bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA-137 Targets Microphthalmia-Associated Transcription Factor in Melanoma Cell Lines
Authors: Bemis Lynne T. , Chen Robert , Amato Carol M. , Classen Elizabeth H. , Robinson Steven E. , Coffey David G. , Erickson Paul F. , Shellman Yiqun G. , Robinson William A. 
Published: March 2008

Abstract
Micropthalmia-associated transcription factor (MITF) is the master regulator of melanocyte development, survival, and function. Frequent alteration in the expression of MITF is detected in melanoma, but the mechanism(s) underlying the alteration in expression have not been completely determined. In these studies, we have identified microRNA-137 (miR-137) as a regulator of MITF expression. The genomic locus of miR-137 at chromosome 1p22 places it in a region of the human genome previously determined to harbor an allele for melanoma susceptibility. Here, we show that expression of mature miR-137 in melanoma cell lines down-regulates MITF expression. Further, we have identified a 15-bp variable nucleotide tandem repeat located just 5′ to the pre-miR-137 sequence, which alters the processing and function of miR-137 in melanoma cell lines. [Cancer Res 2008;68(5):1362–8]
T-cadherin Supports Angiogenesis and Adiponectin Association with the Vasculature in a Mouse Mammary Tumor Model
Authors: Hebbard Lionel W. , Garlatti Michèle , Young Lawrence J.T. , Cardiff Robert D. , Oshima Robert G. , Ranscht Barbara 
Published: March 2008

AbstractT-cadherin delineates endothelial, myoepithelial, and ductal epithelial cells in the normal mouse mammary gland, and becomes progressively restricted to the vasculature during mammary tumorigenesis. To test the function of T-cadherin in breast cancer, we inactivated the T-cadherin (Cdh13) gene in mice and evaluated tumor development and pathology after crossing the mutation into the mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyV-mT) transgenic model. We report that T-cadherin deficiency limits mammary tumor vascularization and reduces tumor growth. Tumor transplantation experiments confirm the stromal role of T-cadherin in tumorigenesis. In comparison with wild-type MMTV-PyV-mT controls, T-cadherin–deficient tumors are pathologically advanced and metastasize to the lungs. T-cadherin is a suggested binding partner for high molecular weight forms of the circulating, fat-secreted hormone adiponectin. We discern adiponectin in association with the T-cadherin–positive vasculature in the normal and malignant mammary glands and report that this interaction is lost in the T-cadherin null condition. This work establishes a role for T-cadherin in promoting tumor angiogenesis and raises the possibility that vascular T-cadherin-adiponectin association may contribute to the molecular cross-talk between tumor cells and the stromal compartment in breast cancer. [Cancer Res 2008;68(5):1407–16]
Selective Induction of Expression of a Ligand for the NKG2D Receptor by Proteasome Inhibitors
Authors: Valés-Gómez Mar , Chisholm Susan E. , Cassady-Cain Robin L. , Roda-Navarro Pedro , Reyburn Hugh T. 
Published: March 2008

AbstractThe interaction of the activating receptor NKG2D with its ligands plays an important role in immunosurveillance of tumors and infectious pathogens, but dysregulation of this system may lead to autoimmunity. The expression of NKG2D ligands is induced by cellular “stress.” However, the regulation of expression of these molecules is not well understood. Here, we show that cells treated with proteasome inhibitors can become more susceptible to cytotoxicity mediated by natural killer cells because of the induction of expression of ligands for NKG2D, specifically ULBP2, but not down-regulation of MHC class I. Treatment with proteasome inhibitors led to up-regulation of ULBP2 expression in multiple, but not all, cell lines tested. This increase in expression of ULBP2 at the cell surface correlated with induction of transcription of the ULBP2 gene and synthesis of ULBP2 protein. In contrast, treatment with inhibitors of histone deacetylases led to increased levels of mRNA and protein, for both ULBP2 and MHC class I–related chain A/B molecules. Thus, different types of stress can trigger up-regulated expression of different sets of NKG2D ligands. Proteasome inhibitors are proving to be of significant value in the treatment of hematologic malignancies and these observations may help to better understand the biology of therapy with these compounds. [Cancer Res 2008;68(5):1546–54]
Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth
Authors: Ohta Tsutomu , Iijima Kumiko , Miyamoto Mamiko , Nakahara Izumi , Tanaka Hiroshi , Ohtsuji Makiko , Suzuki Takafumi , Kobayashi Akira , Yokota Jun , Sakiyama Tokuki , Shibata Tatsuhiro , Yamamoto Masayuki , Hirohashi Setsuo 
Published: March 2008

Abstract
Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug-metabolizing and antioxidative stress enzymes/proteins. Because oxidative and electrophilic stresses cause many diseases, including cancer, we hypothesized that an abnormality in the Nrf2-Keap1 system may facilitate the growth of cancer cells. We sequenced the KEAP1 gene of 65 Japanese patients with lung cancer and identified five nonsynonymous somatic mutations at a frequency of 8%. We also identified two nonsynonymous somatic KEAP1 gene mutations and two lung cancer cell lines expressing KEAP1 at reduced levels. In lung cancer cells, low Keap1 activity (due to mutations or low-level expression) led to nuclear localization and constitutive activation of Nrf2. The latter resulted in constitutive expression of cytoprotective genes encoding multidrug resistance pumps, phase II detoxifying enzymes, and antioxidative stress enzymes/proteins. Up-regulation of these target genes in lung cancer cells led to cisplatin resistance. Nrf2 activation also stimulated growth of lung cancer–derived cell lines expressing KEAP1 at low levels and in mutant cell lines and in Keap1-null mouse embryonic fibroblasts under homeostatic conditions. Thus, inhibition of NRF2 may provide new therapeutic approaches in lung cancers with activation of Nrf2. [Cancer Res 2008;68(5):1303–9]
Discovery and Validation of Protein Abundance Differences between Follicular Thyroid Neoplasms
Authors: Netea-Maier Romana T. , Hunsucker Stephen W. , Hoevenaars Brigiet M. , Helmke Steve M. , Slootweg Pieter J. , Hermus Ad R. , Haugen Bryan R. , Duncan Mark W. 
Published: March 2008

AbstractDistinguishing between benign follicular thyroid adenoma (FTA) and malignant follicular thyroid carcinoma (FTC) by cytologic features alone is not possible. Molecular markers may aid distinguishing FTA from FTC in patients with indeterminate cytology. The aim of this study is to define protein abundance differences between FTC from FTA through a discovery (proteomics) and validation (immunohistochemistry) approach. Difference gel electrophoresis (DIGE) and peptide mass fingerprinting were performed on protein extracts from five patients with FTC and compared with six patients with FTA. Individual gel comparisons (i.e., each FTC extract versus FTA pool) were also performed for the five FTC patients. Immunohistochemical validation studies were performed on three of the identified proteins. Based on DIGE images, 680 protein spots were matched on individual gels. Of these, 102 spots showed statistically significant differences in abundance between FTC and FTA in the individual gel analyses and were therefore studied further. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to identify 54 of these protein spots. Three candidates involved in protein folding (heat shock protein gp96, protein disulfide isomerase A3, and calreticulin) were studied by immunohistochemistry. Moderate calreticulin immunohistochemical staining was the best single marker with a high negative predictive value (88%); combining all three markers (any marker less than moderate staining) had the best positive predictive value (75%) while still retaining a good negative predictive value (68%). With DIGE, we identified 54 proteins differentially abundant between FTC and FTA. Three of these were validated by immunohistochemistry. These findings provide further insights into the diagnosis, prognosis, and pathophysiology of follicular-derived thyroid neoplasms. [Cancer Res 2008;68(5):1572–80]
An Actin-Binding Protein Girdin Regulates the Motility of Breast Cancer Cells
Authors: Jiang Ping , Enomoto Atsushi , Jijiwa Mayumi , Kato Takuya , Hasegawa Taisaku , Ishida Maki , Sato Tomoko , Asai Naoya , Murakumo Yoshiki , Takahashi Masahide 
Published: March 2008

Abstract
Girdin (girders of actin filaments) is a novel actin-binding Akt substrate that plays an important role in actin organization and Akt-dependent cell motility in fibroblasts. Here, we find that Girdin is expressed in a variety of cancer cell lines, including the breast cancer cell line MDA-MB-231, and is phosphorylated by the stimulation of insulin-like growth factor (IGF-I). In vitro migration and invasion assays showed that Girdin is required for the IGF-I–dependent cell movement of MDA-MB-231 cells. Short hairpin interfering RNA directed against Girdin markedly inhibited the metastasis of s.c. transplanted MDA-MB-231 cells in nude mice. In addition, Girdin is highly expressed in a variety of human malignant tissues, including breast, colon, lung, and uterine cervical carcinomas. These findings highlight the important role of Girdin in tumor progression in which the Akt signaling pathway is aberrantly activated. [Cancer Res 2008;68(5):1310–8]
Tempol Protects against Oxidative Damage and Delays Epithelial Tumor Onset in Fanconi Anemia Mice
Authors: Zhang Qing-Shuo , Eaton Laura , Snyder Eric R. , Houghtaling Scott , Mitchell James B. , Finegold Milton , Van Waes Carter , Grompe Markus 
Published: March 2008

Abstract
Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure, and marked cancer susceptibility. FA patients have an elevated risk of developing hematologic malignancies and solid tumors. Using Fancd2−/− knockout mice as a model of FA, we examined the potential of tempol, a nitroxide antioxidant and a superoxide dismutase mimetic, as a tumor-delaying agent for solid tumors. Dietary tempol increased the mean tumor-free survival time of Fancd2−/− Trp53+/− mice by 27% (P &lt; 0.01), from 308 to 390 days, without changing the overall tumor spectrum. More strikingly, tempol delayed the onset of epithelial tumors and increased the mean epithelial tumor-free survival time by 38% (P &lt; 0.0001), from 312 to 432 days, in Fancd2−/− Trp53+/− mice. These results show that tempol can significantly delay tumor formation in Fancd2−/− Trp53+/− mice. Furthermore, tempol treatment did not adversely affect the repopulating ability of FA hematopoietic stem cells. The reduction in oxidative DNA damage in tempol-treated FA fibroblasts and mice suggests that its tumor-delaying function may be attributed to its antioxidant activity. [Cancer Res 2008;68(5):1601–8]
TGFBR1*6A Enhances the Migration and Invasion of MCF-7 Breast Cancer Cells through RhoA Activation
Authors: Rosman Diana S. , Phukan Sharbani , Huang Chiang-Ching , Pasche Boris 
Published: March 2008

Abstract
TGFBR1*6A is a common hypomorphic variant of the type 1 transforming growth factor β receptor (TGFBR1), which has been associated with increased cancer risk in some studies. Although TGFBR1*6A is capable of switching TGF-β growth-inhibitory signals into growth-stimulatory signals when stably transfected into MCF-7 breast cancer cells, the biological effects of TGFBR1*6A are largely unknown. To broadly explore the potential oncogenic properties of TGFBR1*6A, we assessed its effects on NIH-3T3 cells as well as its effect on the migration and invasion of MCF-7 cells. We found that TGFBR1*6A has decreased oncogenic properties compared with TGFBR1. However, TGFBR1*6A significantly enhances MCF-7 cell migration and invasion in a TGF-β signaling–independent manner. Gene expression profiling studies identified two down-regulated genes involved in cell migration and invasion: ARHGAP5, encoding ARHGAP5, and FN1, encoding fibronectin-1 (FN1). ARHGAP5 and FN1 expression was similarly down-regulated in MCF-7 cells stably transfected with a kinase-inactivated TGFBR1*6A construct. Functional assays show that TGFBR1*6A-mediated decreased ARHGAP5 expression is associated with higher RhoA activation, a crucial mediator of cell migration. Extracellular signal-regulated kinase (ERK) activation is also higher in cells that harbor the TGFBR1*6A allele. We conclude that TGFBR1*6A is not an oncogene but enhances MCF-7 cell migration and invasion through RhoA and ERK pathway activation and down-regulates two crucial mediators of this phenotype. These results provide the first evidence that TGFBR1*6A may contribute to cancer progression in a TGF-β signaling–independent manner. [Cancer Res 2008;68(5):1319–28]
Synergistic Effect of Oncogenic RET and Loss of p18 on Medullary Thyroid Carcinoma Development
Authors: van Veelen Wendy , van Gasteren Carola J.R. , Acton Dennis S. , Franklin David S. , Berger Ruud , Lips Cornelis J.M. , Höppener Jo W.M. 
Published: March 2008

Abstract
Activating mutations in the RET proto-oncogene are associated with both familial and sporadic medullary thyroid carcinoma (MTC) development; however, the genetic mechanisms underlying MTC tumorigenesis remain largely unknown. Recently, we have identified somatic inactivating mutations in the cell cycle inhibitor gene P18 in human MTC, which coincided with activating RET mutations, suggesting a role for loss of P18 in combination with oncogenic RET in the multistep process of MTC development. Therefore, we crossed transgenic mice expressing oncogenic RET (RET2B) with mice lacking p18 (and p27, another cell cycle inhibitor) and monitored MTC development. RET2B;p18+/− mice and RET2B;p18−/− mice developed MTC with a highly increased incidence compared with their corresponding single mutant littermates. In addition, expression of oncogenic RET causes an earlier age of onset and larger MTCs in p18−/−;p27+/− mice. In a subset of MTCs of RET2B;p18+/−(;p27+/−) mice, p18Ink4c expression was completely lost. This loss of p18Ink4c expression correlated with higher proliferation rates as well as with larger MTCs, indicating that loss of p18 in combination with oncogenic RET not only increases the risk for MTC development but also enhances MTC progression. Our data strongly indicate that oncogenic RET and loss of p18 cooperate in the multistep tumorigenesis of MTC. [Cancer Res 2008;68(5):1329–37]
Preclinical Cancer Therapy in a Mouse Model of Neurofibromatosis-1 Optic Glioma
Authors: Hegedus Balazs , Banerjee Debasish , Yeh Tu-Hsueh , Rothermich Stefan , Perry Arie , Rubin Joshua B. , Garbow Joel R. , Gutmann David H. 
Published: March 2008

Abstract
Mouse models of human cancers afford unique opportunities to evaluate novel therapies in preclinical trials. For this purpose, we analyzed three genetically engineered mouse (GEM) models of low-grade glioma resulting from either inactivation of the neurofibromatosis-1 (Nf1) tumor suppressor gene or constitutive activation of KRas in glial cells. Based on tumor proliferation, location, and penetrance, we selected one of these Nf1 GEM models for preclinical drug evaluation. After detection of an optic glioma by manganese-enhanced magnetic resonance imaging, we randomized mice to either treatment or control groups. We first validated the Nf1 optic glioma model using conventional single-agent chemotherapy (temozolomide) currently used for children with low-grade glioma and showed that treatment resulted in decreased proliferation and increased apoptosis of tumor cells in vivo as well as reduced tumor volume. Because neurofibromin negatively regulates mammalian target of rapamycin (mTOR) signaling, we showed that pharmacologic mTOR inhibition in vivo led to decreased tumor cell proliferation in a dose-dependent fashion associated with a decrease in tumor volume. Interestingly, no additive effect of combined rapamycin and temozolomide treatment was observed. Lastly, to determine the effect of these therapies on the normal brain, we showed that treatments that affect tumor cell proliferation or apoptosis did not have a significant effect on the proliferation of progenitor cells within brain germinal zones. Collectively, these findings suggest that this Nf1 optic glioma model may be a potential preclinical benchmark for identifying novel therapies that have a high likelihood of success in human clinical trials. [Cancer Res 2008;68(5):1520–8]
Molecular Basis of Nuclear Factor-κB Activation by Astrocyte Elevated Gene-1
Authors: Sarkar Devanand , Park Eun Sook , Emdad Luni , Lee Seok-Geun , Su Zao-zhong , Fisher Paul B. 
Published: March 2008

Abstract
Malignant glioma is a consistently fatal brain cancer. The tumor invades the surrounding tissue, limiting complete surgical removal and thereby initiating recurrence. Identifying molecules critical for glioma invasion is essential to develop targeted, effective therapies. The expression of astrocyte elevated gene-1 (AEG-1) increases in malignant glioma and AEG-1 regulates in vitro invasion and migration of malignant glioma cells by activating the nuclear factor-κB (NF-κB) signaling pathway. The present studies elucidate the domains of AEG-1 important for mediating its function. Serial NH2-terminal and COOH-terminal deletion mutants were constructed and functional analysis revealed that the NH2-terminal 71 amino acids were essential for invasion, migration, and NF-κB–activating properties of AEG-1. The p65-interaction domain was identified between amino acids 101 to 205, indicating that p65 interaction alone is not sufficient to mediate AEG-1 function. Coimmunoprecipitation assays revealed that AEG-1 interacts with cyclic AMP-responsive element binding protein–binding protein (CBP), indicating that it might act as a bridging factor between NF-κB, CBP, and the basal transcription machinery. Chromatin immunoprecipitation assays showed that AEG-1 is associated with the NF-κB binding element in the interleukin-8 promoter. Thus, AEG-1 might function as a coactivator for NF-κB, consequently augmenting expression of genes necessary for invasion of glioma cells. In these contexts, AEG-1 represents a viable potential target for the therapy of malignant glioma. [Cancer Res 2008;68(5):1478–84]
Enhanced Expression of RAD51 Associating Protein-1 Is Involved in the Growth of Intrahepatic Cholangiocarcinoma Cells
Authors: Obama Kazutaka , Satoh Seiji , Hamamoto Ryuji , Sakai Yoshiharu , Nakamura Yusuke , Furukawa Yoichi 
Published: March 2008

Abstract
Purpose: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary cancer in the liver, and its incidence is increasing in developed countries.
Experimental Design: To discover novel molecular targets for the diagnosis and treatment of ICCs, we earlier analyzed expression profiles of 25 ICCs using a cDNA microarray containing 27,648 genes. In this study, we focused on the RAD51 associating protein-1 (RAD51AP1) gene because its expression was frequently elevated in our microarray data.
Results: Quantitative PCR confirmed that RAD51AP1 expression was elevated in the great majority of the ICCs examined. Immunohistochemical analysis with anti-RAD51AP1 antibody further corroborated its accumulation in 14 of 23 ICC tissues (61%). Notably, suppression of RAD51AP1 by short interfering RNA resulted in growth suppression of cholangiocarcinoma cells, suggesting its involvement in the development and/or progression of ICC. Because RAD51AP1 interacts with RAD51, a molecule involved in DNA repair, we investigated whether RAD51AP1 is implicated in DNA strand breaks using γ-irradiation. As a result, γ-irradiation augmented RAD51AP1 protein expression and brought a focus formation in the nuclei, where accumulated RAD51AP1 colocalized with phosphorylated histone 2AX (γ-H2AX) and RAD51. These data suggest that RAD51AP1 may play a role in cell proliferation as well as DNA repair.
Conclusion: Our findings may contribute to the better understanding of cholangiocarcinogenesis and open a new avenue to the development of novel therapeutic and/or diagnostic approach to this type of tumor.
Therapeutic Nanoparticles for Drug Delivery in Cancer
Authors: Cho Kwangjae , Wang Xu , Nie Shuming , Chen Zhuo (Georgia) , Shin Dong M. 
Published: March 2008

AbstractCancer nanotherapeutics are rapidly progressing and are being implemented to solve several limitations of conventional drug delivery systems such as nonspecific biodistribution and targeting, lack of water solubility, poor oral bioavailability, and low therapeutic indices. To improve the biodistribution of cancer drugs, nanoparticles have been designed for optimal size and surface characteristics to increase their circulation time in the bloodstream. They are also able to carry their loaded active drugs to cancer cells by selectively using the unique pathophysiology of tumors, such as their enhanced permeability and retention effect and the tumor microenvironment. In addition to this passive targeting mechanism, active targeting strategies using ligands or antibodies directed against selected tumor targets amplify the specificity of these therapeutic nanoparticles. Drug resistance, another obstacle that impedes the efficacy of both molecularly targeted and conventional chemotherapeutic agents, might also be overcome, or at least reduced, using nanoparticles. Nanoparticles have the ability to accumulate in cells without being recognized by P-glycoprotein, one of the main mediators of multidrug resistance, resulting in the increased intracellular concentration of drugs. Multifunctional and multiplex nanoparticles are now being actively investigated and are on the horizon as the next generation of nanoparticles, facilitating personalized and tailored cancer treatment.
Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells
Authors: Black Peter C. , Brown Gordon A. , Inamoto Teruo , Shrader Marissa , Arora Ameeta , Siefker-Radtke Arlene O. , Adam Liana , Theodorescu Dan , Wu Xifeng , Munsell Mark F. , Bar-Eli Menashe , McConkey David J. , Dinney Colin P.N. 
Published: March 2008

AbstractPurpose: Epidermal growth factor receptor (EGFR) is an attractive target for the treatment of urothelial carcinoma, but a clinical response can be expected in only a small proportion of patients. The aim of this study was to define molecular markers of response to cetuximab therapy in a panel of urothelial carcinoma cell lines.Experimental Design: Eleven cell lines were investigated for antiproliferative response to cetuximab based on [3H]thymidine incorporation. A variety of markers, including EGFR expression, phosphorylation, and gene amplification, as well as the expression of other growth factor receptors, their ligands, and markers of epithelial-to-mesenchymal transition were investigated. Cohen's κ statistic was used to estimate the agreement between response and expression of these markers. E-cadherin was silenced by small interfering RNA in two sensitive cell lines, and the effect on the response to cetuximab was measured.Results: We were able to identify a panel of relevant markers pertaining especially to alternate growth factor receptor expression and epithelial-to-mesenchymal transition that predicted response to cetuximab. The data suggested that expression of intact HER-4 (κ, 1.00; P = 0.008), E-cadherin (κ, 0.81; P = 0.015), and β-catenin (κ, 0.81; P = 0.015) and loss of expression of platelet-derived growth factor receptor β (κ, 0.57; P = 0.167) were associated with response to cetuximab therapy. Silencing E-cadherin in two sensitive cell lines reduced responsiveness to cetuximab in both (P &lt; 0.001).Conclusions: A panel of predictive markers for cetuximab response has been established in vitro and is currently being evaluated in a prospective clinical trial of neoadjuvant EGFR-targeted therapy. Most importantly, E-cadherin seems to play a central role in modulation of EGFR response in urothelial carcinoma.