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)

Many mitogens and human oncogenes activate extracellular regulated kinases (ERKs), which in turn convey proliferation signals. ERKs or mitogen-activated protein (MAP) kinases are inactivated in vitro by MAP kinase phosphatases (MKPs). The gene encoding one of these MKPs, MKP-1, is a serum-inducible gene and is transcriptionally activated by mitogenic signals in cultured cells. As MKP-1 has been shown to block DNA synthesis by inhibiting ERKs when expressed at elevated levels in cultured cells, it has been suggested that it may act as a tumor suppressor. MKP-1 mRNA and MAP kinase (ERK-1 and -2) protein expression was assessed in 164 human epithelial tumors of diverse tissue origin by in situ hybridization and immunohistochemistry. MKP-1 was overexpressed in the early phases of prostate, colon, and bladder carcinogenesis, with progressive loss of expression with higher histological grade and in metastases. In contrast, breast carcinomas showed significant MKP-1 expression even when poorly differentiated or in late stages of the disease. MKP-1, ERK-1, and ERK-2 were co-expressed in most tumors examined. In a subset of 15 tumors, ERK-1 enzymatic activity as well as structural alterations that might be responsible for loss of function of MKP-1 during tumor progression, were examined. ERK-1 enzymatic activity was found to be elevated despite MKP-1 overexpression. No loss of 5q35-ter (containing the MKP-1 locus) was detected by polymerase chain reaction in metastases compared with primary tumors. Finally, no mutations were found in the catalytic domain of MKP-1. These data indicate that MKP-1 is an early marker for a wide range of human epithelial tumors and suggest that MKP-1 does not behave as a tumor suppressor in epithelial tumors.
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PMID:Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. 890 45

CD44 has been implicated in tumor progression and metastasis, but the mechanism(s) involved is as yet poorly understood. Recent studies have shown that CD44 isoforms containing the alternatively spliced exon v3 carry heparan sulfate side chains and are able to bind heparin-binding growth factors. In the present study, we have explored the possibility of a physical and functional interaction between CD44 and hepatocyte growth factor/scatter factor (HGF/SF), the ligand of the receptor tyrosine kinase c-Met. The HGF/SF-c-Met pathway mediates cell growth and motility and has been implicated in tumor invasion and metastasis. We demonstrate that a CD44v3 splice variant efficiently binds HGF/SF via its heparan sulfate side chain. To address the functional relevance of this interaction, Namalwa Burkitt's lymphoma cells were stably co-transfected with c-Met and either CD44v3 or the isoform CD44s, which lacks heparan sulfate. We show that, as compared with CD44s, CD44v3 promotes: (i) HGF/SF-induced phosphorylation of c-Met, (ii) phosphorylation of several downstream proteins, and (iii) activation of the MAP kinases ERK1 and -2. By heparitinase treatment and the use of a mutant HGF/SF with greatly decreased affinity for heparan sulfate, we show that the enhancement of c-Met signal transduction induced by CD44v3 was critically dependent on heparan sulfate moieties. Our results identify heparan sulfate-modified CD44 (CD44-HS) as a functional co-receptor for HGF/SF which promotes signaling through the receptor tyrosine kinase c-Met, presumably by concentrating and presenting HGF/SF. As both CD44-HS and c-Met are overexpressed on several types of tumors, we propose that the observed functional collaboration might be instrumental in promoting tumor growth and metastasis.
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PMID:Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met. 1003 43

Tumor necrosis factor-alpha (TNF alpha) can function as both an autocrine and a paracrine growth factor and may therefore play a role in ovarian tumor progression. TNF alpha initiates multiple cellular responses, many of which are mediated through the mitogen-activated protein kinase pathways, which transduce signals from the TNF alpha receptors through the cytoplasm to the nucleus, resulting in regulation of gene expression. We examined the role of c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinase (ERK) 1 and 2 in the cellular growth response to TNF alpha in the ovarian carcinoma cell line UCI 101. JNK1 activity was increased to a maximum level ninefold above the basal level after 10-20 min of treatment with 10 ng/mL TNF alpha. A maximum threefold induction of ERK1/2 activity was observed after 1 min of treatment. At concentrations up to 100 ng/mL, TNF alpha had neither a stimulatory nor an inhibitory effect on growth of UCI 101 cells. However, inhibition of TNF alpha-induced ERK1/2 activity by the MAP/ERK kinase 1 inhibitor PD 98059 resulted in 60% inhibition of cell growth in TNF alpha-treated UCI 101 cells. This decrease in cell growth was accompanied by apoptosis, as demonstrated by the presence of a 180-bp DNA ladder. Thus, the inhibition of TNF alpha-induced ERK1/2 activity was associated with induction of apoptosis in the TNF alpha-resistant cell line UCI 101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a subsequent transient increase in TNF alpha-induced JNK1 activity. The significance of this increase with respect to apoptosis induction remains to be determined. These findings demonstrated that ERK1/2 activity can modulate cellular sensitivity to TNF alpha and suggested that the balance between the levels of ERK1/2 and JNK1 activation may be critical in the cellular growth response to TNF alpha.
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PMID:Association of apoptosis with the inhibition of extracellular signal-regulated protein kinase activity in the tumor necrosis factor alpha-resistant ovarian carcinoma cell line UCI 101. 1033 40

We previously showed that enhanced expression of MMP-9, an endopeptidase that digests basement-membrane type IV collagen, is related to tumor progression in vitro and in vivo; antisense-MMP-9 stably transfected clones were less invasive than untransfected parental cells and did not form tumors in nude mice. In this study, we examined the role of ERK-1 in the regulation of MMP-9 production and the invasive behavior of the human glioblastoma cell line SNB19, in which ERK1 is constitutively activated. SNB19 cells were stably transfected with mt-ERK, a vector encoding ERK-1 cDNA in which the conserved lysine at codon 71 was changed to arginine, thus impairing the catalytic efficiency of this enzyme. Gelatin zymography showed reduced levels of MMP-9 in the mt-ERK-transfected cell lines relative to those in vector-transfected and parental control cells. Reductions in MMP-9 protein mRNA levels were also detected in the mt-ERK-transfected cells by Western and Northern blotting. The mt-ERK-transfected cells were much less invasive than parental or vector control cells in a Matrigel invasion assay and in a spheroid coculture assay. Thus an ERK-dependent signaling pathway seems to regulate MMP-9 mediated glioma invasion in SNB19 cells; interfering with this pathway could be developed into a therapeutic approach, which aims at a reduction of cancer cell invasion.
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PMID:Downregulation of MMP-9 in ERK-mutated stable transfectants inhibits glioma invasion in vitro. 1216 59

Lung cancer is currently the most frequent cause of cancer death in North America. Hepatocyte growth factor (HGF) and its receptor Met are frequently over-expressed in non-small-cell lung carcinomas (NSCLC), but their potential role in tumor progression is not clearly known. To assess the role of HGF/Met signaling in lung carcinomas, we have examined the expression, activation status, and function of Met in NSCLC cell lines (n = 7), established from primary tumors or pleural fluids of cancer patients. We observed Met expression in three NSCLC cell lines, two of which exhibited constitutive tyrosine-phosphorylation of Met, and Met kinase activity. In addition, the observed constitutive activation of Met was sustained under anchorage-independent conditions, and correlated with phosphatidyl inositol 3-kinase-dependent cell survival. Immunoreactive HGF-like protein was secreted by two Met-positive and two Met-negative NSCLC cell lines. However HGF activity, as determined by the ability to induce cell scattering and tyrosine-phosphorylation of Met in reporter cell lines, was detected in conditioned medium from only one Met-negative NSCLC cell line: none of the conditioned media from Met-expressing NSCLC cell lines showed detectable HGF activity. Thus, constitutive activation of Met in NSCLC cell lines may occur at least in part through intracrine, or HGF-independent mechanisms. Interestingly, additional paracrine stimulation with exogenous recombinant HGF was required for DNA synthesis and correlated with increased activation of ERK1/2 in all Met-positive NSCLC cell lines, regardless of the basal activation status of Met. These findings indicate that a medium level of constitutive activation of Met occurs in some NSCLC cell lines, and correlates with survival of detached carcinoma cells; whereas additional paracrine stimulation by recombinant HGF is required for DNA synthesis. Thus constitutive and paracrine activation of Met may provide complementary signals that promote survival and proliferation, respectively, during tumor progression of NSCLC.
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PMID:Constitutive activation of met kinase in non-small-cell lung carcinomas correlates with anchorage-independent cell survival. 1221 Jul 33

We have investigated mechanisms of mitochondrial stress-induced phenotypic changes and cell invasion in tumorigenic but poorly invasive human pulmonary carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA). Depletion of mtDNA (genetic stress) caused a markedly lower electron transport-coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of steady state [Ca(2+)](c), and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFbeta1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-X(L) were increased, and the cellular levels of pro-apoptotic proteins Bid and Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress) exhibited higher invasive behavior than control cells in a Matrigel basement membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense cathepsin L RNA, TGFbeta1 RNA, or treated with specific inhibitors showed reduced invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein levels, cell morphology and invasive property closer to control cells. Our results suggest that the mitochondria-to-nucleus signaling pathway operating through increased [Ca(2+)](c) plays an important role in cancer progression and metastasis.
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PMID:Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. 1242 Feb 21

Because of similarities in histopathology and tumor progression stages between mouse and human lung adenocarcinomas, the mouse lung tumor model with lung adenomas as the endpoint has been used extensively to evaluate the efficacy of putative lung cancer chemopreventive agents. In this study, a competitive cDNA library screening (CCLS) was employed to determine changes in the expression of mRNA in chemically induced lung adenomas compared with paired normal lung tissues. A total of 2555 clones having altered expression in tumors were observed following competitive hybridization between normal lung and lung adenomas after primary screening of over 160,000 clones from a mouse lung cDNA library. Among the 755 clones confirmed by dot blot hybridization, 240 clones were underexpressed, whereas 515 clones were overexpressed in tumors. Sixty-five clones with the most frequently altered expression in six individual tumors were confirmed by semiquantitative RT-PCR. When examining the 58 known genes, 39 clones had increased expression and 19 had decreased expression, whereas the 7 novel genes showed overexpression. A high percentage (>60%) of overexpressed or underexpressed genes was observed in at least two or three of the lesions. Reproducibly overexpressed genes included ERK-1, JAK-1, surfactant proteins A, B, and C, NFAT1, alpha-1 protease inhibitor, helix-loop-helix ubiquitous kinase (CHUK), alpha-adaptin, alpha-1 PI2, thioether S-methyltransferase, and CYP2C40. Reproducibly underexpressed genes included paroxanase, ALDH II, CC10, von Ebner salivary gland protein, and alpha- and beta-globin. In addition, CCLS identified several novel genes or genes not previously associated with lung carcinogenesis, including a hypothetical protein (FLJ11240) and a guanine nucleotide exchange factor homologue. This study shows the efficacy of this methodology for identifying genes with altered expression. These genes may prove to be helpful in our understanding of the genetic basis of lung carcinogenesis and in developing biomarkers for lung cancer chemoprevention studies in mice.
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PMID:Differential gene expression in chemically induced mouse lung adenomas. 1265 69

Interleukin (IL)-8 serves as a major chemoattractant for neutrophils and has also been proposed to affect cancer progression. In the present study, we show that IGF-I stimulates IL-8 mRNA expression and IL-8 secretion in the leukemic cell line HL-60. Stimulation of IL-8 expression was completely attenuated by two inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK), which phosphorylates the MAPKs extracellular-regulated kinase (ERK)1 and ERK2, and by the c-Jun NH2-terminal kinase (JNK) inhibitor SP600125. In contrast, inhibitors of p38 MAPK and phosphatidylinositol-3 kinase (PI3K) did not abrogate the effect of IGF-I. We also show that IGF-I stimulates the activation of ERK1 and ERK2, but we could not detect any effect of IGF-I on the phosphorylation of p38, JNK(p46) or JNK(p54). Collectively, our results suggest that basal JNK activity and activation of the MEK-ERK pathway are required for upregulation of IL-8 by IGF-I in HL-60 cells.
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PMID:IGF-I stimulates IL-8 production in the promyelocytic cell line HL-60 through activation of extracellular signal-regulated protein kinase. 1457 64

Ultraviolet radiation may cause non-melanoma skin cancer by genetic and epigenetic events. In this study, we investigated in a squamous cell carcinoma cell line, SCL-1, whether UV irradiation modulates the expression of matrix metalloproteinases, known to be involved in tumor progression and metastasis by degradation of extracellular matrix components. UVA or UVB irradiation of SCL-1 resulted in a rapid transcriptional up-regulation and increased secretion of two members of the matrix metalloproteinase family, MMP-10 (stromelysin-2) and MMP-1 (interstitial collagenase). The increase in MMP-10 steady-state mRNA levels was detected 1 hour after UVA and 4 h after UVB irradiation, whereas MMP-1 was upregulated 4 h after UVA and 16 h after UVB irradiation of tumor cells. UV-induced phosphorylation of extracellular regulated kinases (ERK-1/2) and p38 stress kinase and increased binding of AP-1 transcription factor preceded the rapid stimulation of MMPs in SCL-1 cells. Incubation of cells with the MEK1/2 inhibitor U0126 or the p38 inhibitor SB202190 abolished the UVA and UVB mediated induction of MMP-1 and MMP-10. In conclusion, this study shows that UV irradiation of squamous cell carcinoma results in a rapid up-regulation of MMPs. Our results suggest that the time course of induction of target genes, like MMPs, differs between cell types depending on the stimulus.
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PMID:Induction of MMP-10 and MMP-1 in a squamous cell carcinoma cell line by ultraviolet radiation. 1497 49

We used an experimental in vitro model of human ovarian surface epithelium (OSE), the tissue of origin of >90% of ovarian cancers, to more precisely define the contribution of hepatocyte growth factor (HGF) to various OSE phenotypes at different stages of neoplastic progression. Neoplastic transformation of OSE in cultures was achieved by multiple genetic manipulations, resulting in the nontumorigenic line IOSE-29, the tumorigenic IOSE-Ov29, and the tumor-derived, more highly malignant IOSE-Ov29/T4. We demonstrate here that, compared to IOSE-29, IOSE-Ov29 and IOSE-Ov29/T4 exhibited higher levels of the HGF receptor Met and an increasing duration of ERK1/2 activation with malignant progression, in conjunction with other neoplastic properties. HGF activated Met signaling in all lines but elicited different responses: HGF induced cell dispersion (scattering) and collagen gel invasion in IOSE-Ov29 and IOSE-Ov29/T4 but did not alter the growth pattern of IOSE-29. Inhibition with PD98059 and LY294002 independently prevented HGF-induced invasive growth. Furthermore, our results show that HGF-induced invasion can be mediated through a rapamycin-sensitive p70 S6K cascade, which demonstrates that p70S6K can regulate cell motility in addition to its well-established role in protein synthesis. Taken together, our data correlate specific responses to HGF-mediated signaling with specific signaling pathways and with progressive neoplastic changes.
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PMID:Progressive changes in Met-dependent signaling in a human ovarian surface epithelial model of malignant transformation. 1530 91


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