key determinant of heritable gene expression patterns and is critical for normal cellular function. Dysregulation of epigenetic transcriptional control is a fundamental feature of cancer, particularly manifesting as increased promoter DNA methylation with associated aberrant gene silencing, which plays a significant role in tumor progression. We now globally map key chromatin parameters for genes with promoter CpG island DNA hypermethylation in colon cancer cells by combining microarray gene expression analyses with chromatin immunoprecipitation-on-chip technology. We first show that the silent state of such genes universally correlates with a broad distribution of a low but distinct level of the PcG-mediated histone modification, methylation of lysine 27 of histone 3 (H3K27me), and a very low level of the active mark H3K4me2. This chromatin pattern, and particularly H3K4me2 levels, crisply separates DNA-hypermethylated genes from those where histone deacetylation is responsible for transcriptional silencing. Moreover, the chromatin pattern can markedly enhance identification of truly silent and DNA-hypermethylated genes. We additionally find that when DNA-hypermethylated genes are demethylated and reexpressed, they adopt a bivalent chromatin pattern, which is associated with the poised gene expression state of a large group of embryonic stem cell genes and is characterized by an increase in levels of both the H3K27me3 and H3K4me2 marks. Our data have great relevance for the increasing interest in reexpression of DNA-hypermethylated genes for the treatment of cancer.
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PMID:Defining a chromatin pattern that characterizes DNA-hypermethylated genes in colon cancer cells. 1863 28

CpG-oligodeoxynucleotides (CpG-ODN) are potent stimulators of the innate immune system. They promote a Th1-biased immune response with antineoplastic potential. We recently demonstrated antitumoral effects of CpG-ODN in murine transitional cell carcinoma (TCC) models. The purpose of the present work was to more precisely define the immunological nature of this immunotherapeutic approach to TCC.MB-49 TCC was established in female C57/Bl6 mice by intravesical tumor cell instillation after poly-L-lysine conditioning of the bladder (day 0) as described previously. Three groups of six mice were treated: intravesical instillation of 50 microl PBS on days 1, 3, 5, and 7 (group 1, untreated control); 10 nmol CpG 1668 on days 1, 3, 5, and 7 (group 2); and 10 nmol GpC 1668 on days 1, 3, 5, and 7 (group 3). Six native bladders served as no-treatment/no-tumor controls (group 4). Mice were sacrificed on day 11; bladders and draining lymph nodes were removed, and mRNA was prepared for quantitative real-time polymerase chain reaction. Samples were analyzed on a Bio-Rad iCycler for IL 10, TGF-beta, IL 12, and IFNgamma expression; threshold values were compared to beta-actin as housekeeping gene.Tumor take was 100%. Three animals in group 1 had to be sacrificed in advance due to rapid tumor progression. Relative cytokine expression was comparable in groups 1 and 4. IL-10, IL-12, TGF-beta, and IFNgamma were overexpressed in groups 2 and 3. CpG-ODN treatment of murine TCC results in overexpression of both classic Th1 cytokines (IL 12 and IFNgamma) and the Th2 marker IL 10. TGF-beta expression is increased as well. These phenomena are not induced by the growing TCC but by CpG-ODN therapy. They are accompanied by an objective clinical response, as we were able to show recently. Immunostimulatory DNA holds promise to be a novel therapeutic agent in TCC.
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PMID:[Immunostimulatory CpG oligodeoxynucleotides (CpG-ODN) in an orthotopic murine transitional cell carcinoma (TCC) model. Effect on local cytokine expression]. 1867 50

Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML-RARalpha fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARalpha degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.
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PMID:The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. 1871 20

Matrilysin (matrix metalloproteinase-7) plays important roles in tumor progression. It was previously found that matrilysin binds to the surface of colon cancer cells to promote their metastatic potential. In this study, we identified annexin II as a novel membrane-bound substrate of matrilysin. Treatment of human colon cancer cell lines with active matrilysin released a 35 k Da annexin II form, which lacked its N-terminal region, into the culture supernatant. The release of the 35 k Da annexin II by matrilysin was significantly enhanced in the presence of serotonin or heparin. Matrilysin hydrolyzed annexin II at the Lys9-Leu10 bond, thus dividing the protein into an N-terminal nonapeptide and the C-terminal 35 k Da fragment. Annexin II is known to serve as a cell surface receptor for tissue-type plasminogen activator (tPA). Although the matrilysin treatment liberated the 35 k Da fragment of annexin II from the cell surface, it significantly increased tPA binding to the cell membrane. A synthetic N-terminal nonapeptide of annexin II bound to tPA more efficiently than intact annexin II. This peptide formed a heterodimer with intact annexin II in test tubes and on cancer cell surfaces. These and other results suggested that the nonapeptide generated by matrilysin treatment might be anchored to the cell membrane, possibly by binding to intact annexin II, and interact with tPA via its C-terminal lysine. It is supposed that the cleavage of cell surface annexin II by matrilysin contributes to tumor invasion and metastasis by enhancing tPA-mediated pericellular proteolysis by cancer cells.
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PMID:Matrilysin (matrix metalloprotease-7) cleaves membrane-bound annexin II and enhances binding of tissue-type plasminogen activator to cancer cell surfaces. 1872 Nov 40

EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that targets lysine-27 of histone H3. This methylated H3-K27 chromatin mark is commonly associated with silencing of differentiation genes in organisms ranging from plants to flies to humans. Studies on human tumors show that EZH2 is frequently over-expressed in a wide variety of cancerous tissue types, including prostate and breast. Although the mechanistic contributions of EZH2 to cancer progression are not yet determined, functional links between EZH2-mediated histone methylation and DNA methylation suggest partnership with the gene silencing machinery implicated in tumor suppressor loss. Here we review the basic molecular biology of EZH2 and the findings that implicate EZH2 in different cancers. We also discuss EZH2 connections to other silencing enzymes, such as DNA methyltransferases and histone deacetylases, and we consider progress on deciphering mechanistic consequences of EZH2 overabundance and its potential roles in tumorigenesis. Finally, we review recent findings that link EZH2 roles in stem cells and cancer, and we consider prospects for integrating EZH2 blockade into strategies for developing epigenetic therapies.
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PMID:Roles of the EZH2 histone methyltransferase in cancer epigenetics. 1872 33


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