bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell Adhesion Regulates CDC25A Expression and Proliferation in Acute Myeloid Leukemia
Authors: Fernandez-Vidal Anne , Ysebaert Loïc , Didier Christine , Betous Remy , De Toni Fabienne , Prade-Houdellier Naïs , Demur Cécile , Contour-Galcéra Marie-Odile , Prévost Grégoire P. , Ducommun Bernard , Payrastre Bernard , Racaud-Sultan Claire , Manenti Stéphane 
Published: July 2006

AbstractThe effects of cell adhesion on leukemia cell proliferation remain poorly documented and somehow controversial. In this work, we investigated the effect of adhesion to fibronectin on the proliferation of acute myeloid leukemia (AML) cell lines (U937 and KG1a) and CD34+ normal or leukemic primary cells. We observed an increased rate of proliferation of AML cells when adhered to fibronectin, concomitant with accelerated S-phase entry and accumulation of CDC25A. Conversely, normal CD34+ cell proliferation was decreased by adhesion to fibronectin with a concomitant drop in CDC25A expression. Importantly, we showed that both small interfering RNA (siRNA)–mediated CDC25A down-regulation and a recently developed CDC25 pharmacologic inhibitor impaired this adhesion-dependent proliferation, establishing a functional link between CDC25A accumulation and adhesion-dependent proliferation in leukemic cells. CDC25A accumulation was found only slightly dependent on transcriptional regulation and essentially due to modifications of the proteasomal degradation of the protein as shown using proteasome inhibitors and reverse transcription-PCR. Interestingly, CDC25A regulation was Chk1 dependent in these cells as suggested by siRNA-mediated down-regulation of this protein. Finally, we identified activation of the phosphatidylinositol 3-kinase/Akt pathway as an adhesion-dependent regulation mechanism of CDC25A protein expression. Altogether, our data show that in leukemic cells adhesion to fibronectin increases CDC25A expression through proteasome- and Chk1-dependent mechanisms, resulting in enhanced proliferation. They also suggest that these adhesion-dependent proliferation properties of hematopoietic cells may be modified during leukemogenesis. (Cancer Res 2006; 66(14): 7128-35)
AIMP3 Haploinsufficiency Disrupts Oncogene-Induced p53 Activation and Genomic Stability
Authors: Park Bum-Joon , Oh Young Sun , Park Seung Yong , Choi So Jung , Rudolph Cornelia , Schlegelberger Brigitte , Kim Sunghoon 
Published: July 2006

Abstract
AIMP3 (previously known as p18) was shown to up-regulate p53 in response to DNA damage. Here, we show that AIMP3 couples oncogenic stresses to p53 activation to prevent cell transformation. Growth factor– or Ras-dependent induction of p53 was blocked by single allelic loss of AIMP3 as well as by suppression of AIMP3. AIMP3 heterozygous cells became susceptible to cell transformation induced by oncogenes such as Ras or Myc alone. The transformed AIMP3+/− cells showed severe abnormality in cell division and chromosomal structure. Thus, AIMP3 plays crucial roles in p53-mediated tumor-suppressive response against oncogenic stresses via differential activation of ATM and ATR, and in the maintenance of genomic stability. (Cancer Res 2006; 66(14): 6913-8)
Expression of the FUS-CHOP Fusion Protein in Primary Mesenchymal Progenitor Cells Gives Rise to a Model of Myxoid Liposarcoma
Authors: Riggi Nicolò , Cironi Luisa , Provero Paolo , Suvà Mario-Luca , Stehle Jean-Christophe , Baumer Karine , Guillou Louis , Stamenkovic Ivan 
Published: July 2006

Abstract
A subset of sarcomas is associated with specific chromosomal translocations that give rise to fusion genes believed to participate in transformation and oncogenesis. Identification of the primary cell environment that provides permissiveness for the oncogenic potential of these fusion genes is essential to understand sarcoma pathogenesis. We have recently shown that expression of the EWS-FLI-1 fusion protein in primary mesenchymal progenitor cells (MPCs) suffices to develop Ewing's sarcoma-like tumors in mice. Because most sarcomas bearing unique chromosomal translocations are believed to originate from common progenitor cells, and because MPCs populate most organs, we expressed the sarcoma-associated fusion proteins FUS/TLS-CHOP, EWS-ATF1, and SYT-SSX1 in MPCs and tested the tumorigenic potential of these cells in vivo. Whereas expression of EWS-ATF1 and SYT-SSX1 failed to transform MPCs, FUS-CHOP–expressing cells formed tumors resembling human myxoid liposarcoma. Transcription profile analysis of these tumors revealed induction of transcripts known to be associated with myxoid liposarcoma and novel candidate genes, including PDGFA, whose expression was confirmed in human tumor samples. MPCFUS-CHOP and the previously described MPCEWS-FLI-1 tumors displayed distinct transcription profiles, consistent with the different target gene repertoires of their respective fusion proteins. Unexpectedly, a set of genes implicated in cell survival and adhesion displayed similar behavior in the two tumors, suggesting events that may be common to primary MPC transformation. Taken together, our observations suggest that expression of FUS-CHOP may be the initiating event in myxoid liposarcoma pathogenesis, and that MPCs may constitute one cell type from which these tumors originate. (Cancer Res 2006; 66(14): 7016-23)
Regulation of Human Nitric Oxide Synthase 2 Expression by Wnt β-Catenin Signaling
Authors: Du Qiang , Park Kyung Soo , Guo Zhong , He Peijun , Nagashima Makoto , Shao Lifang , Sahai Rohit , Geller David A. , Hussain S. Perwez 
Published: July 2006

AbstractNitric oxide (NO·), an important mediator of inflammation, and β-catenin, a component of the Wnt–adenomatous polyposis coli signaling pathway, contribute to the development of cancer. We have identified two T-cell factor 4 (Tcf-4)-binding elements (TBE1 and TBE2) in the promoter of human inducible NO synthase 2 (NOS2). We tested the hypothesis that β-catenin regulates human NOS2 gene. Mutation in either of the two TBE sites decreased the basal and cytokine-induced NOS2 promoter activity in different cell lines. The promoter activity was significantly reduced when both TBE1 and TBE2 sites were mutated (P &lt; 0.01). Nuclear extract from HCT116, HepG2, or DLD1 cells bound to NOS2 TBE1 or TBE2 oligonucleotides in electrophoretic mobility shift assays and the specific protein-DNA complexes were supershifted with anti-β-catenin or anti-Tcf-4 antibody. Overexpression of β-catenin and Tcf-4 significantly increased both basal and cytokine-induced NOS2 promoter activity (P &lt; 0.01), and the induction was dependent on intact TBE sites. Overexpression of β-catenin or Tcf-4 increased NOS2 mRNA and protein expression in HCT116 cells. Lithium chloride (LiCl), an inhibitor of glycogen synthase kinase-3β, increased cytosolic and nuclear β-catenin level, NOS2 expression, and NO· production in primary human and rat hepatocytes and cancer cell lines. Treatment with Wnt-3A-conditioned medium increased β-catenin and NOS2 expression in fetal human hepatocytes. When administered in vivo, LiCl increased hepatic β-catenin level in a dose-dependent manner with simultaneous increase in NOS2 expression. These data are consistent with the hypothesis that β-catenin up-regulates NOS2 and suggest a novel mechanism by which the Wnt/β-catenin signaling pathway may contribute to cancer by increasing NO· production. (Cancer Res 2006; 66(14): 7024-31)
Differential Effect of Bryostatin 1 and Phorbol 12-Myristate 13-Acetate on HOP-92 Cell Proliferation Is Mediated by Down-regulation of Protein Kinase Cδ
Authors: Choi Sung Hee , Hyman Tehila , Blumberg Peter M. 
Published: July 2006

AbstractBryostatin 1 is currently in clinical trials as a cancer chemotherapeutic agent. Although bryostatin 1, like phorbol 12-myristate 13-acetate (PMA), is a potent activator of protein kinase C (PKC), it induces only a subset of those responses induced by PMA and antagonizes others. We report that, in the HOP-92 non–small cell lung cancer line, bryostatin 1 induced a biphasic proliferative response, with maximal proliferation at 1 to 10 nmol/L. This biphasic response mirrored a biphasic suppression of the level of PKCδ protein, with maximal suppression likewise at 1 to 10 nmol/L bryostatin 1. The typical phorbol ester PMA, in contrast to bryostatin 1, had no effect on the level of PKCδ and modest suppression of cell proliferation, particularly evident at later treatment times. Flow cytometric analysis revealed changes in the fraction of cells in the G0-G1 and S phases corresponding to the effects on proliferation. Cells overexpressing PKCδ exhibited a lower rate of cell proliferation compared with control untreated cells and showed neither a proliferative response nor a loss of PKCδ in response to bryostatin 1. Conversely, treatment with PKCδ small interfering RNA significantly increased the cellular growth compared with controls. We conclude that the differential effect on cellular proliferation induced by bryostatin 1 compared with PMA reflects the differential suppression of PKCδ. (Cancer Res 2006; 66(14): 7261-9)
Gene Expression Preferentially Regulated by Tamoxifen in Breast Cancer Cells and Correlations with Clinical Outcome
Authors: Frasor Jonna , Chang Edmund C. , Komm Barry , Lin Chin-Yo , Vega Vinsensius B. , Liu Edison T. , Miller Lance D. , Smeds Johanna , Bergh Jonas , Katzenellenbogen Benita S. 
Published: July 2006

AbstractThe beneficial effect of the selective estrogen receptor (ER) modulator tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here, we report that, in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of &gt;60 genes, which are minimally regulated by estradiol (E2) or raloxifene in ERα-positive MCF-7 human breast cancer cells. This gene regulation by tamoxifen is mediated by ERα and reversed by E2 or ICI 182,780. Introduction of ERβ into MCF-7 cells reverses tamoxifen action on ∼75% of these genes. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, their expression level was examined in breast cancers of women who had received adjuvant therapy with tamoxifen. High expression of two of the tamoxifen-stimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive cancers and hence seem to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. This may have a potential effect on the choice of tamoxifen versus aromatase inhibitors as adjuvant endocrine therapy. (Cancer Res 2006; 66(14): 7334-40)
Differential Binding of Plasminogen, Plasmin, and Angiostatin4.5 to Cell Surface β-Actin: Implications for Cancer-Mediated Angiogenesis
Authors: Wang Hao , Doll Jennifer A. , Jiang Keyi , Cundiff Deborah L. , Czarnecki Jarema S. , Wilson Mindy , Ridge Karen M. , Soff Gerald A. 
Published: July 2006

Abstract
Angiostatin4.5 (AS4.5) is the product of plasmin autoproteolysis and consists of kringles 1 to 4 and ∼85% of kringle 5. In culture, cancer cell surface globular β-actin mediates plasmin autoproteolysis to AS4.5. We now show that plasminogen binds to prostate cancer cells and that the binding colocalizes with surface β-actin, but AS4.5 does not bind to the cell surface. Plasminogen and plasmin bind to immobilized β-actin similarly, with a Kd of ∼140 nmol/L. The binding is inhibited by ε-aminocaproic acid (εACA), indicating the requirement for a lysine-kringle domain interaction. Using a series of peptides derived from β-actin in competitive binding studies, we show that the domain necessary for plasminogen binding is within amino acids 55 to 69 (GDEAQSKRGILTLKY). Substitution of Lys61 or Lys68 with arginine results in the loss of the ability of the peptide to block plasminogen binding, indicating that Lys61 and Lys68 are essential for plasminogen binding. Other actin peptides, including peptides with lysine, did not inhibit the plasminogen-actin interaction. AS4.5 did not bind actin at concentrations up to 40 μmol/L. Plasminogen, plasmin, and AS4.5 all contain kringles 1 to 4; however, kringle 5 is truncated in AS4.5. Isolated kringle 5 binds to actin, suggesting intact kringle 5 is necessary for plasminogen and plasmin to bind to cell surface β-actin, and the truncated kringle 5 in AS4.5 results in its release from β-actin. These data may explain the mechanism by which AS4.5 is formed locally on cancer cell surfaces and yet acts on distant sites. (Cancer Res 2006; 66(14): 7211-5)
Prx1 Suppresses Radiation-Induced c-Jun NH2-Terminal Kinase Signaling in Lung Cancer Cells through Interaction with the Glutathione S-Transferase Pi/c-Jun NH2-Terminal Kinase Complex
Authors: Kim Yun-Jeong , Lee Weon-Sup , Ip Clement , Chae Ho-Zoon , Park Eun-Mi , Park Young-Mee 
Published: July 2006

Abstract
Radiotherapy is one of the major treatment modalities for lung cancer. Cell killing by ionizing radiation is mediated primarily through the reactive oxygen species (ROS) and ROS-driven oxidative stress. Prx1, a peroxiredoxin family member, was shown to be frequently elevated in lung cancer cells and tissues. Although the antioxidant function of Prx1 is expected to affect the radiotherapy response of lung cancer, the physiologic significance of its peroxidase activity in irradiated cells is unclear because the catalytic Cys52 is easily inactivated by ROS due to its overoxidation to sulfinic or sulfonic acid. In this study, we investigated the role of Prx1 in radiation sensitivity of human lung cancer cells, with special emphasis on the redox status of the catalytic Cys52. We found that overexpression of Prx1 enhances the clonogenic survival of irradiated cells and suppresses ionizing radiation–induced c-Jun NH2-terminal kinase (JNK) activation and apoptosis. The peroxidase activity of Prx1, however, is not essential for inhibiting JNK activation. The latter effect is mediated through its association with the glutathione S-transferase pi (GSTpi)-JNK complex, thereby preventing JNK release from the complex. Reduced JNK activation is observed when the peroxidase activity of Prx1 is compromised by Cys52 overoxidation or in the presence of the Cys52 to Ser52 mutant (Prx1C52S) lacking peroxidase activity. We show that both Prx1 and Prx1C52S interact with the GSTpi-JNK complex and suppress the release of JNK from the complex. Our study provides new insight into the antiapoptotic function of Prx1 in modulating radiosensitivity and provides the impetus to monitor the influence of Prx1 levels in the management of lung cancer. (Cancer Res 2006; 66(14): 7136-42)
Periostin Promotes Invasion and Anchorage-Independent Growth in the Metastatic Process of Head and Neck Cancer
Authors: Kudo Yasusei , Ogawa Ikuko , Kitajima Shojiro , Kitagawa Masae , Kawai Hidehiko , Gaffney Patrick M. , Miyauchi Mutsumi , Takata Takashi 
Published: July 2006

Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer. Typically, HNSCC cells show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. However, molecular mechanisms associated with the invasion and metastasis of HNSCC remain poorly understood. Here, we identified periostin as an invasion-promoting factor in HNSCC by comparing the gene expression profiles between parent HNSCC cells and a highly invasive clone. Indeed, periostin overexpression promoted invasion and anchorage-independent growth both in vitro and in vivo in HNSCC cells. Moreover, periostin-overexpressing cells spontaneously metastasized to cervical lymph nodes and to the lung through their aggressive invasiveness in an orthotopic mouse model of HNSCC. Interestingly, periostin was highly expressed in HNSCCs in comparison with normal tissues, and the level of periostin expression was well correlated with the invasiveness of HNSCC cases. In summary, these findings suggest that periostin plays an important role in the invasion and anchorage-independent growth of HNSCC. (Cancer Res 2006; 66(14): 6928-35)
Identification and Clinical Significance of Circulating Endothelial Progenitor Cells in Human Non–Small Cell Lung Cancer
Authors: Dome Balazs , Timar Jozsef , Dobos Judit , Meszaros Livia , Raso Erzsebet , Paku Sandor , Kenessey Istvan , Ostoros Gyula , Magyar Melinda , Ladanyi Andrea , Bogos Krisztina , Tovari Jozsef 
Published: July 2006

Abstract
Until recently, it was generally accepted that vascularization of tumors arises exclusively from endothelial sprouting. Whether circulating bone marrow–derived endothelial progenitor cells (EPC) participate in the progression of non–small cell lung cancer (NSCLC) has not yet been evaluated. EPCs labeled with CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR2) antibodies were counted by flow cytometry in the peripheral blood of 53 NSCLC patients. Furthermore, by means of a quantitative reverse transcription-PCR approach, we measured VEGFR2, CD133, CD34, and VE-cadherin mRNA in the peripheral blood samples of the same patient population. EPCs in tumor samples were identified by confocal microscopy using CD31, CD34, CD133, and VEGFR2 antibodies. Although immunofluorescent labeling of microvessels made clear that incorporation of EPCs is a rare phenomenon in NSCLC tissue (9 of 22 cases), circulating EPC levels before therapeutic intervention were increased in NSCLC patients (P &lt; 0.002, versus healthy controls), and high pretreatment circulating EPC numbers correlated with poor overall survival (P &lt; 0.001). Furthermore, in the subgroup of responders to treatment, the posttreatment EPC numbers in the peripheral blood were significantly lower compared with nonresponding patients. Interestingly, pretreatment mRNA levels of CD133, VE-cadherin, and CD34 were not significantly increased in NSCLC patients, whereas VEGFR2 expression was increased by 80-fold. Moreover, posttreatment VEGFR2 mRNA level in the peripheral blood was significantly higher in the subgroup of nonresponding patients when compared with posttreatment level of patients responding to antitumor therapy. Circulating levels of bone marrow–derived EPCs are significantly increased in NSCLC patients and correlate with clinical behavior. (Cancer Res 2006; 66(14): 7341-7)
Synergy between In situ Cryoablation and TLR9 Stimulation Results in a Highly Effective In vivo Dendritic Cell Vaccine
Authors: den Brok Martijn H.M.G.M. , Sutmuller Roger P.M. , Nierkens Stefan , Bennink Erik J. , Toonen Liza W.J. , Figdor Carl G. , Ruers Theo J.M. , Adema Gosse J. 
Published: July 2006

Abstract
Dendritic cells (DC) are professional antigen-presenting cells that play a pivotal role in the induction of immunity. Ex vivo–generated, tumor antigen–loaded mature DC are currently exploited as cancer vaccines in clinical studies. However, antigen loading and maturation of DC directly in vivo would greatly facilitate the application of DC-based vaccines. We have previously shown that in situ tumor destruction by ablative treatments efficiently delivers antigens for the in vivo induction of antitumor immunity. In this article, we show that although 20% of the draining lymph node DCs acquire intratumorally injected model antigens after in situ cryoablation, only partial protection against a subsequent tumor rechallenge is observed. However, we also show that a combination treatment of cryoablation plus TLR9 stimulation via CpG-oligodeoxynucleotides is far more effective in the eradication of local and systemic tumors than either treatment modality alone. Analysis of the underlying mechanism revealed that in situ tumor ablation synergizes with TLR9 stimulation to induce DC maturation and efficient cross-presentation in tumor-bearing mice, leading to superior DC function in vivo. Therefore, in situ tumor destruction in combination with CpG-oligodeoxynucleotide administration creates a unique “in situ DC vaccine” that is readily applicable in the clinic. (Cancer Res 2006; 66(14): 7285-92)
Polo-Like Kinase 1: Target and Regulator of Anaphase-Promoting Complex/Cyclosome–Dependent Proteolysis
Authors: Eckerdt Frank , Strebhardt Klaus 
Published: July 2006

Abstract
Polo-like kinase 1 (Plk1) is a key regulator of progression through mitosis. Although Plk1 seems to be dispensable for entry into mitosis, its role in spindle formation and exit from mitosis is crucial. Recent evidence suggests that a major role of Plk1 in exit from mitosis is the regulation of inhibitors of the anaphase-promoting complex/cyclosome (APC/C), such as the early mitotic inhibitor 1 (Emi1) and spindle checkpoint proteins. Thus, Plk1 and the APC/C control mitotic regulators by both phosphorylation and targeted ubiquitylation to ensure the fidelity of chromosome separation at the metaphase to anaphase transition. The mechanisms underlying the control of genomic stability by Plk1 are discussed in this review. (Cancer Res 2006; 66(14): 6895-8)
Systemic Induction of the Angiogenesis Switch by the Tetraspanin D6.1A/CO-029
Authors: Gesierich Sabine , Berezovskiy Igor , Ryschich Eduard , Zöller Margot 
Published: July 2006

Abstract
Expression of the tetraspanin CO-029 is associated with poor prognosis in patients with gastrointestinal cancer. In a pancreatic tumor line, overexpression of the rat homologue, D6.1A, induces lethally disseminated intravascular coagulation, suggesting D6.1A engagement in angiogenesis. D6.1A-overexpressing tumor cells induce the greatest amount of angiogenesis in vivo, and tumor cells as well as exosomes derived thereof strikingly increase endothelial cell branching in vitro. Tumor cell–derived D6.1A stimulates angiogenic factor transcription, which includes increased matrix metalloproteinase and urokinase-type plasminogen activator secretion, pronounced vascular endothelial growth factor expression in fibroblasts, vascular endothelial growth factor receptor expression, and strong D6.1A up-regulation in sprouting endothelium. Thus, D6.1A initiates an angiogenic loop that, probably due to the abundance of D6.1A in tumor-derived exosomes, reaches organs distant from the tumor. Most importantly, because of the strong D6.1A up-regulation on sprouting capillaries, angiogenesis could be completely inhibited by a D6.1A-specific antibody, irrespective of whether or not the tumor expresses D6.1A. Tetraspanins have been suggested to be involved in morphogenesis. This is the first report that a tetraspanin, CO-029/D6.1A, promotes tumor growth by its capacity to induce systemic angiogenesis that can effectively, and with high selectivity for sprouting endothelium, be blocked by a D6.1A-specific antibody. (Cancer Res 2006; 66(14): 7083-94)