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)

Inducible nitric oxide synthase (iNOS) has been shown to be frequently expressed in melanomas; up-regulation of this enzyme is though to be associated with tumor progression. In this study, we investigated whether diverse cytokines such as: IL-6, TNF-alpha, IL-1beta, IFN-gamma and IL6RIL6 (a highly active fusion protein of the soluble form of the IL-6R (sIL-6R) and IL-6) enhance the iNOS gene expression in B16/F10.9 murine metastatic melanoma cells. An increase at iNOS expression and NO production was observed with the co-treatment of IL6RIL6 plus TNF-alpha. Gel shift and reporter gene analyses revealed that IL6RIL6 selectively activated AP-1; while TNF-alpha increased the activities of both NF-kappaB and AP-1. Persistent activation of AP-1 was also seen in cells treated with IL6RIL6 plus TNF-alpha. Stimulation of cells with IL6RIL6/TNF-alpha resulted in the activation of mitogen-activated protein kinases (MAPK) such as c-Jun N-terminal kinase (JNK) and p38, and the abrogation by pretreatment with JNK or p38 MAPK inhibitor. IL6RIL6 or IL6RIL6/TNFalpha-inducible AP-1 binding increase was supershifted by anti-c-Jun or c-Fos antibodies, and the activation of c-Jun and c-Fos was dependent on JNK and p38, respectively. These results suggest that IL-6/sIL-6R/gp130 complex signaling has an unexpected positive effect on iNOS gene expression through JNK/p38 MAPK mediated-AP-1 activation in melanoma cells.
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PMID:Novel role of IL-6/SIL-6R signaling in the expression of inducible nitric oxide synthase (iNOS) in murine B16, metastatic melanoma clone F10.9, cells. 1718 27

S100A7 (psoriasin) is highly expressed in preinvasive breast carcinomas and in a subset of poor prognosis invasive tumors. To determine the influence of S100A7 expression on ERalpha negative breast cancer, we profiled mRNA gene expression by Microarray and SAGE analysis, using the ERalpha negative MDA-MB-231 cell line model. Statistically significant transcripts of genes with very high differential expression were further validated by QPCR in both MDA-MB-231 and MDA-MB-468 cell lines expressing exogenous and endogenous S100A7. S100A7 expression correlated with increases in genes associated with MHC class II receptor activity, antigen processing and antigen presentation, and immune cell activation. The transcription factors (TFs) prediction tool CARRIE confirmed an association between TFs reported to be upregulated by S100A7 (NF-kappaB, AP-1, and HIF1) and the regulation of many genes in this dataset. The relationship between S100A7 up-regulation and the MHC class II and HLA-class II molecule coding gene CD74 was examined further in a cohort of ERalpha negative breast tumors by tissue microarray (TMA) and immunohistochemistry (IHC), confirming a significant association in vivo (p=0.042, n=149). These results are consistent with a role for S100A7 in modulating the immune response which may be a factor in early breast tumor progression.
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PMID:S100A7 (psoriasin) influences immune response genes in human breast cancer. 1756 May 71

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of cytokine signaling, is expressed in breast cancer cells where it can modify sensitivity and responsiveness to cytokine signaling through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Although it is widely accepted that SOCS3 expression is in itself regulated by STATs, we and others have shown that prostaglandins can also up-regulate SOCS3 expression. Here we used T47D breast cancer cells treated with prostaglandin E2 (PGE2) to examine this pathway. T47D cells responded to PGE2 stimulation with a significant increase in SOCS3 mRNA that was independent of de novo protein synthesis. PGE2 stimulation resulted in STAT3 serine and tyrosine phosphorylation, although mutation of either of the two previously characterized STAT response elements on the SOCS3 promoter did not affect SOCS3 promoter activation by PGE2. In addition, overexpression of STAT3 wild-type, constitutively active or dominant-negative constructs did not affect PGE2-induced SOCS3 promoter activation, indicating that STATs are unlikely mediators of this pathway in these cells. PGE2 is a known activator of the cAMP/protein kinase A (PKA) pathway, and in T47D cells, up-regulation of SOCS3 mRNA by PGE2 was abolished by pretreatment with H89, a PKA inhibitor and increased by cAMP and forskolin treatment. Consistent with this, PGE2 treatment increased cAMP response element (CRE)-binding protein serine phosphorylation. However, mutation of the activator protein 1/CRE on the promoter did not affect basal or PGE2-stimulated activation, suggesting a role for cAMP/PKA that is independent of CRE-binding protein binding. Mutation of the GC-rich region of the SOCS3 promoter, a putative Sp1/Sp3 binding site, abolished both basal and PGE2-stimulated activation. Gel-shift assays showed increased complex formation after treatment, and this was inhibited by the addition of an Sp1 antibody or pretreatment with PKA inhibitor. Chromatin immunoprecipitation assay verified Sp1 binding to the promoter in response to PGE2. Sp1 overexpression increased SOCS3 promoter activation, and both basal and PGE2-induced SOCS3 mRNA expression was prevented by mithramycin, an inhibitor of Sp1 DNA binding. Finally, a physiological role for PGE2 was demonstrated with PGE2 pretreatment reducing lipopolysaccharide-induced STAT3 activation. Collectively, this study details a novel mechanism of SOCS3 up-regulation by PGE2 in breast cancer cells that appears to be STAT independent and involve Sp1 binding to the promoter. This process has possible implications for cytokine responsiveness and tumor progression.
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PMID:Characterization of the SOCS3 promoter response to prostaglandin E2 in T47D cells. 1763 39

Programmed cell death 4 (Pdcd4) is a tumor suppressor that inhibits neoplastic transformation and tumor invasion. Tissue microarray analysis showed that Pdcd4 expression is downregulated in colon adenocarcinoma and carcinoma relative to adjacent normal tissues. To address the issue of whether reduced Pdcd4 expression is sufficient to promote tumor progression, we knocked down Pdcd4 expression in colon tumor HT29 cells using pdcd4 short hairpin RNA (shRNA). Pdcd4 knockdown results in a fibroblast-like transition, while the control cells (expressing LacZ shRNA) remain as clumped similar to the parental cells. In addition, expression of pdcd4 shRNA in HT29 cells promotes invasion. In an effort to characterize the molecular mechanism underlying these observations, we discovered that knockdown of Pdcd4 results in reduction of E-cadherin expression, and accumulation of active beta-catenin in the nucleus. The active beta-catenin binds with T-cell factor 4 (Tcf4) and activates beta-catenin/Tcf-dependent transcription. Furthermore, Pdcd4 knockdown dramatically increases AP-1-dependent transcription. Thus, the mechanism by which reduced Pdcd4 expression promotes invasion appears to involve the activation of beta-catenin/Tcf and AP-1-dependent transcription.
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PMID:Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both beta-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells. 1782 98

Vanillin is one of the most widely used flavor compounds in food and personal products. It has been reported that vanillin is able to inhibit mutagenesis induced by chemical and physical mutagens, and to suppress the invasion and migration of cancer cells. Herein we used the oligonucleotide microarray approach to study gene expression profile of vanillin-treated human hepatocarcinoma cells. Microarray data followed by gene ontology (GO) investigation displayed that vanillin-affected clusters of genes involved in cell cycle and apoptosis. Genes down-regulated by vanillin were grouped into three GO categories, regulation of cellular process, cell cycle, and death. Furthermore, most of the down-regulated genes were associated with cancer progression. Knowledge-based analysis further indicated that Fos may play a central role in the regulation of gene expression network. Analysis of Fos-related transcription factor, activator protein 1 (AP-1), showed that vanillin inhibited AP-1 activity in a dose-dependent manner. Furthermore, the phosphorylation of extracellular signal-regulated protein kinase (ERK) was diminished with increasing concentrations of vanillin, indicating that vanillin-regulated AP-1 activity via ERK pathway. In conclusion, our data suggested that vanillin exhibited the anticancer potential by the regulations of cell cycle and apoptosis. Moreover, its regulation may involve the suppression of a central molecule, AP-1.
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PMID:Microarray analysis of vanillin-regulated gene expression profile in human hepatocarcinoma cells. 1794 90

The Maf oncoproteins are b-Zip transcription factors of the AP-1 superfamily. They are involved in developmental, metabolic, and tumorigenic processes. Maf proteins are overexpressed in about 50% of human multiple myelomas. Here, we show that Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and that phosphorylation by GSK-3 can increase the oncogenic activity of a protein. Using microarray analysis, we identify a gene-expression subprogram regulated by GSK-3-mediated Maf phosphorylation involved in extracellular matrix remodeling and relevant to cancer progression. We also demonstrate that GSK-3 triggers MafA sequential phosphorylation on residues S61, T57, T53, and S49, inducing its ubiquitination and degradation. Paradoxically, this phosphorylation increases MafA-transcriptional activity through the recruitment of the coactivator P/CAF. We further demonstrate that P/CAF protects MafA from ubiquitination and degradation, suggesting that, upon the release of the coactivator complex, MafA becomes polyubiquitinated and degraded to allow the response to terminate.
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PMID:GSK-3-mediated phosphorylation enhances Maf-transforming activity. 1804 54

Aberrant gene expression is one of the driving forces for cancer progression and is considered an ideal target for chemical intervention. Although emerging bioluminescence reporter systems allow high-throughput searches for small molecules regulatory for gene expression, frequent silencing of reporter genes by epigenetic mechanisms hinders wide application of this drug discovery strategy. Here we report a novel system that directs the integration of a promoter-reporter construct to an open chromosomal location by Flp-mediated homologous recombination, thereby overcoming reporter-gene silencing. Using this system, we have screened more than 8000 compounds in the DIVERSet chemical library for repressors of a matrix metalloproteinase-9 (MMP-9) promoter and identified 5-methyl-2-(4-methylphenyl)-1H-benzimidazole (MPBD) inhibitory for MMP-9 gene expression. Consistent with this effect, MPBD inhibits MMP-9-dependent invasion of UMSCC-1 oral cancer cells, preosteoclast migration, and receptor activator of nuclear factor-kappaB ligand-induced osteoclast activity over concentration ranges that repressed MMP-9 expression. Mechanistic studies indicated that MPBD antagonizes AP-1 function by inhibiting its transactivation activity. We conclude that the Flp-mediated homologous recombination system to direct reporter integration into open chromatin regions represents a novel strategy allowing for the development of high-throughput systems screening for lead compounds targeting aberrant gene expression in cancer.
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PMID:A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9 expression. 1806 84

Overexpression of ACTR/AIB1 is frequently found in different cancers with distant metastasis. To address its possible involvement in tumor metastasis, we performed invasion assays to examine the effect of ACTR alteration on the invasiveness of breast cancer cells (MDA-MB-231 or T-47D) and found that high levels of ACTR are required for their strong invasiveness. Molecular analysis indicates that ACTR functions as a coactivator of AP-1 to up-regulate the expression of matrix metalloproteinases such as MMP-7 and MMP-10 and reduce cell adhesion to specific extracellular matrix proteins. These novel findings provide a mechanistic link between ACTR and MMPs, and suggest that ACTR may also play an important role in cancer progression by facilitating tumor invasion.
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PMID:Proto-oncogene ACTR/AIB1 promotes cancer cell invasion by up-regulating specific matrix metalloproteinase expression. 1816 90

The mechanisms involved in the epithelial to mesenchymal transition (EMT) are integrated in concert with master developmental and oncogenic pathways regulating in tumor growth, angiogenesis, metastasis, as well as the reprogrammation of specific gene repertoires ascribed to both epithelial and mesenchymal cells. Consequently, it is not unexpected that EMT has profound impacts on the neoplastic progression, patient survival, as well as the resistance of cancers to therapeutics (taxol, vincristine, oxaliplatin, EGF-R targeted therapy and radiotherapy), independent of the "classical" resistance mechanisms linked to genotoxic drugs. New therapeutic combinations using genotoxic agents and/or EMT signaling inhibitors are therefore expected to circumvent the chemotherapeutic resistance of cancers characterized by transient or sustained EMT signatures. Thus, targeting critical orchestrators at the convergence of several EMT pathways, such as the transcription pathways NF-kappaB, AKT/mTOR axis, MAPK, beta-catenin, PKC and the AP-1/SMAD factors provide a realistic strategy to control EMT and the progression of human epithelial cancers. Several inhibitors targeting these signaling platforms are already tested in preclinical and clinical oncology. In addition, upstream EMT signaling pathways induced by receptor and nonreceptor tyrosine kinases (e.g. EGF-R, IGF-R, VEGF-R, integrins/FAK, Src) and G-protein-coupled receptors (GPCR) constitute practical options under preclinical research, clinical trials or are currently used in the clinic for cancer treatment: e.g. small molecule inhibitors (Iressa: targeting selectively the EGF-R; CP-751,871, AMG479, NVP-AEW541, BMS-536924, PQIP, AG1024: IGF-R; AZD2171, ZD6474: VEGF-R; AZD0530, BMS-354825, SKI606: Src; BIM-46174: GPCR; rapamycin, CCI-779, RAD-001: mTOR) and humanized function blocking antibodies (Herceptin: ErbB2; Avastin: VEGF-A; Erbitux: EGF-R; Abegrin: alphavbeta3 integrins). We can assume that silencing RNA and adenovirus-based gene transfer of therapeutic miR and dominant interferring expression vectors targeting EMT pathways and signaling elements will bring additional ways for the treatment of epithelial cancers. Identification of the factors that initiate, modulate and effectuate EMT signatures and their underlying upstream oncogenic pathways should provide the basis of more efficient strategies to fight cancer progression as well as genetic and epigenetic forms of drug resistance. This goal can be accomplished using global screening of human clinical tumors by EMT-associated cDNA, proteome, miRome, and tissue arrays.
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PMID:Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. 1871 6

Human papillomaviruses (HPV) are the known cause for a variety of cancers including cervical and epithelial cancers. The cottontail-rabbit papillomavirus (CRPV) serves as a suitable animal model to study the development of these cancers in vivo. We have previously demonstrated that CRPV-induced skin carcinomas express high levels of MMP-9, a metalloproteinase contributing to cancer progression by extracellular matrix remodelling. Based on our previously reported finding that CRPV early protein 2 can activate a truncated human 670bp MMP-9 promoter fragment, we hypothesized that MMP-9 expression in the rabbit carcinomas is a consequence of activation of the rabbit MMP-9 promoter in-trans by CRPV early protein 2. Further elucidation of the mechanism revealed the requirement for both a proximal and distal AP-1 transcription factor binding site in the rabbit MMP-9 promoter and the AP-1 complex as demonstrated by the inhibitory effect of TAM67, a trans-activation deficient c-jun mutant. The characterization of signal-transduction requirements revealed predominantly ERK1 to be required for CRPV early protein 2-dependent MMP-9 promoter activation, but not JNK nor p38. In summary CRPV early protein 2 activates the expression of MMP-9 in-trans through AP-1 and ERK1 and may contribute to cancer development and progression via this mechanism within the animal model.
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PMID:AP-1 and ERK1 but not p38 nor JNK is required for CRPV early protein 2-dependent MMP-9 promoter activation in rabbit epithelial cells. 1895 30


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