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)

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

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

The objective of the present investigation was to examine the spatio-temporal expression of three members of the ETS family of transcription factors, ERM, ER81, and PEA3, in the peri-implantation mouse uterus and in the ovary. These three factors belong to the PEA3 subfamily and are known to mediate diverse functions ranging from neuronal development to tumor progression. As transcription factors, they regulate the expression of a number of genes with various biological functions. Since several genes with known roles in the reproductive processes have been shown to be under the regulation of one of these factors, we sought to investigate the expression of ERM, ER81, and PEA3 in the mouse ovary and uterus. Quantitative RT-PCR analyses showed that ERM, ER81, and PEA3 were all expressed in the peri-implantation mouse uterus, with higher levels of expression on days 4 and 5 of pregnancy. To determine the cell type-specific expression of these factors, we employed in situ hybridization, the results of which revealed that ERM was expressed in both the epithelium and the stroma on days 4 and 5 of pregnancy. Uterine glands showed a high expression of ERM on those days. ERM was also highly expressed in the corpora lutea of the mouse ovary. Both ER81 and PEA3 were expressed at low levels in the stroma on days 4 and 5. On day 8, while ERM and PEA3 were mainly expressed in the embryo and were at low levels in the maternal decidua in a diffused pattern, ER81 was highly expressed in the vascular bed of the mesometrial deciduum. Both ER81 and PEA3 were undetectable in the mouse ovary. Collectively, these data show that ERM is implicated in the early event of implantation as well as in ovarian functions, while ER81 is involved in the establishment of the maternal vasculature for subsequent placental development. PEA3 is apparently an embryonic factor for early embryogenesis.
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PMID:Differential expression of the PEA3 subfamily of ETS transcription factors in the mouse ovary and peri-implantation uterus. 1585 28

Melanoma cells exhibit a high level of intrinsic or acquired resistance to the cytotoxic agents often associated with the over-expression of drug transporters such as P-glycoprotein (P-gp). In this in vitro study, we investigated the possible relationship between P-gp and CD44, the cell adhesion molecule involved in metastasis and tumor progression of melanoma cells. CD44 expression appeared to be similar in the parental sensitive M14 WT cells and in their resistant counterparts M14 ADR cells. Double-labeling of cryosectioned cells showed that P-gp and CD44 were transported from the synthesis loci to the cell periphery by different vesicles and began to coalesce in proximity of the plasma membrane; thus, P-gp and CD44 seemed to reach together the cell surface. Moreover, P-gp and CD44 appeared to be associated with ERM proteins. The invasive activities of both M14 WT and M14 ADR cells were analyzed by the "transwell chamber invasion" assay. M14 WT cells revealed low capacity to traverse the filters, both in the absence (motility) and in the presence (invasion) of a Matrigel coating. In comparison, M14 ADR cells displayed significantly higher motility and invasion. SEM observations showed that sensitive cells employed lamellar cytoplasmic extrusions to pass through the filter pores whereas resistant cells elongated along the hole through globular processes. In conclusion, the results herein reported suggest that drug resistance in melanoma cells appears associated with a more aggressive behaviour. P-gp and CD44 might cooperate to confer this more invasive phenotype.
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PMID:Invasive properties of multidrug resistant human melanoma cells. 1610 Oct 31

We have described recently the Ets family transcription factor, ERM/ETV5, specifically up-regulated in endometrioid endometrial carcinoma (EEC) and associated with myometrial infiltration. Ets family members have been correlated to tumor progression by up-regulating the expression of matrix-degrading proteases. In the present study, we investigated the possibility that in EEC, ERM/ETV5 may act by inducing the expression of genes involved in extracellular matrix remodeling. Unraveling the molecular events associated with the initiation of tumor invasion would represent an obvious improvement for EEC patients. The overexpression of ERM/ETV5 induced scattering in the endometrial cancer cell line Hec-1A, correlating to increased matrix metalloproteinase-2 (MMP-2) gelatinase activity. Both chromatin immunoprecipitation and reversion experiments with RNA interference and specific MMP-2 inhibitor showed a functional link between ERM/ETV5 overexpression and MMP-2 activation. The increased MMP-2 activity associated with overexpressed ERM/ETV5 in a mouse model conferred invasive capacity to endometrial tumors. Orthotopically implanted overexpressing ERM/ETV5 tumors presented a more aggressive and infiltrative pattern of myometrial invasion. Finally, the specific localization of ERM/ETV5 and MMP-2 at the invasive front of myometrial infiltrating human endometrial carcinomas further reinforced the hypothesis of a role for ERM/ETV5 in the early steps of endometrial dissemination. Taken together, these results lead us to propose that in EEC, ERM/ETV5 acts through MMP-2 gelatinolytic activity to confer invasive capabilities, associated with an initial switch to myometrial infiltration. They also postulate ERM/ETV5 as a valuable marker for patient stratification and a transcription pathway that should be evaluated for therapies specifically targeting the initial steps of EEC dissemination.
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PMID:ERM/ETV5 up-regulation plays a role during myometrial infiltration through matrix metalloproteinase-2 activation in endometrial cancer. 1763 86

Ezrin is a member of the ERM (ezrin, radixin, moesin) protein family and links F-actin to the cell membrane following phosphorylation. Ezrin has been associated with tumor progression and metastasis in several cancers including the pediatric solid tumors, osteosarcoma and rhabdomyosarcoma. In this study, we were surprised to find that ezrin was not constitutively phosphorylated but rather was dynamically regulated during metastatic progression in osteosarcoma. Metastatic osteosarcoma cells expressed phosphorylated ERM early after their arrival in the lung, and then late in progression, only at the invasive front of larger metastatic lesions. To pursue mechanisms for this regulation, we found that inhibitors of PKC (protein kinase C) blocked phosphorylation of ezrin, and that ezrin coimmunoprecipitated in cells with PKCalpha, PKCiota and PKCgamma. Furthermore, phosphorylated forms of ezrin and PKC had identical expression patterns at the invasive front of pulmonary metastatic lesions in murine and human patient samples. Finally, we showed that the promigratory effects of PKC were linked to ezrin phosphorylation. These data are the first to suggest a dynamic regulation of ezrin phosphorylation during metastasis and to connect the PKC family members with this regulation.
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PMID:The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC. 1906 Sep 19

Membrane-cytoskeleton linker organizer ezrin is a member of the ERM (ezrin-radixin-moesin) protein family. It has been suggested as an important element in the oncogenic process, particularly in conferring a metastatic ability on tumor cells. We hypothesized that the KIT oncogenic form is one of the proteins that modulates expression of the ezrin protein via phosphorylated ezrin at different residues; furthermore, it may interact with the protein merlin, and promoting tumor development via the PI3K or MAPK pathway. In the present study, we observed that differential expression of ezrin was a common feature in gastrointestinal stromal tumors (GISTs). We further demonstrated that cases exhibiting expression of phosphorylated Thr567 in the ezrin protein were associated with immunoactivities of KIT and merlin expression (p=0.039 and 0.013, respectively). In conclusion, GISTs harbor activation of KIT protein may induce phosphorylation of the downstream protein ezrin at certain residues, thereby triggering subsequent signal transduction cascades and driving downstream pathways of tumor progression. However, a larger series of tumor samples should be analyzed in future studies, as well as the identification of phosphorylated sites to determine the role of ezrin in tumor progression thus shedding light on clinical outcomes.
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PMID:Phosphorylated T567 ezrin is associated with merlin expression in KIT-mutant gastrointestinal stromal tumors. 2197 8

The cause of death for the vast majority of cancer patients is the development of metastases at sites distant from that of the primary tumor. For most pediatric sarcoma patients such as those with osteosarcoma (OS), despite successful management of the primary tumor through multimodality approaches, the development of metastases, commonly to the lungs, is the cause of death. Significant improvements in long-term outcome for these patients have not been seen in more than 30 years. Furthermore, the long-term outcome for patients who present with metastatic disease is grave [1-5]. New treatment options are needed.Opportunities to improve outcomes for patients who present with metastases and those at-risk for progression and metastasis require an improved understanding of cancer progression and metastasis. With this goal in mind we and others have identified ezrin as a metastasis-associated protein that associated with OS and other cancers. Ezrin is the prototypical ERM (Ezrin/Radixin/Moesin) protein family member. ERMs function as linker proteins connecting the actin cytoskeleton and the plasma membrane. Since our initial identification of ezrin in pediatric sarcoma, an increasing understanding the role of ezrin in metastasis has emerged. Briefly, ezrin appears to allow metastatic cells to overcome a number of stresses experienced during the metastatic cascade, most notably the stress experienced as cells interact with the microenvironment of the secondary site. Cells must rapidly adapt to this environment in order to survive. Evidence now suggests a connection between ezrin expression and a variety of mechanisms linked to this important cellular adaptation including the ability of metastatic cells to initiate the translation of new proteins and to allow the efficient generation of ATP through a variety of sources. This understanding of the role of ezrin in the biology of metastasis is now sufficient to consider ezrin as an important therapeutic target in osteosarcoma patients. This chapter reviews our understanding of ezrin and the related ERM proteins in normal tissues and physiology, summarizes the expression of ezrin in human cancers and associations with clinical parameters of disease progression, reviews reports that detail a biological understanding of ezrin's role in metastatic progression, and concludes with a rationale that may be considered to target ezrin and ezrin biology in osteosarcoma.
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PMID:Role of ezrin in osteosarcoma metastasis. 2492 75

The transcriptional factor Snail has been reported to possess properties related to cancer progression; however, the mechanism for it is not fully understood. Our data showed that Snail knockdown by small interfering RNA in two OSCC cell lines, WSU-HN6 and CAL27, significantly inhibited cell migration and invasion which also resulted in decreased cell motility, such as impaired cell spreading on type I collagen substrate, reduced filopodia, and premature assembly of stress fibers. In addition, Snail-silencing decreased Cdc42 activity but increased RhoA activity, accompanied by the downregulation in both p-ERM expression and cell motility. Meanwhile, endogenous p-ERM was found specifically co-precipitated with activated Cdc42, but not RhoA, and this co-association was decreased by Snail-silencing. The small molecule inhibitors of Rho-associated kinase (Y27632) markedly enhanced Cdc42 activity and the association of p-ERM with activated Cdc42, increasing cell motility remarkably. Using immunohistochemistry, Snail and p-ERM overexpressions were found in OSCC tissues correlated with nodal metastasis and shorter survival. Taken together, these results demonstrate that Snail regulates cell motility through RhoA/Cdc42/p-ERM pathway and may serve as a biomarker to predict prognosis for OSCC patients. Although RhoA and Cdc42 are concurrently regulated downstream of Snail, there is a direct interplay between them, which indicates RhoA has to be inactivated at some point in cell motility cycle.
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PMID:Snail regulates the motility of oral cancer cells via RhoA/Cdc42/p-ERM pathway. 2517 58

Radixin, a member of the ERM (ezrin-radixin-moesin) family, plays important roles in cell motility, invasion and tumor progression. It is expressed in a variety of normal and neoplastic cells, including many types of epithelial and lymphoid examples. However, its function in glioblastomas remains elusive. Thus, in this study, radixin gene expression was first examined in the glioblastoma cells, then suppressed with a lentivirus-mediated short-hairpin RNA (shRNA) method.We found that there were high levels of radixin expression in glioblastoma U251cells. Radixin shRNA caused down-regulation of radixin gene expression and when radixin-silenced cells were implanted into nude mice, tumor growth was significantly inhibited as compared to blank control cells or non- sense shRNA cells. In addition, microvessel density in the tumors was significantly reduced. Thrombospondin-1 (TSP-1) and E-cadherin were up-regulated in radixin- suppressed glioblastoma U251 cells. In contrast, MMP9 was down-regulated. Taken together, our findings suggest that radixin is involved in GBM cell migration and invasion, and implicate TSP-1, E-cadherin and MMP9 as metastasis-inducing factors.
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PMID:Radixin knockdown by RNA interference suppresses human glioblastoma cell growth in vitro and in vivo. 2552 Jan 9


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