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1.
Pituitary tumors are commonly encountered, and result from clonal expansion of a single mutated cell. Hypothalamic hormones, local growth factors and circulating sex steroid hormones promote pituitary tumor growth and expansion into large invasive tumors. Estrogen acting directly through its receptor and by stimulation of fibroblast growth factor regulates prolactin synthesis and secretion. Fibroblast growth factor-2 (bFGF) modulates angiogenesis, tumor formation and progression in many tissues, including the anterior pituitary. A pituitary tumor-derived transforming gene (PTTG) has been isolated, which is tumorigenic in vivo, regulates bFGF secretion, and inhibits chromatid separation. The human PTTG family consists of at least three homologous genes, of which PTTG1 is located on chromosome 5q33 and is expressed at low levels in most normal human tissues but is highly expressed in malignant human cell lines and in pituitary tumors. We report here that pituitary pttg is regulated in vivo and in vitro by estrogen. Maximal induction of rat pituitary pttg mRNA in vivo occurred early in pituitary transformation (normal cell to hypertrophic/hyperplastic cell), coincident with bFGF and vascular endothelial growth factor induction and pituitary angiogenesis. We also demonstrate that pttg expression is induced by bFGF, and show concordant pttg and bFGF expression in experimental and human pituitary adenomas. As bFGF and estrogen both induce pttg, and pttg expression coincides with the early lactotrophic hyperplastic response, angiogenesis and prolactinoma development, we propose a previously unknown paracrine growth factor-mediated mechanism for pituitary tumor pathogenesis and potentially other estrogen-regulated tumors.  相似文献   

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Osteosarcoma is the most common primary tumor of the bone. It leads to many deaths because of its rapid proliferation and metastasis. Recent studies have shown that microRNAs are important gene regulators that are involved in various cancer-related processes. In this study, we found that miR-135b was down-regulated in both osteoscarcoma patient tumor tissues and osteoscarcoma cell lines in comparison to paired adjacent non-tumor bone tissue. We observed that a lower level of miR-135b was associated with metastasis. The ectopic expression of miR-135b markedly suppressed osteoscarcoma cell proliferation, migration, and invasion. Conversely, the inhibition of miR-135b expression dramatically accelerated cell proliferation, migration, and invasion. The forced expression of miR-135b in osteosarcoma cells resulted in a significant reduction in the protein level of c-Myc and repressed the activity of a luciferase reporter that contained the 3′-untranslated region of the c-Myc mRNA. These effects were abolished by the mutation of the predicted miR-135b-binding site, which indicates that c-Myc may be a miR-135b target gene. Moreover, the ectopic expression of c-Myc partially reversed the inhibition of cell proliferation and invasion that was caused by miR-135b. These data therefore suggest that miR-135b may function as a tumor suppressor to regulate osteosarcoma cell proliferation and invasion through a mechanism that targets the c-Myc oncogene. These findings indicate that miR-135b may play a role in the pathogenesis of osteosarcoma.  相似文献   

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Cyclin-dependent kinase inhibitor 3 (CDKN3) belongs to the protein phosphatases family and has a dual function in cell cycling. The function of this gene has been studied in several kinds of cancers, but its role in human hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we found that CDKN3 was frequently overexpressed in both HCC cell lines and clinical samples, and this overexpression was correlated with poor tumor differentiation and advanced tumor stage. Functional studies showed that overexpression of CDKN3 could promote cell proliferation by stimulating G1-S transition but has no impact on cell apoptosis and invasion. Microarray-based co-expression analysis identified a total of 61 genes co-expressed with CDKN3, with most of them involved in cell proliferation, and BIRC5 was located at the center of CDKN3 co-expression network. These results suggest that CDKN3 acts as an oncogene in human hepatocellular carcinoma and antagonism of CDKN3 may be of interest for the treatment of HCC.  相似文献   

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K Weston  J M Bishop 《Cell》1989,58(1):85-93
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Although functional roles have been assigned to many genes, e.g. those involved in cell-cycle regulation, growth signaling, or cancer, considerably less is known about the quantitative relationship between gene expression levels and outcome. We devised an intra-population competition to study oncogene dosage. Cell populations were engineered to express a range of H-Ras oncogene levels. Cells with different levels of H-Ras then “competed” for an increased share of the total cell population. Using flow cytometry to track the population composition over time, we determined the relationship between the different H-Ras oncogene expression levels and the net proliferation rate. Under culture conditions in which wild-type Ras activation was suppressed, we found that increased and maximal net proliferation occurred when the H-Ras G12V oncogene was expressed at a level 1.2-fold that of wild-type Ras. As the H-Ras G12V expression levels increased above this optimal level, proliferation rates decreased. Our findings suggest that the tumor evolution process may optimize gene expression levels for maximal cell proliferation. In principle, engineered intra-population competitions can be used to determine proliferation rates associated with the level of any ectopically expressed gene. The approach also may be used to determine proliferation rates associated with different cell species in a heterogeneous population or to improve the proliferation rate of a cell line. We also envision that the tracking of intra-population competitions could be utilized to investigate the evolution of tumors in the body.  相似文献   

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Background  

Ablation of an oncogene or of the activity of the protein it encodes can result in apoptosis and/or inhibit tumor cell proliferation. Therefore, if the oncogene or set of oncogenes contributing maximally to a tumor cell's survival can be identified, such oncogene(s) are the most appropriate target(s) for maximizing tumor cell kill.  相似文献   

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目的研究RNA干扰人pttg表达对肺癌SPC-A-1细胞恶性表型的影响。方法构建针对人pttg的RNA干扰真核表达载体,运用脂质体介导转染SPC-A-1细胞并用G418筛选出阳性克隆株;半定量PCR和Western blot检测转染后PTTG mRNA及蛋白的表达水平;人工计数法检测阳性克隆株SPC-A-1细胞染色体倍性的变化;氚-胸腺嘧啶核苷掺入法观察抑制人pttg表达后SPC-A-1细胞增殖能力的改变;TUNEL法检测细胞凋亡的变化情况。结果成功构建针对人pttg基因的RNA干扰真核表达载体(命名为Si-hPTTG),转染后筛选获得人pttg下调表达的SPC-A-1细胞株;Si-hPTTG转染使SPC-A-1细胞PTTG mRNA和蛋白的表达较未转染组和阴性对照质粒组均显著下调;Si-hPTTG转染后SPC-A-1细胞染色体众数和平均数增加,3H掺入量显著降低,细胞凋亡明显增加。结论人pttg下调表达可增加SPC-A-1细胞染色体众数和平均数,伴有减轻染色体结构畸变的趋势;显著抑制SPC-A-1细胞增殖,增加细胞凋亡。人pttg可能是肺癌治疗的新靶点。  相似文献   

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Background

Syndecans are proteoglycans whose core proteins have a short cytoplasmic domain, a transmembrane domain and a large N-terminal extracellular domain possessing glycosaminoglycan chains. Syndecans are involved in many important cellular processes. Our recent publications have demonstrated that syndecan-1 translocates into the nucleus and hampers tumor cell proliferation. In the present study, we aimed to investigate the role of syndecan-1 in tumor cell adhesion and migration, with special focus on the importance of its distinct protein domains, to better understand the structure-function relationship of syndecan-1 in tumor progression.

Methodology/Principal Findings

We utilized two mesenchymal tumor cell lines which were transfected to stably overexpress full-length syndecan-1 or truncated variants: the 78 which lacks the extracellular domain except the DRKE sequence proposed to be essential for oligomerization, the 77 which lacks the whole extracellular domain, and the RMKKK which serves as a nuclear localization signal. The deletion of the RMKKK motif from full-length syndecan-1 abolished the nuclear translocation of this proteoglycan. Various bioassays for cell adhesion, chemotaxis, random movement and wound healing were studied. Furthermore, we performed gene microarray to analyze the global gene expression pattern influenced by syndecan-1. Both full-length and truncated syndecan-1 constructs decrease tumor cell migration and motility, and affect cell adhesion. Distinct protein domains have differential effects, the extracellular domain is more important for promoting cell adhesion, while the transmembrane and cytoplasmic domains are sufficient for inhibition of cell migration. Cell behavior seems to depend also on the nuclear translocation of syndecan-1. Many genes are differentially regulated by syndecan-1 and a number of genes are actually involved in cell adhesion and migration.

Conclusions/Significance

Our results demonstrate that syndecan-1 regulates mesenchymal tumor cell adhesion and migration, and different domains have differential effects. Our study provides new insights into better understanding of the role of syndecans in tumor progression.  相似文献   

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Microarrays are at the center of a revolution in biotechnology, allowing researchers to screen tens of thousands of genes simultaneously. Typically, they have been used in exploratory research to help formulate hypotheses. In most cases, this phase is followed by a more focused, hypothesis-driven stage in which certain specific biological processes and pathways are thought to be involved. Since a single biological process can still involve hundreds of genes, microarrays are still the preferred approach as proven by the availability of focused arrays from several manufacturers. Because focused arrays from different manufacturers use different sets of genes, each array will represent any given regulatory pathway to a different extent. We argue that a functional analysis of the arrays available should be the most important criterion used in the array selection. We developed Onto-Compare as a database that can provide this functionality, based on the Gene Ontology Consortium nomenclature. We used this tool to compare several arrays focused on apoptosis, oncogenes, and tumor suppressors. We considered arrays from BD Biosciences Clontech, PerkinElmer, Sigma-Genosys, and SuperArray. We showed that among the oncogene arrays, the PerkinElmer MICROMAX oncogene microarray has a better representation of oncogenesis, protein phosphorylation, and negative control of cell proliferation. The comparison of the apoptosis arrays showed that most apoptosis-related biological processes are equally well represented on the arrays considered. However, functional categories such as immune response, cell-cell signaling, cell-surface receptor linked signal transduction, and interleukins are better represented on the Sigma-Genoys Panorama human apoptosis array. At the same time, processes such as cell cycle control, oncogenesis, and negative control of cell proliferation are better represented on the BD Biosciences Clontech Atlas Select human apoptosis array.  相似文献   

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Human securin, also known as human pituitary tumor-transforming gene 1 (pttg1), plays a key role in cell-cycle regulation. Two homologous genes, pttg2 and pttg3, have been identified although very little is known about their physiological function. In this study, we aimed at the characterization of these two pttg1 homologs. Real-time PCR analysis using specific probes demonstrated that Pttg2 is expressed at very low levels in various cell lines and tissues whereas Pttg3 was largely undetectable. We focused on the study of Pttg2 and found that, unlike PTTG1, PTTG2 lacks transactivation activity and does not bind to separase, making improbable a role in the control of sister chromatids separation. To further investigate the biological role of pttg2, we used short hairpin RNA inhibition of Pttg2 and found that cells with reduced Pttg2 levels assumed a rounded morphology compatible with a defect in cell adhesion and died by apoptosis in a p53- and p21-dependent manner. Using microarray technology, we generated a gene expression profile of Pttg2-depleted cells versus wild-type cells and found that knockdown of PTTG2 results in concomitant downregulation of E-cadherin and elevated vimentin levels, consistent with EMT induction. The observation of aberrant cellular behaviors in Pttg2-silenced cells reveals functions for pttg2 in cell adhesion and provides insights into a potential role in cell invasion.  相似文献   

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The Drosophila expanded (ex) gene encodes a protein thought to play a role in signaling at apical junctions of epithelial cells. Previous studies have characterized this gene as a tumor suppressor involved in regulating the growth of a subset of Drosophila imaginal discs (Boedigheimer, M., Laughon, A., 1993. expanded: a gene involved in the control of cell proliferation in imaginal discs, Development 118, 1291-1301); although ex negatively regulates cell proliferation in the developing wing, it appeared to have a conflicting role in the eye. In contrast, our analysis of the loss-of-function phenotype indicates that ex does, in fact, regulate growth in the eye. We also show that this gene plays a role in patterning of the eye, mainly at the level of planar polarity. Our studies further demonstrate that, contrary to what was expected based on loss-of-function data, the tissue reduction phenotypes resulting from Ex overexpression are attributable to the induction of apoptotic cell death. Taken together, our data suggest that Ex is a versatile molecule that plays a role in most of the processes that govern disc development.  相似文献   

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Amplification of N-myc oncogene is a frequent event in advanced stages of human neuroblastoma and correlates with poor prognosis and enhanced neovascularization. Angiogenesis is an indispensable prerequisite for the progression and metastasis of solid malignancies, which is modulated by tumor suppressors and oncogenes. We have addressed the possibility that N-myc oncogene might regulate angiogenesis in neuroblastoma. Here, we report that experimental N-Myc overexpression results in down-regulation of leukemia inhibitory factor (LIF), a modulator of endothelial cell proliferation. Reporter assays using the LIF promoter and a series of N-Myc mutants clearly demonstrated that down-regulation of the LIF promoter was independent of Myc/Max interaction and required a contiguous N-terminal N-Myc domain. STAT3, a downstream signal transducer, was essential for LIF activity as infection with adenoviruses expressing a phosphorylation-deficient STAT3 mutant rendered endothelial cells insensitive to the antiproliferative action of LIF. LIF did not influence neuroblastoma cell proliferation suggesting that, at least in the context of neuroblastoma, LIF is involved in paracrine rather than autocrine interactions. Our data shed light on the mechanisms by which N-myc oncogene amplification enhances the malignant phenotype in neuroblastoma.  相似文献   

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