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)

Transgenic mice bearing the rat neu proto-oncogene under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter develop focal mammary adenocarcinomas after long latency that are metastatic to the lung in a high percentage of the tumor-bearing animals. Because expression of the neu gene in the mammary epithelium precedes the occurrence of tumors, it appears that another genetic event in addition to neu transgene expression is required for tumorigenesis. We have investigated the expression of PEA3, a new member of the ets oncogene family of transcriptional regulatory factors, in neu-induced mammary tumors to learn whether PEA3 plays a role in tumor progression in this organ. We observed high levels of PEA3 RNA in neu-induced tumors, but little, if any, PEA3 RNA in the surrounding mammary epithelium. Moreover, mammary tumors that had metastasized to the lung also overexpressed the PEA3 gene, whereas normal lung tissue did not. Similar results were obtained after analyses of other transgenic mouse lines bearing metastatic mammary tumors induced by polyomavirus middle T antigen. These findings suggest that enhanced expression of PEA3 may be required to facilitate mammary tumor progression and metastasis.
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PMID:PEA3 is overexpressed in mouse metastatic mammary adenocarcinomas. 769 72

Matrix metalloproteinases (MMPs) are expressed in normal remodeling tissues in a generally tissue-restricted pattern. Transcripts for stromelysin-1 and collagenase are expressed primarily in stromal fibroblasts, whereas transcripts for matrilysin are expressed primarily in glandular epithelial cells. These expression patterns are maintained at carcinoma tumor sites until the late stages of tumor progression at which point many epithelially-derived tumors begin to express stromal fibroblast MMPs. Coincidentally, late stage carcinomas take on other characteristics of stromal fibroblasts, indicating that these tumor cells have "transdifferentiated', that is, they have begun to exhibit characteristics of cells from a separate developmental lineage. Despite their distinct expression patterns, many of the promoters for MMP genes show the same general arrangement of the nuclear proto-oncoprotein-binding sites, AP-1 and PEA3. However, the specific interaction between these cis-elements and different combinations of Fos, Jun, and Ets proteins which recognize these sites may be important in controlling both the positive and negative regulation involved in the tissue-restricted pattern of MMP expression in normal and neoplastic tissues.
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PMID:Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. 879 95

A weakly tumorigenic cell clone (QR-32) derived from a murine fibrosarcoma (BMT-11) grew lethally in 6 out of 10 syngeneic C57BL/6 mice after co-implantation with gelatin sponge. All six cell lines (QRsP) established from the arising tumors from QR-32 had enhanced tumorigenicity and/or pulmonary metastatic ability in vivo, indicating that those QRsP cell lines acquired progressed phenotypes as compared with those of QR-32 cells. In contrast, the frequency of tumor progression was suppressed to 50% (3/6) in the cell lines (QRsP/PSK) established from those arising in the mice treated with an immunopotentiating protein-bound polysaccharide, PSK. The enhanced metastatic ability was accompanied by enhanced expressions of a tumor-associated transcription factor, E1AF and by increased production of matrix metalloproteinase (MMP) in five lines of QRsP and two lines of QRsP/PSK. It was found that administration of PSK augmented the production of an antioxidative enzyme, manganese superoxide dismutase (Mn-SOD), in the tumor tissues co-implanted with gelatin sponge. PSK administration also brought about up-regulation of interferon-gamma (IFN-gamma)-expression and down-regulation of transforming growth factor-beta (TGF-beta)-expression in the tumor tissues, which were examined by RT-PCR on day 7, 14 and 21 after the co-implantation. Other inflammatory cytokines such as interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) were expressed equally both in PSK-treated and untreated tumor tissues. In vitro experiments proved that although IFN-gamma did not increase the production of Mn-SOD by itself, concomitant treatment with both IFN-gamma and TNF-alpha enhanced the Mn-SOD-production in QR-32 cells greatly. On the contrary, TGF-beta treatment lowered the Mn-SOD level in QR-32 cells. PSK-treatment did not induce Mn-SOD in cultured QR-32 cells directly. These results indicated that PSK inhibits the malignant progression of QR-32 cells promoted by co-implantation with gelatin sponge, most possibly through elevating the Mn-SOD level in QR-32 cells via modulation of the production of inflammatory cytokines, that is, increasing IFN-gamma and decreasing TGF-beta at the site of tumor growth.
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PMID:[Induction of manganese superoxide dismutase by an immunopotentiator as a mechanism of inhibiting of malignant progression of murine tumor cells]. 984 81

Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector inducing invasion and metastasis of tumor cells that express the Met tyrosine kinase receptor. One of the effectors of HGF/SF is the urokinase-type plasminogen activator, a serine protease that facilitates tumor progression and metastasis by controlling the synthesis of the extracellular matrix degrading plasmin. Stimulation of NIH 3T3 cells that were stably transfected with the human Met receptor (NIH 3T3-Methum) with HGF/SF induced a trans-activation of the urokinase promoter and urokinase secretion. Induction of the urokinase promoter by HGF/SF via the Met receptor was blocked by co-expression of a dominant-negative Grb2 and Sos1 expression construct. Further, the expression of the catalytically inactive mutants of Ha-Ras, RhoA, c-Raf, and Erk2 or addition of the Mek1-specific inhibitor PD 098059 abrogated the stimulation of the urokinase promoter by HGF/SF. A sequence residing between -2109 and -1870 base pairs (bp) was critical for stimulation of the urokinase gene by HGF/SF. Mobility shift assays with oligonucleotides spanning an AP-1 site at -1880 bp or a combined PEA3/AP-1 site at -1967 bp showed binding of nuclear factors from NIH 3T3-Methum cells. Expression of an expression plasmid that inhibits DNA binding of AP-1 proteins (A-Fos) abrogated inducible and basal activation of the urokinase promoter. Nuclear extract from unstimulated NIH 3T3-Methum cells contained more JunD and showed a stronger JunD supershift with the AP-1 oligonucleotides, compared with HGF/SF-stimulated cells. Consistent with the levels of JunD expression being functionally important for basal expression of the urokinase promoter, we found that overexpression of wild type JunD inhibited the induction of the urokinase promoter by HGF/SF. These data suggest that the induction of urokinase by HGF/SF is regulated by a Grb2/Sos1/Ha-Ras/c-Raf/RhoA/Mek1/Erk2/c-++ +Jun-dependent mitogen-activated protein kinase pathway.
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PMID:Activation mechanisms of the urokinase-type plasminogen activator promoter by hepatocyte growth factor/scatter factor. 1034 97

Cancer is a progressive disease in which a tumor cell temporally develops qualitatively new transformation related phenotypes or a further elaboration of existing transformation associated properties. Subtraction hybridization identified a novel gene associated with transformation progression in mutant adenovirus type 5, H5ts125, transformed rat embryo cells, progression elevated gene-3 (PEG-3). To define the mechanism by which expression of PEG-3 is enhanced as a function of cancer progression a 5'-flanking promoter region of approximately 2.0-kb, PEG-Prom, was isolated, cloned and characterized. The full-length and various mutated regions of the PEG-Prom were linked to a luciferase reporter construct and evaluated for promoter activity during cancer progression. These assays demonstrate a requirement for AP1 and PEA3 sites adjacent to the TATA box region of PEG-3 in mediating basal promoter activity and the enhanced expression of PEG-3 in progressed H5ts125-transformed rat embryo cells. An involvement of AP1 and PEA3 in PEG-3 regulation was also confirmed by electrophoretic mobility shift assays (EMSA) and transfection studies with cJun and PEA3 expression vectors. Our findings document the importance of both AP1 and PEA3 transcription factors in mediating basal and elevated expression of PEG-3 in H5ts125-transformed rat embryo cells displaying an aggressive and progressed cancer phenotype.
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PMID:Cooperation between AP1 and PEA3 sites within the progression elevated gene-3 (PEG-3) promoter regulate basal and differential expression of PEG-3 during progression of the oncogenic phenotype in transformed rat embryo cells. 1091 98

Transformation of normal cloned rat embryo fibroblast (CREF) cells with cellular oncogenes results in acquisition of anchorage-independent growth and oncogenic potential in nude mice. These cellular changes correlate with an induction in the expression of a cancer progression-promoting gene, progression elevated gene-3 (PEG-3). To define the mechanism of activation of PEG-3 as a function of transformation by the Ha-ras and v-raf oncogenes, evaluations of the signaling and transcriptional regulation of the approximately 2.0 kb promoter region of the PEG-3 gene, PEG-Prom, was undertaken. The full-length and various mutated regions of the PEG-Prom were linked to a luciferase reporter construct and tested for promoter activity in CREF and oncogene-transformed CREF cells. An analysis was also performed using CREF cells doubly transformed with Ha-ras and the Ha-ras specific suppressor gene Krev-1, which inhibits the transformed phenotype in vitro. These assays document an association between expression of the transcription regulator PEA3 and PEG-3. The levels of PEA3 and PEG-3 RNA and proteins are elevated in the oncogenically transformed CREF cells, and reduced in transformation and tumorigenic suppressed Ha-ras/Krev-1 doubly transformed CREF cells. Enhanced tumorigenic behavior, PEG-3 promoter function and PEG-3 expression in Ha-ras transformed cells were all dependent upon increased activity within the mitogen-activated protein kinase (MAPK) pathway. Electrophoretic mobility shift assays and DNase I footprinting experiments indicate that PEA3 binds to sites within the PEG-Prom in transformed rodent cells in an area adjacent to the TATA box in a MAPK-dependent fashion. These findings demonstrate an association between Ha-ras and v-raf transformation of CREF cells with elevated PEA3 and PEG-3 expression, and they implicate MAPK signaling via PEA3 as a signaling cascade involved in activation of the PEG-Prom.
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PMID:PEA3 sites within the progression elevated gene-3 (PEG-3) promoter and mitogen-activated protein kinase contribute to differential PEG-3 expression in Ha-ras and v-raf oncogene transformed rat embryo cells. 1129 38

Urokinase-type plasminogen activator (u-PA) contributes to tumor progression in prostate cancer (CaP). We have previously shown that u-PA expression is upregulated through the AP-1 and PEA3 sites and repressed by androgen. However, signaling pathways mediating u-PA gene expression in CaP are not delineated. We hypothesized that MAPK pathways mediate u-PA in CaP, and thereby studied specific ERK, JNK, and P38-MAPK pathway mutant constructs and inhibitors in vitro. Human, androgen insensitive CaP PC3 cells stably transfected with the androgen receptor expression vector and vector alone were used. A u-PA promoter CAT vector transiently expressed with dominant negative mutant signaling constructs was studied. All mutants drastically reduced u-PA promoter activity. Furthermore, inhibition of PI3K, an upstream regulator in the JNK/SAPK pathway, decreased u-PA promoter transcription. Collectively, these results show that MAPK pathways ERK, JNK/SAPK, and P38-MAPK represent a significant component in the regulation of u-PA expression in human CaP.
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PMID:Signal transduction-mediated regulation of urokinase gene expression in human prostate cancer. 1167 74

The events that mediate tumor progression in ovarian carcinoma are poorly understood to date. This review summarizes our results studying metastasis-associated molecules in advanced-stage ovarian carcinomas, details the co-expression of mRNA of these genes, and discusses their prognostic role. Fifty-five primary and metastatic FIGO stage III-IV ovarian carcinomas were analyzed for the expression of alpha v and beta1 integrin subunits, the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP, the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), PEA3 and Ets-1 using mRNA in situ hybridization. Tumor and adjacent stromal cell expression was scored. The association between integrin subunit expression and the expression of MMP, TIMP-2, angiogenic genes, PEA3 and Ets-1 was statistically analyzed. Alpha v integrin subunit mRNA expression in carcinoma cells showed significant association with that of MMP-2 and IL-8 in this cellular compartment, while the presence of beta1 integrin subunit mRNA showed similar association with that of PEA3, Ets-1, IL-8, bFGF and MMP-2. Expression of beta1 integrin subunit mRNA in stromal cells was associated with that of TIMP-2 and Ets-1 in this compartment. In addition, significant intercellular associations were found between alpha v integrin subunit mRNA expression in carcinoma cells and stromal cell expression of Ets-1, as well as between stromal cell expression of alpha v integrin subunit and labeling for IL-8 in carcinoma cells. The presence of beta1 integrin subunit mRNA in carcinoma cells showed a significant association with that of Ets-1, IL-8 and bFGF in stromal cells, while the presence of beta1 integrin subunit mRNA in stromal cells was associated with tumor PEA3 mRNA expression. To the best of our knowledge, this is the first evidence for coordinated autocrine and paracrine expression of members of these four families of metastasis-associated genes in human cancer. The results of this analysis support experimental data regarding cross-talk between carcinoma cells and peritumoral fibroblasts. They also suggest the existence of a putative activation sequence of metastatic genes, involving the beta1 (and possibly alpha v) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma.
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PMID:Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: a possible activation pathway? 1271 42

Expression of E1AF/PEA3 (ETV4), an ets family transcriptional factor, has been implicated in tumor progression through induction of matrix metalloproteinase (MMP) expression. The aim of this study was to examine E1AF mRNA expression and to determine whether it is correlated with progression of, and/or MMP expression in, human gastric cancer. Using the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we analyzed 100 gastric cancer tissues for E1AF mRNA expression. Expression of ER81 (ETV1) and ERM (ETV5), the other two members of the PEA3 subfamily, and Ets-1 and Ets-2 was also analyzed. The results were correlated with clinicopathological characteristics and MMP expression. Immunohistochemical analysis and an in vitro invasion assay were also performed. E1AF mRNA expression was detected in 64% of the 100 gastric cancer tissues, but was undetectable or only faintly detected in adjacent non-tumor tissues. E1AF expression was significantly correlated with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advance in pathological tumor-node-metastasis stage and recurrence. Patients with E1AF-positive tumors had significantly shorter overall and disease-free survival periods than did those with E1AF-negative tumors (P < 0.0001 and P < 0.0001, respectively). E1AF expression retained its significant predictive value for overall and disease-free survival in multivariate analysis that included conventional clinicopathological factors (P = 0.0082 and P = 0.0096, respectively). Among the MMPs analyzed, expression of matrilysin (MMP-7) was significantly correlated with E1AF expression. Immunohistochemical expression of E1AF was predominantly observed at the invasive front, where the expression of matrilysin was often co-localized. Antisense E1AF-transfected MKN45 gastric cancer cells expressed reduced levels of matrilysin and were less invasive in vitro than mock-transfected MKN45 cells. The results of this study suggest that E1AF, the expression of which is closely correlated with the expression of matrilysin, plays a key role in the progression of gastric cancer.
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PMID:Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer. 1460 92

Interfering with Ets transcription factor function reverses multiple aspects of the transformed phenotype of mouse or human tumor cells. However, the unknown number of individual Ets factors expressed in any cellular context and the similar DNA binding specificities of Ets family members complicates the identification of those that mediate transformation. By utilizing quantitative PCR assays for 25 mouse Ets factors, we analyzed the expression of essentially the entire Ets family in normal mammary tissue, mammary-related cell lines, and mammary tumors. In normal mammary tissue, 24 Ets factors were expressed. Even clonal derived cell lines expressed 14-20 Ets members. The most abundant Ets factor mRNAs measured in normal mammary tissue were Elk4, Elf1, and Ets2. Subtractive analysis of mammary tissue identified which Ets factors were predominantly expressed in the myeloid/lymphoid or epithelial cell compartments. Comparison of Ets factor expression in normal mammary tissue and mammary tumors identified significantly elevated expression of Pse/PDEF, Ese2/Elf5, Ese3/Ehf, TEL/Etv6, and Elf2/NERF in mammary tumors and confirmed previously reported alterations in expression of Ese1/Elf3 and the PEA3 subfamily. Expression of 13 Ets target genes, implicated in various aspects of tumor progression, was also analyzed. Altered expression of particular Ets target genes was significantly correlated with particular Ets factors (e.g. maspin and Ese2), suggesting specific in vivo regulatory roles. Together, this comprehensive analysis revealed unexpectedly diverse Ets family gene expression, characterized novel Ets factor changes in mammary tumors, and implicated specific Ets factors in the regulation of multiple genes involved in mammary tumor progression.
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PMID:Changes in the expression of many Ets family transcription factors and of potential target genes in normal mammary tissue and tumors. 1466 58


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