bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conjugal Transfer of Chromosomal DNA Contributes to Genetic Variation in the Oral Pathogen
Porphyromonas gingivalis
Authors: Tribble Gena D. , Lamont Gwyneth J. , Progulske-Fox Ann , Lamont Richard J. 
Published: June 2007

ABSTRACT

Porphyromonas gingivalis
is a major oral pathogen that contributes to the development of periodontal disease. There is a significant degree of genetic variation among strains of
P. gingivalis
, and the population structure has been predicted to be panmictic, indicating that horizontal DNA transfer and recombination between strains are likely. The molecular events underlying this genetic exchange are not understood, although a putative type IV secretion system is present in the genome sequence of strain W83, implying that DNA conjugation may be responsible for genetic transfer in these bacteria. In this study, we provide in vitro evidence for the horizontal transfer of DNA using plasmid- and chromosome-based assays. In the plasmid assays,
Bacteroides
-derived shuttle vectors were tested for transfer from
P. gingivalis
strains into
Escherichia coli
. Of the eight strains tested, five were able to transfer DNA into
E. coli
by a mechanism most consistent with conjugation. Additionally, strains W83 and 33277 tested positive for the transfer of chromosomally integrated antibiotic resistance markers. Ten chimeras resulting from the chromosomal transfer assay were further analyzed by Southern hybridization and were shown to have exchanged DNA fragments of between 1.1 and 5.6 kb, but the overall strain identity remained intact. Chimeras showed phenotypic changes in the ability to accrete into biofilms, implying that DNA transfer events are sufficient to generate measurable changes in complex behaviors. This ability to transfer chromosomal DNA between strains may be an adaptation mechanism in the complex environment of the host oral cavity.
Inhibition of Epidermal Growth Factor Receptor Signaling Elevates 15-Hydroxyprostaglandin Dehydrogenase in Non–Small-Cell Lung Cancer
Authors: Yang Li , Amann Joseph M. , Kikuchi Takefumi , Porta Rut , Guix Marta , Gonzalez Adriana , Park Kyung-Ho , Billheimer Dean , Arteaga Carlos L. , Tai Hsin-Hsiung , DuBois Raymond , Carbone David P. , Johnson David H. 
Published: June 2007

Abstract
Evidence indicates that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of non–small-cell lung cancer (NSCLC). In addition to overproduction by COX-2, PGE2 concentrations also depend upon the levels of the PGE2 catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). We find a dramatic down-regulation of PGDH protein in NSCLC cell lines and in resected human tumors when compared with matched normal lung. Affymetrix array analysis of 10 normal lung tissue samples and 49 resected lung tumors revealed a much lower expression of PGDH transcripts in all NSCLC histologic groups. In addition, treatment with the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) erlotinib increased the expression of 15-PGDH in a subset of NSCLC cell lines. This effect may be due in part to an inhibition of the extracellular signal-regulated kinase (ERK) pathway as treatment with mitogen-activated protein kinase kinase (MEK) inhibitor U0126 mimics the erlotinib results. We show by quantitative reverse transcription-PCR that the transcript levels of ZEB1 and Slug transcriptional repressors are dramatically reduced in a responsive cell line upon EGFR and MEK/ERK inhibition. In addition, the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. As these repressors function by recruiting histone deacetylases to promoters, it is likely that PGDH is repressed by an epigenetic mechanism involving histone deacetylation, resulting in increased PGE2 activity in tumors. This effect is reversible in a subset of NSCLC upon treatment with an EGFR TKI. [Cancer Res 2007;67(12):5587–93]
Genetic Ablation of the Amplified-in-Breast Cancer 1 Inhibits Spontaneous Prostate Cancer Progression in Mice
Authors: Chung Arthur C-K. , Zhou Suoling , Liao Lan , Tien Jean Ching-Yi , Greenberg Norman M. , Xu Jianming 
Published: June 2007

Abstract
Although the amplified-in-breast cancer 1 (AIB1; SRC-3, ACTR, or NCoA3) was defined as a coactivator for androgen receptor (AR) by in vitro studies, its role in AR-mediated prostate development and prostate cancer remained unexplored. We report here that AIB1 is expressed in the basal and stromal cells but not in the epithelial cells of the normal mouse prostates. AIB1 deficiency only slightly delayed prostate growth and had no effect on androgen-dependent prostate regeneration, suggesting an unessential role of AIB1 in AR function in the prostate. Surprisingly, when prostate tumorigenesis was induced by the SV40 transgene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, AIB1 expression was observed in certain epithelial cells of the prostate intraepithelial neoplasia (PIN) and well-differentiated carcinoma and in almost all cells of the poorly differentiated carcinoma. After AIB1 was genetically inactivated in AIB1−/−/TRAMP mice, the progression of prostate tumorigenesis in most AIB1−/−/TRAMP mice was arrested at the well-differentiated carcinoma stage. Wild-type (WT)/TRAMP mice developed progressive, multifocal, and metastatic prostate tumors and died between 25 and 34 weeks. In contrast, AIB1−/−/TRAMP mice only exhibited PIN and early-stage well-differentiated carcinoma by 39 weeks. AIB1−/−/TRAMP prostates showed much lower cell proliferation than WT/TRAMP prostates. Most AIB1−/−/TRAMP mice could survive more than 35 weeks and died with other types of tumors or unknown reasons. Our results indicate that induction of AIB1 expression in partially transformed epithelial cells is essential for progression of prostate tumorigenesis into poorly differentiated carcinoma. Inhibition of AIB1 expression or function in the prostate epithelium may be a potential strategy to suppress prostate cancer initiation and progression. [Cancer Res 2007;67(12):5965–75]
Enhanced Spontaneous and Benzo(a)pyrene-Induced Mutations in the Lung of Nrf2-Deficient gpt Delta Mice
Authors: Aoki Yasunobu , Hashimoto Akiko H. , Amanuma Kimiko , Matsumoto Michi , Hiyoshi Kyoko , Takano Hirohisa , Masumura Ken-ichi , Itoh Ken , Nohmi Takehiko , Yamamoto Masayuki 
Published: June 2007

Abstract
The lung is an organ that is sensitive to mutations induced by chemicals in ambient air, and transgenic mice harboring guanine phosphoribosyltransferase (gpt) gene as a target gene are a well-established model system for assessing genotoxicity in vivo. Transcription factor Nrf2 mediates inducible and constitutive expression of cytoprotective enzymes against xenobiotics and mutagens. To address whether Nrf2 is also involved in DNA protection, we generated nrf2+/−::gpt and nrf2−/−::gpt mice. The spontaneous mutation frequency of the gpt gene in the lung was approximately three times higher in nrf2-null (nrf2−/−) mice than nrf2 heterozygous (nrf2+/−) and wild-type (nrf2+/+) mice, whereas in the liver, the mutation frequency was higher in nrf2−/− and nrf2+/− mice than in nrf2+/+ wild-type mice. By contrast, no difference in mutation frequency was observed in testis among the three genotypes. A single intratracheal instillation of benzo(a)pyrene (BaP) increased the lung mutation frequency 3.1- and 6.1-fold in nrf2+/− and nrf2−/− mice, respectively, compared with BaP-untreated nrf2+/− mice, showing that nrf2−/− mice are more susceptible to genotoxic carcinogens. Surprisingly, mutation profiles of the gpt gene in BaP-treated nrf2+/− mice was substantially different from that in BaP-untreated nrf2−/− mice. In nrf2−/− mice, spontaneous and BaP-induced mutation hotspots were observed at nucleotides 64 and 140 of gpt, respectively. These results thus show that Nrf2 aids in the prevention of mutations in vivo and suggest that Nrf2 protects genomic DNA against certain types of mutations. [Cancer Res 2007;67(12):5643–8]
c-FLIP: A Key Regulator of Colorectal Cancer Cell Death
Authors: Wilson Timothy R. , McLaughlin Kirsty M. , McEwan Miranda , Sakai Hidekazu , Rogers Katherine M.A. , Redmond Kelly M. , Johnston Patrick G. , Longley Daniel B. 
Published: June 2007

Abstract
c-FLIP is an inhibitor of apoptosis mediated by the death receptors Fas, DR4, and DR5 and is expressed as long (c-FLIPL) and short (c-FLIPS) splice forms. We found that small interfering RNA (siRNA)-mediated silencing of c-FLIP induced spontaneous apoptosis in a panel of p53 wild-type, mutant, and null colorectal cancer cell lines and that this apoptosis was mediated by caspase-8 and Fas-associated death domain. Further analyses indicated the involvement of DR5 and/or Fas (but not DR4) in regulating apoptosis induced by c-FLIP siRNA. Interestingly, these effects were not dependent on activation of DR5 or Fas by their ligands tumor necrosis factor–related apoptosis-inducing ligand and FasL. Overexpression of c-FLIPL, but not c-FLIPS, significantly decreased spontaneous and chemotherapy-induced apoptosis in HCT116 cells. Further analyses with splice form–specific siRNAs indicated that c-FLIPL was the more important splice form in regulating apoptosis in HCT116, H630, and LoVo cells, although specific knockdown of c-FLIPS induced more apoptosis in the HT29 cell line. Importantly, intratumoral delivery of c-FLIP–targeted siRNA duplexes induced apoptosis and inhibited the growth of HCT116 xenografts in BALB/c severe combined immunodeficient mice. In addition, the growth of c-FLIPL–overexpressing colorectal cancer xenografts was more rapid than control xenografts, an effect that was significantly enhanced in the presence of chemotherapy. These results indicate that c-FLIP inhibits spontaneous death ligand–independent, death receptor–mediated apoptosis in colorectal cancer cells and that targeting c-FLIP may have therapeutic potential for the treatment of colorectal cancer. [Cancer Res 2007;67(12):5754–62]
Monoclonal Antibodies to Six-Transmembrane Epithelial Antigen of the Prostate-1 Inhibit Intercellular Communication In vitro and Growth of Human Tumor Xenografts In vivo
Authors: Challita-Eid Pia M. , Morrison Kendall , Etessami Soudabeh , An Zili , Morrison Karen J. , Perez-Villar Juan J. , Raitano Arthur B. , Jia Xiao-Chi , Gudas Jean M. , Kanner Steven B. , Jakobovits Aya 
Published: June 2007

Abstract
Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a novel cell surface protein highly expressed in primary prostate cancer, with restricted expression in normal tissues. In this report, we show STEAP-1 expression in prostate metastases to lymph node and bone and in the majority of human lung and bladder carcinomas. We identify STEAP-1 function in mediating the transfer of small molecules between adjacent cells in culture, indicating its potential role in tumor cell intercellular communication. The successful generation of two monoclonal antibodies (mAb) that bind to cell surface STEAP-1 epitopes provided the tools to study STEAP-1 susceptibility to naked antibody therapy. Both mAbs inhibited STEAP-1–induced intercellular communication in a dose-dependent manner. Furthermore, both mAbs significantly inhibited tumor growth in mouse models using patient-derived LAPC-9 prostate cancer xenografts and established UM-UC-3 bladder tumors. These studies validate STEAP-1 as an attractive target for antibody therapy in multiple solid tumors and provide a putative mechanism for mAb-induced tumor growth inhibition. [Cancer Res 2007;67(12):5798–805]
Repression of RUNX1 Activity by EVI1: A New Role of EVI1 in Leukemogenesis
Authors: Senyuk Vitalyi , Sinha Kislay K. , Li Donglan , Rinaldi Ciro R. , Yanamandra Sastry , Nucifora Giuseppina 
Published: June 2007

Abstract
Recurring chromosomal translocations observed in human leukemia often result in the expression of fusion proteins that are DNA-binding transcription factors. These altered proteins acquire new dimerization properties that result in the assembly of inappropriate multimeric transcription complexes that deregulate hematopoietic programs and induce leukemogenesis. Recently, we reported that the fusion protein AML1/MDS1/EVI1 (AME), a product of a t(3;21)(q26;q22) associated with chronic myelogenous leukemia and acute myelogenous leukemia, displays a complex pattern of self-interaction. Here, we show that the 8th zinc finger motif of MDS1/EVI1 is an oligomerization domain involved not only in interaction of AME with itself but also in interactions with the parental proteins, RUNX1 and MDS1/EVI1, from which AME is generated. Because the 8th zinc finger motif is also present in the oncoprotein EVI1, we have evaluated the effects of the interaction between RUNX1 and EVI1 in vitro and in vivo. We found that in vitro, this interaction alters the ability of RUNX1 to bind to DNA and to regulate a reporter gene, whereas in vivo, the expression of the isolated 8th zinc finger motif of EVI1 is sufficient to block the granulocyte colony-stimulating factor–induced differentiation of 32Dcl3 cells, leading to cell death. As EVI1 is not detected in normal bone marrow cells, these data suggest that its inappropriate expression could contribute to hematopoietic transformation in part by a new mechanism that involves EVI1 association with key hematopoietic regulators, leading to their functional impairment. [Cancer Res 2007;67(12):5658–66]
Patterns of EGFR, HER2, TP53, and KRAS Mutations of p14arf Expression in Non–Small Cell Lung Cancers in Relation to Smoking History
Authors: Mounawar Mounia , Mukeria Anush , Le Calvez Florence , Hung Rayjean J. , Renard Helene , Cortot Alexis , Bollart Claire , Zaridze David , Brennan Paul , Boffetta Paolo , Brambilla Elisabeth , Hainaut Pierre 
Published: June 2007

Abstract
Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in non–small cell lung cancer (NSCLC) of never smokers, whereas HER2 mutations are rare. We have analyzed EGFR and HER2 mutations and the expression of the two products of the CDKN2A gene (p14arf and p16INK4a) in 116 NSCLC that have been previously analyzed for TP53 and KRAS mutations in relation to smoking history of patients. EGFR mutations were detected in 20 of 116 (17%) tumors, whereas five (4.3%) tumors contained HER2 mutations. No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from never smokers, and 32% were from former smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among never smokers, 11 of 16 tumors with EGFR mutation also had TP53 mutation, in contrast with two of 17 tumors without EGFR mutation (P = 0.0008). Expression of p14arf, but not p16ink4a, was more frequently down-regulated in never smokers (62.5%) than ever smokers (35%; P = 0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14arf expression. These observations suggest that functional inactivation of the p14arf/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals. [Cancer Res 2007;67(12):5667–72]
Combination of Tumor Site–Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses
Authors: Tuve Sebastian , Chen Bing-Mae , Liu Ying , Cheng Tian-Lu , Touré Papa , Sow Papa Salif , Feng Qinghua , Kiviat Nancy , Strauss Robert , Ni Shaoheng , Li Zong-Yi , Roffler Steve R. , Lieber André 
Published: June 2007

AbstractAccumulating data indicate that tumor-infiltrating regulatory T cells (Treg) are present in human tumors and locally suppress antitumor immune cells. In this study, we found an increased Treg/CD8 ratio in human breast and cervical cancers. A similar intratumoral lymphocyte pattern was observed in a mouse model for cervical cancer (TC-1 cells). In this model, systemic Treg depletion was inefficient in controlling tumor growth. Furthermore, systemic CTL-associated antigen-4 (CTLA-4) blockade, an approach that can induce tumor immunity in other tumor models, did not result in TC-1 tumor regression but led to spontaneous development of autoimmune hepatitis. We hypothesized that continuous expression of an anti–CTLA-4 antibody localized to the tumor site could overcome Treg-mediated immunosuppression and locally activate tumor-reactive CD8+ cells, without induction of autoimmunity. To test this hypothesis, we created TC-1 cells that secrete a functional anti–CTLA-4 antibody (TC-1/αCTLA-4-γ1 cells). When injected into immunocompetent mice, the growth of TC-1/αCTLA-4-γ1 tumors was delayed compared with control TC-1 cells and accompanied by a reversion of the intratumoral Treg/CD8 ratio due to an increase in tumor-infiltrating IFNγ-producing CD8+ cells. When local anti–CTLA-4 antibody production was combined with Treg inhibition, permanent TC-1 tumor regression and immunity was induced. Importantly, no signs of autoimmunity were detected in mice that received local CTLA-4 blockade alone or in combination with Treg depletion. [Cancer Res 2007;67(12):5929–39]
Macrophages Mediate Inflammation-Enhanced Metastasis of Ovarian Tumors in Mice
Authors: Robinson-Smith Toni M. , Isaacsohn Idit , Mercer Carol A. , Zhou Mingfu , Van Rooijen Nico , Husseinzadeh Nader , McFarland-Mancini Molly M. , Drew Angela F. 
Published: June 2007

AbstractThe tumor microenvironment is known to have a profound effect on tumor progression in a highly context-specific manner. We have investigated whether peritoneal inflammation plays a causative role in ovarian tumor metastasis, a poorly understood process. Implantation of human ovarian tumor cells into the ovaries of severe combined immunodeficient mice resulted in peritoneal inflammation that corresponds temporally with tumor cell dissemination from the ovaries. Enhancement of the inflammatory response with thioglycolate accelerated the development of ascites and metastases. Suppression of inflammation with acetyl salicylic acid delayed ascites development and reduced tumor implant formation. A similar prometastatic effect for inflammation was observed when tumor cells were injected directly into the peritoneum of severe combined immunodeficient mice, and in a syngeneic immunocompetent mouse model. Inflammation-modulating treatments did not affect primary tumor development or in vitro tumor cell growth. Depletion of peritoneal macrophages, but not neutrophils or natural killer cells, reduced tumor progression, as assessed by ascites formation and peritoneal metastasis. We conclude that inflammation facilitates ovarian tumor metastasis by a mechanism largely mediated by macrophages, and which may involve stromal vascular endothelial growth factor production. The confirmation of these findings in immunocompetent mice suggests relevance to human disease. Identifying the mechanisms by which macrophages contribute to tumor metastasis may facilitate the development of new therapies specifically targeting immune cell products in the tumor microenvironment. [Cancer Res 2007;67(12):5708–16]
Tumor αvβ3 Integrin Is a Therapeutic Target for Breast Cancer Bone Metastases
Authors: Zhao Yingshe , Bachelier Richard , Treilleux Isabelle , Pujuguet Philippe , Peyruchaud Olivier , Baron Roland , Clément-Lacroix Philippe , Clézardin Philippe 
Published: June 2007

Abstract
In breast cancer bone metastasis, tumor cells stimulate osteoclast-mediated bone resorption, and bone-derived growth factors released from resorbed bone stimulate tumor growth. The αvβ3 integrin is an adhesion receptor expressed by breast cancer cells and osteoclasts. It is implicated in tumor cell invasion and osteoclast-mediated bone resorption. Here, we hypothesized that the therapeutic targeting of tumor αvβ3 integrin would prevent bone metastasis formation. We first showed that, compared with mock-transfected cells, the i.v. inoculation of αvβ3-overexpressing MDA-MB-231 breast cancer cells in animals increased bone metastasis incidence and promoted both skeletal tumor burden and bone destruction. The direct inoculation of αvβ3-overexpressing transfectants into the tibial bone marrow cavity did not however enhance skeletal tumor burden and bone destruction, suggesting that αvβ3 controls earlier events during bone metastasis formation. We next examined whether a nonpeptide antagonist of αvβ3 (PSK1404) exhibits meaningful antitumor effects in experimental breast and ovarian cancer bone metastasis. A continuous PSK1404 treatment, which inhibited osteoclast-mediated bone resorption in an animal model of bone loss, substantially reduced bone destruction and decreased skeletal tumor burden. Importantly, a short-term PSK1404 treatment that did not inhibit osteoclast activity also decreased skeletal tumor burden and bone destruction. This dosing regimen caused a profound and specific inhibition of bone marrow colonization by green fluorescent protein, αvβ3-expressing tumor cells in vivo and blocked tumor cell invasion in vitro. Overall, our data show that tumor αvβ3 integrin stands as a therapeutic target for the prevention of skeletal metastases. [Cancer Res 2007;67(12):5821–30]
Effect of a Single Nucleotide Polymorphism in the Murine Double Minute 2 Promoter (SNP309) on the Sensitivity to Topoisomerase II–Targeting Drugs
Authors: Nayak Mamatha S. , Yang Jin-Ming , Hait William N. 
Published: June 2007

Abstract
A single nucleotide polymorphism (SNP) SNP309 (T→G) in the murine double minute 2 (MDM2) promoter creates a high-affinity Sp1 binding site and increases the expression of MDM2 mRNA and protein. Approximately 40% of the populations harbor at least one variant allele and 12% to 17% are homozygous G/G at codon 309. This MDM2 SNP increases susceptibility to cancer and decreases the response of cancer cells to certain forms of treatment, such as radiation therapy and DNA-damaging drugs. Topoisomerase II (TopoII)–targeting agents are commonly used chemotherapeutic drugs with a broad spectrum of activity. However, resistance to TopoII poisons limits their effectiveness. We show that MDM2 SNP309 rendered a panel of cancer cell lines that are homozygous for SNP309 selectively resistant (∼10-fold) to certain TopoII-targeting chemotherapeutic drugs (etoposide, mitoxantrone, amsacrine, and ellipticine). The mechanism underlying this observation was Mdm2-mediated down-regulation of TopoII; on drug exposure, MDM2 bound to TopoII and resulted in decreased cellular enzyme content. Knockdown of MDM2 by RNA interference stabilized TopoIIα and decreased resistance to TopoII-targeting drugs. Thus, MDM2 SNP309 (T→G) may represent a relatively common, previously unappreciated determinant of drug sensitivity. Given the frequency of SNP309 in the general population (40% in heterozygous T/G and 12% in homozygous G/G condition), our observation may have important implications for the individualization of cancer chemotherapy. [Cancer Res 2007;67(12):5831–9]