bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Papillomavirus E7 Oncoprotein Overrides the Tumor Suppressor Activity of p21Cip1 in Cervical Carcinogenesis
Authors: Shin Myeong-Kyun , Balsitis Scott , Brake Tiffany , Lambert Paul F. 
Published: July 2009

Abstract
The E7 oncoprotein of the high-risk human papillomaviruses (HPV) is thought to contribute to cervical carcinogenesis at least in part by abrogating cell cycle regulation. E7 can dysregulate the cell cycle through its interaction with several cellular proteins including the retinoblastoma suppressor protein pRb, as well as the cyclin-dependent kinase inhibitor p21Cip1. Inactivation of pRb in cervical epithelia is not sufficient to explain the ability of E7 to cause cervical cancers in transgenic mice. In the current study, we focused on the role of p21Cip1 in cervical cancer. Cervical disease was significantly increased in p21−/− mice compared with p21+/+ mice, showing that p21Cip1 can function as a tumor suppressor in this tissue. Importantly, the ability of E7 to induce cervical cancers was not significantly enhanced on the p21-null background, consistent with the hypothesis that the ability of E7 to inhibit p21Cip1 contributes to its carcinogenic properties. Further supportive of this hypothesis, cervical carcinogenesis in mice expressing a mutant form of HPV-16 E7, E7CVQ, which fails to inactivate p21Cip1, was significantly reduced compared with that in K14E7WT mice expressing wild-type HPV-16 E7. However, K14E7CVQ mice still displayed heightened levels of cervical carcinogenesis compared with that in nontransgenic mice, indicating that activities of E7 besides its capacity to inactivate p21Cip1 also contribute to cervical carcinogenesis. Taken together, we conclude that p21Cip1 functions as a tumor suppressor in cervical carcinogenesis and that p21Cip1 inactivation by HPV-16 E7 partially contributes to the contribution of E7 to cervical carcinogenesis. [Cancer Res 2009;69(14):5656–63]
Antimyeloma Activity of the Orally Bioavailable Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235
Authors: McMillin Douglas W. , Ooi Melissa , Delmore Jake , Negri Joseph , Hayden Patrick , Mitsiades Nicolas , Jakubikova Jana , Maira Sauveur-Michel , Garcia-Echeverria Carlos , Schlossman Robert , Munshi Nikhil C. , Richardson Paul G. , Anderson Kenneth C. , Mitsiades Constantine S. 
Published: July 2009

Abstract
The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway mediates proliferation, survival, and drug resistance in multiple myeloma (MM) cells. Here, we tested the anti-MM activity of NVP-BEZ235 (BEZ235), which inhibits PI3K/Akt/mTOR signaling at the levels of PI3K and mTOR. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric survival assays showed that MM cell lines exhibited dose- and time-dependent decreased viability after exposure to BEZ235 (IC50, 25–800 nmol/L for 48 hours). MM cells highly sensitive (IC50, &lt;25 nmol/L) to BEZ235 (e.g., MM.1S, MM.1R, Dox40, and KMS-12-PE) included both lines sensitive and resistant to conventional (dexamethasone, cytotoxic chemotherapeutics) agents. Pharmacologically relevant BEZ235 concentrations (25–400 nmol/L) induced rapid commitment to and induction of MM.1S and OPM-2 cell death. Furthermore, normal donor peripheral blood mononuclear cells were less sensitive (IC50, &gt;800 nmol/L) than the majority of MM cell lines tested, suggesting a favorable therapeutic index. In addition, BEZ235 was able to target MM cells in the presence of exogenous interleukin-6, insulin-like growth factor-1, stromal cells, or osteoclasts, which are known to protect against various anti-MM agents. Molecular profiling revealed that BEZ235 treatment decreased the amplitude of transcriptional signatures previously associated with myc, ribosome, and proteasome function, as well as high-risk MM and undifferentiated human embryonic stem cells. In vivo xenograft studies revealed significant reduction in tumor burden (P = 0.011) and survival (P = 0.028) in BEZ235-treated human MM tumor-bearing mice. Combinations of BEZ235 with conventional (e.g., dexamethasone and doxorubicin) or novel (e.g., bortezomib) anti-MM agents showed lack of antagonism. These results indicate that BEZ235 merits clinical testing, alone and in combination with other agents, in MM. [Cancer Res 2009;69(14):5835–42]
Nimotuzumab, an Antitumor Antibody that Targets the Epidermal Growth Factor Receptor, Blocks Ligand Binding while Permitting the Active Receptor Conformation
Authors: Talavera Ariel , Friemann Rosmarie , Gómez-Puerta Silvia , Martinez-Fleites Carlos , Garrido Greta , Rabasa Ailem , López-Requena Alejandro , Pupo Amaury , Johansen Rune F. , Sánchez Oliberto , Krengel Ute , Moreno Ernesto 
Published: July 2009

Abstract
Overexpression of the epidermal growth factor (EGF) receptor (EGFR) in cancer cells correlates with tumor malignancy and poor prognosis for cancer patients. For this reason, the EGFR has become one of the main targets of anticancer therapies. Structural data obtained in the last few years have revealed the molecular mechanism for ligand-induced EGFR dimerization and subsequent signal transduction, and also how this signal is blocked by either monoclonal antibodies or small molecules. Nimotuzumab (also known as h-R3) is a humanized antibody that targets the EGFR and has been successful in the clinics. In this work, we report the crystal structure of the Fab fragment of Nimotuzumab, revealing some unique structural features in the heavy variable domain. Furthermore, competition assays show that Nimotuzumab binds to domain III of the extracellular region of the EGFR, within an area that overlaps with both the surface patch recognized by Cetuximab (another anti-EGFR antibody) and the binding site for EGF. A computer model of the Nimotuzumab-EGFR complex, constructed by docking and molecular dynamics simulations and supported by mutagenesis studies, unveils a novel mechanism of action, with Nimotuzumab blocking EGF binding while still allowing the receptor to adopt its active conformation, hence warranting a basal level of signaling. [Cancer Res 2009;69(14):5851–9]
Genomic Characterization of Esophageal Squamous Cell Carcinoma from a High-Risk Population in China
Authors: Hu Nan , Wang Chaoyu , Ng David , Clifford Robert , Yang Howard H. , Tang Ze-Zhong , Wang Quan-Hong , Han Xiao-You , Giffen Carol , Goldstein Alisa M. , Taylor Philip R. , Lee Maxwell P. 
Published: July 2009

Abstract
Genomic instability plays an important role in most human cancers. To characterize genomic instability in esophageal squamous cell carcinoma (ESCC), we examined loss of heterozygosity (LOH), copy number (CN) loss, CN gain, and gene expression using the Affymetrix GeneChip Human Mapping 500K (n = 30 cases) and Human U133A (n = 17 cases) arrays in ESCC cases from a high-risk region of China. We found that genomic instability measures varied widely among cases and separated them into two groups: a high-frequency instability group (two-thirds of all cases with one or more instability category of ≥10%) and a low-frequency instability group (one-third of cases with instability of &lt;10%). Genomic instability also varied widely across chromosomal arms, with the highest frequency of LOH on 9p (33% of informative single nucleotide polymorphisms), CN loss on 3p (33%), and CN gain on 3q (48%). Twenty-two LOH regions were identified: four on 9p, seven on 9q, four on 13q, two on 17p, and five on 17q. Three CN loss regions—3p12.3, 4p15.1, and 9p21.3—were detected. Twelve CN gain regions were found, including six on 3q, one on 7q, four on 8q, and one on 11q. One of the most gene-rich of these CN gain regions was 11q13.1-13.4, where 26 genes also had RNA expression data available. CN gain was significantly correlated with increased RNA expression in over 80% of these genes. Our findings show the potential utility of combining CN analysis and gene expression data to identify genes involved in esophageal carcinogenesis. [Cancer Res 2009;69(14):5908–17]
MiR-122/Cyclin G1 Interaction Modulates p53 Activity and Affects Doxorubicin Sensitivity of Human Hepatocarcinoma Cells
Authors: Fornari Francesca , Gramantieri Laura , Giovannini Catia , Veronese Angelo , Ferracin Manuela , Sabbioni Silvia , Calin George Adrian , Grazi Gian Luca , Croce Carlo Maria , Tavolari Simona , Chieco Pasquale , Negrini Massimo , Bolondi Luigi 
Published: July 2009

Abstract
The identification of target genes is a key step for assessing the role of aberrantly expressed microRNAs (miRNA) in human cancer and for the further development of miRNA-based gene therapy. MiR-122 is a liver-specific miRNA accounting for 70% of the total miRNA population. Its down-regulation is a common feature of both human and mouse hepatocellular carcinoma (HCC). We have previously shown that miR-122 can regulate the expression of cyclin G1, whose high levels have been reported in several human cancers. We evaluated the role of miR-122 and cyclin G1 expression in hepatocarcinogenesis and in response to treatment with doxorubicin and their relevance on survival and time to recurrence (TTR) of HCC patients. We proved that, by modulating cyclin G1, miR-122 influences p53 protein stability and transcriptional activity and reduces invasion capability of HCC-derived cell lines. In addition, in a therapeutic perspective, we assayed the effects of a restored miR-122 expression in triggering doxorubicin-induced apoptosis and we proved that miR-122, as well as cyclin G1 silencing, increases sensitivity to doxorubicin challenge. In patients resected for HCC, lower miR-122 levels were associated with a shorter TTR, whereas higher cyclin G1 expression was related to a lower survival, suggesting that miR-122 might represent an effective molecular target for HCC. Our findings establish a basis toward the development of combined chemo- and miRNA-based therapy for HCC treatment. [Cancer Res 2009;69(14):5761–7]
Long-lived Min Mice Develop Advanced Intestinal Cancers through a Genetically Conservative Pathway
Authors: Halberg Richard B. , Waggoner Jesse , Rasmussen Kristen , White Alanna , Clipson Linda , Prunuske Amy J. , Bacher Jeffery W. , Sullivan Ruth , Washington Mary Kay , Pitot Henry C. , Petrini John H.J. , Albertson Donna G. , Dove William F. 
Published: July 2009

Abstract
C57BL/6J mice carrying the Min allele of Adenomatous polyposis coli (Apc) develop numerous adenomas along the entire length of the intestine and consequently die at an early age. This short lifespan would prevent the accumulation of somatic genetic mutations or epigenetic alterations necessary for tumor progression. To overcome this limitation, we generated F1 ApcMin/+ hybrids by crossing C57BR/cdcJ and SWR/J females to C57BL/6J ApcMin/+ males. These hybrids developed few intestinal tumors and often lived longer than 1 year. Many of the tumors (24-87%) were invasive adenocarcinomas, in which neoplastic tissue penetrated through the muscle wall into the mesentery. In a few cases (3%), lesions metastasized by extension to regional lymph nodes. The development of these familial cancers does not require chromosomal gains or losses, a high level of microsatellite instability, or the presence of Helicobacter. To test whether genetic instability might accelerate tumor progression, we generated ApcMin/+ mice homozygous for the hypomorphic allele of the Nijmegen breakage syndrome gene (Nbs1ΔB) and also treated ApcMin/+ mice with a strong somatic mutagen. These imposed genetic instabilities did not reduce the time required for cancers to form nor increase the percentage of cancers nor drive progression to the point of distant metastasis. In summary, we have found that the ApcMin/+ mouse model for familial intestinal cancer can develop frequent invasive cancers in the absence of overt genomic instability. Possible factors that promote invasion include age-dependent epigenetic changes, conservative somatic recombination, or direct effects of alleles in the F1 hybrid genetic background. [Cancer Res 2009;69(14):5768–75]
Activating Transcription Factor 2 and c-Jun–Mediated Induction of FoxP3 for Experimental Therapy of Mammary Tumor in the Mouse
Authors: Liu Yan , Wang Yin , Li Weiquan , Zheng Pan , Liu Yang 
Published: July 2009

Abstract
FOXP3 is inactivated in breast cancer cells by a number of mechanisms, including somatic mutations, deletion, and epigenetic silencing. Because the mutation and deletion are usually heterozygous in the cancer samples, it is of interest to determine whether the gene can be induced for the purpose of cancer therapy. Here, we report that anisomycin, a potent activator of activating transcription factor (ATF) 2, and c-Jun-NH2-kinase, induces expression of FoxP3 in both normal and malignant mammary epithelial cells. The induction is mediated by ATF2 and c-Jun. Targeted mutation of ATF2 abrogates both constitutive and inducible expression of FoxP3 in normal epithelial cells. Both ATF2 and c-Jun interact with a novel enhancer in the intron 1 of the FoxP3 locus. Moreover, shRNA silencing of ATF2 and FoxP3 reveals an important role of ATF2-FoxP3 pathway in the anisomycin-induced apoptosis of breast cancer cells. A low dose of anisomycin was also remarkably effective in treating established mammary tumor in the mice. Our data showed that FoxP3 can be reactivated for cancer therapy. [Cancer Res 2009;69(14):5954–60]
MicroRNA-661, a c/EBPα Target, Inhibits Metastatic Tumor Antigen 1 and Regulates Its Functions
Authors: Reddy Sirigiri Divijendra Natha , Pakala Suresh B. , Ohshiro Kazufumi , Rayala Suresh K. , Kumar Rakesh 
Published: July 2009

Abstract
MicroRNAs (miR) have been identified as posttranscriptional modifiers of target gene regulation and control the expression of gene products important in cancer progression. Here, we show that miR-661 inhibits the expression of metastatic tumor antigen 1 (MTA1), a widely up-regulated gene product in human cancer, by targeting the 3′ untranslated region (UTR) of MTA1 mRNA. We found that endogenous miR-661 expression was positively regulated by the c/EBPα transcription factor, which is down-regulated during cancer progression. c/EBPα directly interacted with the miR-661 chromatin and bound to miR-661 putative promoter that contains a c/EBPα-consensus motif. In addition, we found that the level of MTA1 protein was progressively up-regulated, whereas that of miR-661 and its activator, c/EBPα, were down-regulated in a breast cancer progression model consisting of MCF-10A cell lines whose phenotypes ranged from noninvasive to highly invasive. c/EBPα expression in breast cancer cells resulted in increased miR-661 expression and reduced MTA1 3′UTR-luciferase activity and MTA1 protein level. We also provide evidence that the introduction of miR-661 inhibited the motility, invasiveness, anchorage-independent growth, and tumorigenicity of invasive breast cancer cells. We believe our findings show for the first time that c/EBPα regulates the level of miR-661 and in turn modifies the functions of the miR661-MTA1 pathway in human cancer cells. Based on these findings, we suggest that miR-661 be further investigated for therapeutic use in down-regulating the expression of MTA1 in cancer cells. [Cancer Res 2009;69(14):5639–42]
Platelets: Guardians of Tumor Vasculature
Authors: Ho-Tin-Noé Benoit , Goerge Tobias , Wagner Denisa D. 
Published: July 2009

Abstract
Solid tumors generate a prothrombotic environment capable of platelet activation. Recent findings indicate that the activated platelets are crucial regulators of tumor vascular homeostasis in that they prevent tumor hemorrhage. Surprisingly, this effect is independent of platelets' capacity to form thrombi and instead relies on the secretion of their granule content. Thus, targeting platelet secretory activities may represent a new approach to specifically destabilize tumor vasculature. [Cancer Res 2009;69(14):5623–6]
Color Fluorescence Ratio for Detection of Bronchial Dysplasia and Carcinoma In situ
Authors: Lee Pyng , van den Berg Remco M. , Lam Stephen , Gazdar Adi F. , Grunberg Katrien , McWilliams Annette , LeRiche Jean , Postmus Pieter E. , Sutedja Tom G. 
Published: July 2009

Abstract
Background: Autofluorescence bronchoscopy is more sensitive than conventional bronchoscopy for detecting early airway mucosal lesions. Decreased specificity can lead to excessive biopsy and increased procedural time. Onco-LIFE, a device that combines fluorescence and reflectance imaging, allows numeric representation by expressing red-to-green ratio (R/G ratio) within the region of interest. The aim of the study was to determine if color fluorescence ratio (R/G ratio) added to autofluorescence bronchoscopy could provide an objective means to guide biopsy.
Methods: Subjects at risk for lung cancer were recruited at two centers: VU University Medical Centre (Amsterdam) and BC Cancer Agency (Canada). R/G ratio for each site appearing normal or abnormal was measured before biopsy. R/G ratios were correlated with pathology, and a receiver operating characteristic curve of R/G ratio for high-grade and moderate dysplasia was done. Following analysis of the training data set obtained from two centers, a prospective validation study was done.
Results: Three thousand three hundred sixty-two adequate biopsies from 738 subjects with their corresponding R/G ratios were analyzed. R/G ratio 0.54 conferred 85% sensitivity and 80% specificity for the detection of high-grade and moderate dysplasia, area under the curve was 0.90, and 95% confidence interval was 0.88 to 0.92. In another 70 different sites that were assessed, κ measurements of agreement of R/G ratios with visual scores and pathology were 0.66 (P &lt; 0.0001) and 0.61 (P &lt; 0.0001), respectively. R/G ratio combined with visual score improved specificity to 88% (95% confidence interval, 0.73-0.96) for high-grade and moderate dysplasia.
Conclusion: Color fluorescence ratio can objectively guide the bronchoscopist in selecting sites for biopsy with good pathologic correlation.
Combination of Viral Oncolysis and Tumor-Specific Immunity to Control Established Tumors
Authors: Chuang Chi-Mu , Monie Archana , Wu Annie , Pai Sara I. , Hung Chien-Fu 
Published: July 2009

Abstract
Purpose: Advanced-stage cancers are extremely difficult to treat and rarely result in a cure. The application of oncolytic viruses is a potential strategy for controlling advanced-stage cancer because intratumoral (i.t.) injection of an oncolytic virus, such as vaccinia virus, results in tumor cell lysis and subsequent release of tumor antigens into the microenvironment. Furthermore, the viruses can serve as a vehicle for delivering genes of interest to cancer cells.
Experimental Design: In the current study, we hypothesize that in tumor-bearing mice primed with DNA encoding an immunogenic foreign antigen, ovalbumin (OVA) followed by a boost with i.t. administration of vaccinia virus encoding the same foreign antigen, OVA, can generate enhanced antitumor effects through the combination of viral oncolysis and tumor-specific immunity.
Results: We observed that tumor-bearing mice primed with OVA DNA and boosted with vaccinia encoding OVA (Vac-OVA) generated significant therapeutic antitumor effects as well as induced significant levels of OVA-specific CD8+ T cells in two different tumor models. Furthermore, treatment with Vac-OVA not only kills the tumor and stromal cells directly but also renders the tumor cells and surrounding stromal cells susceptible to OVA-specific CD8+ T-cell killing, resulting in enhanced antitumor therapeutic effects.
Conclusions: Thus, the current study may provide a novel therapeutic strategy for the control of advanced-stage cancers.
Activation of Phosphatidylinositol-3′-kinase/AKT Signaling Is Essential in Hepatoblastoma Survival
Authors: Hartmann Wolfgang , Küchler Jan , Koch Arend , Friedrichs Nicolaus , Waha Anke , Endl Elmar , Czerwitzki Jacqueline , Metzger Dagmar , Steiner Susanne , Wurst Peter , Leuschner Ivo , von Schweinitz Dietrich , Buettner Reinhard , Pietsch Torsten 
Published: July 2009

AbstractPurpose: Hepatoblastoma represents the most frequent malignant liver tumor in childhood. The phosphatidylinositol-3′-kinase (PI3K)/AKT pathway is crucial in downstream signaling of multiple receptor tyrosine kinases of pathogenic importance in hepatoblastoma. Increased PI3K/AKT signaling pathway activity and activating mutations of PIK3CA, encoding a PI3K catalytic subunit, have been reported in different childhood tumors. The current study was done to analyze the role of PI3K/AKT signaling in hepatoblastoma.Experimental Design: Immunohistochemical stainings of (Ser473)-phosphorylated (p)-AKT protein, its targets p-(Ser9)-GSK-3β and p-(Ser2448)-mTOR, as well as the cell cycle regulators Cyclin D1, p27KIP1, and p21CIP1 were done and the PIK3CA gene was screened for mutations. In vitro, two hepatoblastoma cell lines treated with the PI3K inhibitor LY294002 were analyzed for AKT and GSK-3β phosphorylation, cell proliferation, and apoptosis. Additionally, simultaneous treatments of hepatoblastoma with LY294002 and cytotoxic drugs were carried out.Results: Most tumors strongly expressed p-AKT, p-GSK-3β, and p-mTOR; subgroups showed significant Cyclin D1, p27KIP1, and p21CIP1 expression. One hepatoblastoma carried an E545A mutation in the PIK3CA gene. In vitro, PI3K inhibition diminished hepatoblastoma cell growth being accompanied by reduced AKT and GSK-3β phosphorylation. Flow cytometry and 4', 6-diamidino-2-phenylindole stainings showed that PI3K pathway inhibition leads to a substantial increase in apoptosis and a decrease in cellular proliferation linked to reduced Cyclin D1 and increased p27KIP1 levels. Simultaneous treatment of hepatoblastoma cell lines with LY294002 and cytotoxic drugs resulted in positive interactions.Conclusions: Our findings imply that PI3K signaling plays an essential role in growth control of hepatoblastoma and might be successfully targeted in multimodal therapeutic strategies.
MSH6 Mutations Arise in Glioblastomas during Temozolomide Therapy and Mediate Temozolomide Resistance
Authors: Yip Stephen , Miao Jiangyong , Cahill Daniel P. , Iafrate A. John , Aldape Ken , Nutt Catherine L. , Louis David N. 
Published: July 2009

Abstract
Purpose: Over the past few years, the alkylating agent temozolomide has become the standard-of-care therapy for patients with glioblastoma, the most common brain tumor. Recently, large-scale cancer genome sequencing efforts have identified a hypermutation phenotype and inactivating MSH6 mismatch repair gene mutations in recurrent, post-temozolomide glioblastomas, particularly those growing more rapidly during temozolomide treatment. This study aimed to clarify the timing and role of MSH6 mutations in mediating glioblastoma temozolomide resistance.
Experimental Design: MSH6 sequence and microsatellite instability (MSI) status were determined in matched prechemotherapy and postchemotherapy glioblastomas identified by The Cancer Genome Atlas (TCGA) as having posttreatment MSH6 mutations. Temozolomide-resistant lines were derived in vitro through selective growth under temozolomide, and the MSH6 gene was sequenced in resistant clones. The role of MSH6 inactivation in mediating resistance was explored using lentiviral short hairpin RNA knockdown and MSH6 reconstitution.
Results: MSH6 mutations were confirmed in posttreatment TCGA glioblastomas but absent in matched pretreatment tumors. The posttreatment hypermutation phenotype displayed a signature bias toward CpC transitions and was not associated with MSI. In vitro modeling through exposure of an MSH6 wild-type glioblastoma line to temozolomide resulted in resistant clones; one clone showed an MSH6 mutation, Thr1219Ile, that had been independently noted in two treated TCGA glioblastomas. Knockdown of MSH6 in the glioblastoma line U251 increased resistance to temozolomide cytotoxicity and reconstitution restored cytotoxicity in MSH6-null glioma cells.
Conclusions: MSH6 mutations are selected in glioblastomas during temozolomide therapy both in vitro and in vivo and are causally associated with temozolomide resistance.