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

Osteopontin (OPN) is a multifunctional protein implicated in mammary development, neoplastic change, and metastasis. OPN is a target gene for beta-catenin-T cell factor signaling, which is commonly disturbed during mammary oncogenesis, but the understanding of OPN regulation is incomplete. Data base-assisted bioinformatic analysis of the OPN promoter region has revealed the presence of T cell factor-, Ets-, and AP-1-binding motifs. Here we report that beta-catenin, Lef-1, Ets transcription factors, and the AP-1 protein c-Jun each weakly enhanced luciferase expression from a OPN promoter-luciferase reporter construct, transiently transfected into a rat mammary cell line. OPN promoter responsiveness to beta-catenin and Lef-1, however, was considerably enhanced by Ets transcription factors including Ets-1, Ets-2, ERM, and particularly PEA3. PEA3 also enhanced promoter responsiveness to the AP-1 protein c-Jun. Co-transfection of cells with beta-catenin, Lef-1, PEA3, and c-Jun in combination increased luciferase expression by up to 280-fold and induced expression of endogenous rat OPN. In six human breast cell lines, those that highly expressed OPN also expressed PEA3 and Ets-1. Moreover, there was a significant association of immunocytochemical staining for OPN and one of beta-catenin, Ets-1, Ets-2, PEA3, or c-Jun, in the 29 human breast carcinomas tested. This study shows that beta-catenin/Lef-1, Ets, and AP-1 transcription factors can cooperate in a rat mammary cell line in stimulating transcription of OPN and that their independent presence is associated with that of OPN in a group of human breast cancers. These results suggest that the presence of these transcription factors in human breast cancer is responsible in part for the overexpression of OPN that, in turn, is implicated in mammary neoplastic progression and metastasis.
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PMID:Ets gene PEA3 cooperates with beta-catenin-Lef-1 and c-Jun in regulation of osteopontin transcription. 1499 May 65

Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular-signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P- cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P- cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention.
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PMID:Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation. 1506 52

Despite the fact that expression of Fas ligand (FasL) in cytotoxic T lymphocytes (CTLs) and in natural killer (NK) cells plays an important role in Fas-mediated tumor killing, During tumor progression FasL-expressing tumor cells are involved in counterattacking to kill tumor-infiltrating lymphocytes (TILs). Soluble FasL levels also increase with tumor progression in solid tumors, and this increase inhibits Fas-mediated tumor killing by CTLs and NK cells. The increased expression of FasL in tumor cells is associated with decreased expression of Fas; and the promoter region of the FASL gene is regulated by transcription factors, such as neuronal factor kappaB (NF-kappaB) and AP-1, in the tumor microenvironment. Although the ratio of FasL expression to Fas expression in tumor cells is not strongly related to the induction of apoptosis in TILs, increased expression of FasL is associated with decreased Fas levels in tumor cells that can escape immune surveillance and facilitate tumor progression and metastasis. Transforming growth factor beta (TGF-beta) is a potent growth inhibitor and has tumor-suppressing activity in the early phases of carcinogenesis. During subsequent tumor progression, the increased secretion of TGF-beta by both tumor cells and, in a paracrine fashion, stromal cells, is involved in the enhancement of tumor invasion and metastasis accompanied by immunosuppression. Herein, the authors review the clinical significance of FasL and TGF-beta expression patterns as features of immune privilege accompanying tumor progression in the tumor microenvironment. Potential strategies for identifying which molecules can serve as targets for effective antitumor therapy also are discussed.
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PMID:The role of Fas ligand and transforming growth factor beta in tumor progression: molecular mechanisms of immune privilege via Fas-mediated apoptosis and potential targets for cancer therapy. 1516 Mar 30

Cancer progression depends on an accumulation of metastasis-supporting cell signaling molecules, which target signal transduction pathways and, ultimately, gene expression. One such molecule, osteopontin (OPN), represents a key molecular signaling event in tumor progression and metastasis. However, the transcriptional regulatory mechanisms that underlie OPN expression in the setting of breast cancer have not been well studied. In this regard, we have examined the differential transcriptional regulation of OPN in the murine mammary epithelial tumor cell lines, 4T1 and 4T07, which are sublines derived from the parental population of 410.4 cells from Balb/cfC3H mice. These lines are phenotypically heterogeneous in their metastatic behavior. 4T1 hematogenously metastasizes to the lung, liver, bone, and brain, whereas 4T07 is highly tumorigenic but fails to metastasize. The tumor growth and metastatic spread of 4T1 cells closely mimics stage IV breast cancer. We demonstrate that a Ras-independent, phosphoinositide-3 kinase-dependent, c-Jun N-terminal kinase-dependent phosphorylation of c-Jun results in binding of an AP-1 c-Jun homodimer to the OPN promoter in 4T1 cells. This differential up-regulation of OPN gene transcription and protein expression in 4T1 cells conveys in vitro correlates of a metastatic phenotype. These results provide new insight into the transcriptional regulation of OPN as a key mediator of metastatic behavior in malignancy.
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PMID:Differential osteopontin expression in phenotypically distinct subclones of murine breast cancer cells mediates metastatic behavior. 1534 45

p21SNFT (21 kDa small nuclear factor isolated from T cells) is a human basic leucine zipper transcription factor that can repress AP-1-mediated transcription. We show here that overexpression of p21SNFT in HepG2 cells leads to repression of matrix metalloproteinase-1 by 70-80%. p21SNFT interacted with Jun at the matrix metalloproteinase-1 promoter -88 Ets/AP-1 enhancer element, where Jun is known to activate transcription via interaction with Fos and Ets proteins. When p21SNFT/Jun dimers bound the element in the presence of Ets, DNA was protected differently than when Fos was paired with Jun. The data suggest a difference in overall conformation between p21SNFT-containing and Fos-containing complexes that may be involved in the repression of matrix metalloproteinase-1 by p21SNFT. Overexpression of p21SNFT led to a reduction in invasiveness of HepG2 cells through type I collagen and reconstituted basement membrane, an effect similar to that obtained via direct immunodepletion of matrix metalloproteinase-1. The results indicate that the mechanism of repression of matrix metalloproteinase-1 by p21SNFT may be exploited in inhibiting pathological matrix remodeling during cancer progression in vivo.
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PMID:Transcriptional repression of MMP-1 by p21SNFT and reduced in vitro invasiveness of hepatocarcinoma cells. 1546 42

Thioredoxin (Trx) is a cellular redox enzyme that plays multiple roles in regulating cell growth and apoptosis. Jun activation domain-binding protein 1 (Jab1) was originally identified as a coactivator of activator protein 1 (AP-1) transcription and was also shown to promote degradation of the cyclin-dependent kinase inhibitor, p27Kip1. Recently, Jab1 expression was associated with the progression and poor prognosis of pituitary, epithelial ovarian, and breast cancers, suggesting that it plays a role in oncogenesis. Here, we report that Trx specifically interacts with and modulates the function of Jab1. Fluorescence resonance energy transfer and co-immunoprecipitation studies revealed that Trx and Jab1 colocalize and directly interact with each other. Further, Trx negatively regulates two important Jab1-controlled signaling pathways, activation of AP-1 transcription and degradation of p27Kip1, probably through a direct interaction between Trx and C-terminal of Jab1. The negative effect of Trx on AP-1 activity is Jab1-dependent, as it disappears when Jab1 levels are suppressed by an antisense approach. In addition, Trx competes with p27Kip1 for Jab1 binding. Taken together, our results suggest that Trx may regulate cell cycle and growth through a novel modulation of Jab1-mediated proliferation signals, further indicating that Trx may have the ability to control tumor progression.
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PMID:Thioredoxin modulates activator protein 1 (AP-1) activity and p27Kip1 degradation through direct interaction with Jab1. 1548 Apr 26

Exposure to cigarette smoke (CS) can lead to the development of lung cancer, but the molecular mechanisms underlying this process remain unclear. Given that activator protein 1 (AP-1) regulates genes involved in both physiologic and pathophysiologic processes, we have investigated the effects of CS on Jun and Fos family member expression and regulation using a nonmalignant human bronchial epithelial cell line, 1HAEo. Exposure to CS caused a marked upregulation of c-Jun, c-Fos, and Fra-1, but not of Fra-2, Jun-B, and Jun-D expression. Because Fra-1 is overexpressed in various tumors and upregulates genes associated with tumor progression, we further elucidated the mechanisms that control CS-stimulated fra-1 induction. CS stimulated fra-1 induction primarily at the transcriptional level. However, epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, completely suppressed CS-stimulated fra-1 expression. Similarly, the specific inhibitors of extracellular signal-regulated kinase (ERK), c-Jun NH2 terminal kinase (JNK), and p38 kinase signaling markedly suppressed fra-1 induction. Consistent with this finding, AG1478 blocked CS-stimulated ERK, JNK, and p38 phosphorylation. These results suggest that EGFR-activated multiple kinase signaling is essential for fra-1 induction. Furthermore, treatment of cells with GM6001, which inhibits matrix metalloproteinase activity, significantly suppressed CS-stimulated EGF shedding, EGFR and ERK kinase phosphorylation, and subsequent fra-1 induction. Collectively, our findings indicate an obligatory role for metalloproteinase-EGFR-mediated mitogen-activated protein kinase signaling in controlling CS-induced fra-1 expression.
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PMID:Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. 1552 91

Nerve growth factor and its high-affinity receptor TrkA are thought to be involved in the progression of various cancers. This study investigated the mechanism that regulates aberrant or increased TrkA expression in various cancer cell lines and in the course of pancreatic cancer progression. We found that the negative cis-acting AP-1-like sequence TGAGCGA was located in the 5'-untranslated region of the TrkA gene. Sodium bisulfite mapping revealed that steady-state TrkA expression correlated positively with the accumulation of methylated CpG around the AP-1-like site. Electrophoretic mobility shift assay showed that the AP-1-like site was bound mainly by c-Jun homodimers; the binding was directly blocked by Sss I methylase-induced methylation or by an excess of oligonucleotides containing consensus AP-1 sequences. Consequently, activation of TrkA gene expression by methylation was considered to be caused by the direct interference of c-Jun binding to the negatively regulating AP-1-like site. Furthermore, the accumulation of methylated CpG around the AP-1-like site was also observed with increased TrkA immunohistochemical staining in cases of advanced pancreatic adenocarcinoma with extensive perineural invasion. Unlike global methylation at CpG islands that leads to gene silencing, specific methylation at non-CpG islands would play a crucial epigenetic role in the versatility and plasticity of TrkA expression during cancer progression.
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PMID:Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression. 1587 Jun 92

We have previously developed an in vitro tumor progression model with mouse skin keratinocytes to study the molecular targets that mediate the tumor cell's progression from a benign to a malignant phenotype. The malignantly transformed cells were found to have elevated MAP kinase signaling and increases in AP-1, NFkappaB and cAMP response element (CRE) transcription factors activities compared to their benign counter-part. In this study, we showed that Rac1, a member of the Rho superfamily of small GTPases, functions as a key signaling molecule that mediates these malignant phenotypes. We used a doxycycline inducible system to express dominant negative Rac1 (N17 Rac1) in the squamous cell carcinomas producing 6M90 cell line. Conditional expression of the N17 Rac1 was able to decrease multiple markers of malignancy including: growth rate, colony formation, migration, invasion and most importantly, in vivo tumor growth. In addition, these phenotypic changes were accompanied by decreases in mitogenic signals, which include ERK1/2, JNK, and PI-3 kinase/Akt activation. Transactivation mediated by AP-1, NFkappaB, and CRE were also attenuated by expression of dominant negative Rac1. These observations led us to conclude that Rac1 signaling is required for the malignant phenotypes of the squamous cell carcinoma cells.
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PMID:The role of Rac1 in maintaining malignant phenotype of mouse skin tumor cells. 1589 75

We immunohistochemically examined 75 human colorectal neoplasms (adenoma, 27; adenocarcinoma, 24; neuroendocrine carcinoma, 24) for the expression of activator protein (AP)-1 family proteins. Nuclear and cytoplasmic expression levels of c-Jun and Fra-1 proteins were markedly elevated in adenomas, adenocarcinomas and neuroendocrine carcinomas compared with nonneoplastic colorectal epithelial cells. JunB also was overexpressed in these tumors but with a predominantly cytoplasmic staining pattern. Overexpression of Fra-2 was evident in carcinomas but less frequent in adenomas. Expression levels of JunD and c-Fos were high in nonneoplastic colorectal epithelial cells and remained so in neoplasms. FosB was undetectable in nonneoplastic and neoplastic colorectal tissues. Neuroendocrine carcinomas exhibited an AP-1 expression profile similar to adenocarcinomas except for infrequent overexpression of c-Jun in poorly differentiated variants. Hierarchical clustering separated the majority of malignant from benign tumors based on AP-1 expression patterns. AP-1 transcription factor family members are expressed differentially in nonneoplastic and neoplastic colorectal tissues. Up-regulation of c-Jun and Fra-1 is an early event in human colorectal tumorigenesis. Overexpression of Fra-2 may participate in tumor progression.
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PMID:Differential expression of the AP-1 transcription factor family members in human colorectal epithelial and neuroendocrine neoplasms. 1592 59


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