bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3021: An in vitro investigation of metabolically sensitive epigenetic biomarkers in breast cancer progression
Authors: Simpson Natalie E. , Tryndyak Volodymyr P. , Beland Frederick A. , Pogribny Igor P. 
Published: June 2012

Abstract
Cancer cells, including breast cancer cells, display unique alterations in major cellular metabolic pathways; therefore, it is widely believed that a better understanding of molecular cancer cell metabolism may reveal new approaches to aid in the diagnosis, treatment, and prevention of breast cancer. Results from recent in vivo and in vitro studies have demonstrated substantial metabolic differences between non-invasive and invasive breast cancers. Epigenetic marks, including histone post-translational modifications and DNA methylation, are emerging as biomarkers for most of the major human cancers. Additionally, the histone modifying enzymes (HME) (i.e., histone acetyltransferases, deacetylases, methyltransferases, and demethylases) that regulate these epigenetic changes are metabolically sensitive. In light of these considerations, the goal of the current study was to determine if any metabolic differences between non-invasive epithelial and invasive mesenchymal breast cancer cells are associated with the differences in histone modifications identified previously as being biomarkers of breast cancer progression. By comparing gene expression profiles from non-invasive breast cancer cells with an epithelial phenotype (i.e., MCF-7, MDA-MB-361, and T-47D cells) to invasive cells with an aggressive mesenchymal phenotype (i.e., Hs-578T, BT-549, and especially MDA-MB-231 cells), we determined that many metabolically regulated HMEs are differentially expressed in these cancer cells. We further demonstrated reduced acetylation of histone H3 lysine 9/18, reduced acetylation of histone H4 lysine 16/20, and reduced tri-methylation of histone H4 lysine 20 in breast cancer cells with a mesenchymal phenotype as compared to cells with an epithelial phenotype. Interestingly, the observed histone modification profile of invasive breast cancer cell lines is similar to what is found in individuals who exhibit disease recurrence and have a poor prognosis. These results suggest that metabolically sensitive histone modifications and their corresponding HMEs may be used as diagnostic and prognostic biomarkers. This makes them attractive targets for chemopreventive and chemotherapeutic strategies in breast cancer management.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3021. doi:10.1158/1538-7445.AM2011-3021
Abstract 3023: Rapid methylation profiling of multiple genes at the same time using the methylation ligation-dependent macroarray (MLM)
Authors: Benhattar Jean , Guilleret Isabelle 
Published: June 2012

Abstract
Background: Aberrant methylation of multiple promoter CpG islands is a common event in human cancers. Methylation profile of cancer-related genes has extraordinary potential in basic research as well as translational medicine. The aim of this study was to replace the tedious and inefficient bisulfite-based methods with a simple technology which could permit a rapid and robust analysis of large numbers of genes in large numbers of tumor samples simultaneously.
Materials and methods: Genomic DNA was first sonicated, then couples of primers for each specific gene promoter were annealed to this DNA. In a one-step reaction, the CfoI methylation-sensitive enzyme digested unmethylated DNA, whereas the Taq ligase joined primers annealed to the methylated sequence. Tagged ligation products were amplified by PCR and finally hybridized to a nylon membrane macroarray. Methylation Ligation-dependent Macroarray (MLM) allows the establishment of DNA methylation profiles on many samples (up to 21) and on many gene promoters (up to 45) in a simple reaction in 2-3 days. To validate this novel method, we used it to detect aberrant methylation in 14 cell lines and in DNA samples of 40 patients with a colorectal cancer.
Results: In tumor cell lines, among the 42 genes investigated 23.7 (11-32) were found methylated whereas only 9 have been observed methylated in a normal fibroblast cell line (BJ). In normal colorectal tissues, about 12/40 gene promoters were found methylated; in colorectal cancers 16 to 36 genes were methylated. Methylated gene promoters identified in colorectal cancers were ADAMTS18 (78%), APC (28%), CDKN2A (20%), DKK2 (50%), GPx3 (48%), Mal (72%), MLH1 (30%), NELL1 (72%), SFRP4 (35%), SFRP5 (52%) and WRN (20%):
Conclusion: The MLM is a fast, non expensive and reliable technology that profiles the DNA methylation status of &gt;40 promoter CpG islands in various human samples. This technology can be used in research for rapid methylation profiling of numerous samples and for identification of new epigenetic biomarkers, but also in clinic for rapid cancer diagnosis, for predictive response to cancer therapy and for distinction between progressive and non-progressive diseases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3023. doi:10.1158/1538-7445.AM2011-3023
Abstract 3041: Focal amplification of chromosome 9p13 is associated with progression risk and activation of multiple oncogenes in oral precancers
Authors: Towle Rebecca M. , Tsui Ivy , Garnis Cathie 
Published: June 2012

Abstract
Oral squamous cell carcinoma, the most common form of head and neck cancer, has a dismal five year survival rate of ∼50%. This is largely due to the late stage of diagnosis and high rates of recurrence. A better understanding of the mechanisms driving early oral tumorigenesis is an essential first step towards increasing survival rates, which have not improved in decades. Specifically, by characterizing genetic alterations in early oral premalignant lesions (OPLs), we will better understand mechanisms of disease progression and discover targets for timely therapeutic intervention that could ultimately improve oral cancer outcomes.
Methods: Whole genome DNA copy number profiling was undertaken on a rare panel of OPLs with extensive longitudinal data (including known progression status for invasive disease). Recurring alterations were characterized and gene lists were refined using independent tumor-associated gene expression datasets. The functional significance of remaining gene candidates was then assessed using lentiviral shRNA and expression vectors in cell model systems.
Results: Analysis of genomic data from OPLs identified four focal recurrent alterations. Three of these alterations were associated with previously identified oncogenes: cMYC, EGFR, and KRAS. The fourth was a novel 2.04 Mbp amplification at chromosome 9p13. Based on our results and publicly available gene expression data, four candidate genes were found in this region: VCP, DCTN3, STOML2, and TLN1. Independent manipulation of each of these genes in cell models revealed changes in oncogenicity (based on changes in rate of proliferation and the degree of anchorage independence), suggesting a critical role in malignant processes associated with cancer progression.
Conclusion: We have shown that a recurring, focal 9p13 amplicon in OPLs is associated with progression to invasive oral cancer. Further, our data indicate that this region spans multiple genes with oncogenic potential. Taken together, our results suggest that a single amplification event may dysregulate multiple genes that drive progression to invasive oral cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3041. doi:10.1158/1538-7445.AM2011-3041
Abstract 3068: Detection of K-RAS mutations in Korean patients using PNAClampTM KRAS
Authors: Cho Minhye , Choi Jae-Jin , Oh Miae , Park Heekyung 
Published: June 2012

Abstract
Mutation of the K-RAS gene located in codons 12 and 13 may play an important role in prognosis of related diseases and responses to certain treatments targeting the pathway. Recent studies suggest that in colon cancer patients, K-RAS mutation status is a strong predictor of success in therapeutics of several tyrosine kinase inhibitors. Therefore, it is important to detect K-RAS mutations fast and accurately.
To detect a minority of mutant K-RAS among abundant wild-type alleles, we have developed a highly sensitive and simple method for the detection of K-RAS mutations using PNA-mediated real-time PCR clamping, PNAClampTM. PNAClampTM relies on the following two unique properties of PNA probes: 1) PNA-DNA duplexes generally have greater thermal stability than the corresponding DNA-DNA duplex; 2) PNA oligomers are not recognized by DNA polymerases and consequently can serve as a sequence-selective clamp during PCR amplification. This method is fast and accurate with a detection limit of approximately 0.1% mutant alleles using 10 ng to 25 ng of normal DNA as a template. The turnaround time for performance of this assay is only 2 hrs. The PNAClampTM method facilitates the detection of mutations in more than 1000-fold excess of wild-type DNA samples.
K-RAS mutations were detected in 28.3% (36/127) of patients. In detail, 29 cases had mutations in codon 12 and 7 cases had mutations in codon 13. To confirm those results, the same clinical samples were analyzed with a direct sequencing assay. Concordant results were obtained from 124 (97.6%) of the 127 clinical samples in the two assays. The discrepancy was observed in three cases. For comparison, the three clinical samples were also analyzed using DxS K-RAS Mutation Kit (DxS Ltd., UK) to give the same outcome. In this study, we will discuss development of PNAClampTM KRAS and its optimization for higher sensitivity. The PNAClampTM KRAS may serve a rapid and reliable alternative for K-RAS mutation detection in the clinical field.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3068. doi:10.1158/1538-7445.AM2011-3068
Abstract 3081: Tristetraprolin Controls let-7 regulator-Lin28 mRNA stability
Authors: Kim Chae Won , Vo Mai-Tram , Kim Hong Kyeung , Kim Hyo Jeong , Lee Hyun Hee , Yun Nal Ae , Lee Sun Young , Min Young Joo , Park Jeong Woo , Cho Wha Ja 
Published: June 2012

Abstract
The RNA binding protein tristetaprolin (TTP) regulates expression of many cancer-associated genes through binding to AU-rich elements (AREs) in the 3’ untranslated region (3’UTR) and facilitating rapid mRNA decay. In this study, we investigated the role of TTP in the control of micro RNA let-7 expression through regulation of Lin28 expression. TTP overexpression significantly suppressed the growth of PA1 human ovarian cancer cell line through down-regulation of CDC34 expression. However, CDC34 does not have the ARE motif within its 3’UTR, suggesting that TTP can not directly regulate CDC34 expression. Instead, CDC34 expression was regulated by let-7. Interestingly, we found that TTP regulates the expression of Lin28 which has been reported to be involved in maturation of let-7. Lin28 mRNA contains two AREs (ARE1 and ARE2) within the 3’UTR, and TTP destabilized a luciferase mRNA containing Lin28 ARE1 and directly bound to the ARE1 of Lin28 mRNA. These studies established Lin28 mRNA as a physiological target of TTP and demonstrate that TTP can control the expression levels of microRNA let-7 through regulation of Lin28 mRNA stability.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3081. doi:10.1158/1538-7445.AM2011-3081
Abstract 3085: The IFN inducible p53 target gene TRIM22 binds to the translation initation factor eIF4E and represses translation through disturbing the assembly of the eIF4F complex
Authors: Petersson Jessica , Ageberg Malin , Olofsson Tor , Gullberg Urban , Drott Kristina 
Published: June 2012

Abstract
TRIM22 (Staf50) is an interferon (IFN)-inducible protein as well as a p53 target gene. It belongs to the TRIM (TRIpartite Motif) family proteins, characterized of a conserved tripartite motif consisting of a RING finger, B-box and a coiled-coil domain. The TRIM family includes more than 70 proteins, involved in various biological processes; e.g. apoptosis and cell proliferation. Consistently, several TRIM family members are involved in cancer. TRIM22 has been suggested to be an antiviral protein, capable of restricting HIV-, hepatitis B- and encephalomyocarditis replication. The molecular mechanisms for TRIM22 are unclear, but the antiviral activity may be dependent on the ubiquitylation capacity of TRIM22. We have previously shown it to suppress the clonogenic growth of leukemic U-937 cells, suggesting anti-proliferative or cell death-inducing effects. Now, we demonstrate that TRIM22 binds to the translation initiation factor eIF4E, and inhibits the binding of eIF4E to eIF4G, thus disturbing the assembly of the eIF4F complex, vital for cap dependent translation of mRNA. As a consequence, TRIM22 represses translation, as shown by decreased reporter protein levels, as well as global protein synthesis. Pulse-chase and cycloheximide experiments reveal that the repressive effects on the reporter protein is not due to increased protein degradation. Taken together, our data show TRIM22 to repress the binding of eIF4E to eIF4G, suggesting a novel translation regulating mechanism, possibly mediated in response to p53 and/or IFN signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3085. doi:10.1158/1538-7445.AM2011-3085
Abstract 3090: Inhibition of p53 DNA binding function by the MDM2 acidic domain
Authors: Cross Brittany L. , Cheng Qain , Li Baozong , Yuan Zhi-Min , Chen Jiandong 
Published: June 2012

Abstract
MDM2 is an important regulator of p53, acting in part by promoting p53 ubiquitination. However, MDM2 has also been implicated in regulation of p53 through ubiquitination-independent mechanisms. Here we show that MDM2 inhibits p53 DNA binding activity in vitro and in vivo. MDM2 binding promotes p53 to adopt a mutant-like conformation, losing reactivity to antibody Pab1620, while exposing the Pab240 epitope. The acidic domain of MDM2 is required to induce p53 conformational change and inhibit p53 DNA binding, possibly by interacting with the p53 DNA binding domain. ARF binding to the MDM2 acidic domain restores p53 wild type conformation and rescues DNA binding activity. Furthermore, histone methyl transferase SUV39H1 binding to the MDM2 acidic domain also restores p53 wild type conformation and allows p53-MDM2-SUV39H1 complex to bind DNA. These results provide further evidence for an ubiquitination-independent mechanism of p53 regulation by MDM2, and reveal how MDM2-interacting repressors gain access to p53 target promoters and repress transcription.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3090. doi:10.1158/1538-7445.AM2011-3090
Abstract 3092: FBW7 targets hypoxia inducible factor-1α (HIF-1α) for proteasomal degradation during hypoxia
Authors: Cassavaugh Jessica , Hale Sarah , Wong Cheung , Lounsbury Karen M. 
Published: June 2012

Abstract
Hypoxia Inducible Factor-1α (HIF-1α) mediates expression of genes associated with endothelial cell-mediated angiogenesis and is associated with poor outcomes in a variety of cancers. In normoxia, HIF-1α is ubiquitinated and degraded through interactions with the E3 ubiqutin ligase, von Hippel-Lindau (vHL); however, little is known about the negative regulation of HIF-1α in hypoxia. FBW7, an E3 ubiquitin ligase, has been shown to interact with several transcription factors including those phosphorylated by glycogen synthase kinase 3β (GSK3β). The current study tested the hypothesis that phosphorylation of HIF-1α by GSK3β increases the FBW7-mediated ubiquitination and degradation of HIF-1α, thereby resulting in suppression of the hypoxia-mediated angiogenic response in SKOV-3 ovarian cancer cells. HIF-1α protein and VEGF transcript levels in hypoxia were increased when GSK3β activity was inhibited and were reduced by expression of constitutively active GSK3β (GSK3S9A). Additionally, expression of GSK3S9A increased HIF-1α ubiquitination. Conditioned media from SKOV-3 cells expressing shRNA against GSK3β (shGSK3) had an enhanced effect on endothelial tube formation in a Matrigel matrix, suggesting that GSK3β exerts an inhibitory effect on hypoxia-mediated angiogenesis. Overexpression of the β and γ isoforms of FBW7 decreased HIF-1α stabilization, and HIF-1α interacts with FBW7 by co-immunoprecipitation. Furthermore, knockdown of FBW7 using siRNA resulted in increased HIF-1α levels in hypoxia. These data suggest a new mechanism for negative regulation of HIF-1α during hypoxia that utilizes phosphorylation by GSK3β and interaction with FBW7 leading to ubiquitination and proteasomal degradation. Results of this study better define the signaling pathways necessary for HIF-1α-mediated signaling and may identify new targets that mediate angiogenesis in disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3092. doi:10.1158/1538-7445.AM2011-3092
Abstract 3107: Semaphorin 4D – plexin B1 signaling in pancreatic ductal adenocarcinoma reflects tumor aggressiveness
Authors: Shingo Kato , Kubota Kensuke , Shimamura Takeshi , Kobayashi Noritoshi , Watanabe Seitaro , Shinohara Yoshiyasu , Ishiguro Hitoshi , Nakaigawa Noboru , Kubota Yoshinobu , Maeda Shin , Nakajima Atsushi 
Published: June 2012

Abstract
Purpose: Semaphorins are a large family of proteins that provide axonal guidance in neuronal tissues and regulate cell motility in many types of cells. In recent studies, Semaphorin 4D (Sema4D) has been demonstrated to enhance the motility and invasiveness of cancer cells through its receptor, plexin B1, in vitro and also to increase the metastatic potential of breast cancer in vivo. However, the expression patterns and functions of Sema4D in pancreatic cancer remain unknown.
Experimental Design: We examined the expressions of Sema4D and plexin B1 in surgically resected specimens of pancreatic ductal adenocarcinoma by immunohistochemistry, and also the effect of Sema4D stimulation on the invasiveness of pancreatic cancer cells.
Results: Immunohistochemical staining revealed that Sema4D was expressed on the T cells and B cells in the cancer stroma. Plexin B1 was expressed in the cancer cells, whereas its expression was only faintly detected in the normal pancreatic ductal cells. Tumors with higher expression levels of Sema4D showed a significantly higher tendency towards lymph node metastasis (p = 0.0068), distant metastasis (p = 0.036), extrapancreatic nerve plexus invasion (p = 0.0073), and a poor prognosis (p = 0.024). Increased expression of both Sema4D and plexin B1 was associated with an additive worsening of the prognosis, independent of the tumor-node-metastasis classification and the World Health Organization tumor grade (p = 0.045). Stimulation with Sema4D caused a significant increase in the invasiveness of pancreatic cancer cells, and the knockdown of plexin B1 by siRNA could block the enhanced invasive activity by Sema4D.
Conclusion: Sema4D could play a role in the interactions between the tumor cells and the tumor microenvironment in pancreatic cancer. In the context of numerous attempts currently ongoing to target the tumor stroma, our findings provide insight into new molecular targets for the development of treatments for pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3107. doi:10.1158/1538-7445.AM2011-3107
Abstract 3124: Tetraspanin CD151-mediated signaling network between cell-matrix and cell-cell adhesions
Authors: Hong In-Kee , Lee Hansoo , Byun Hee-Jung , Park Iha , Kim Young-Myeong 
Published: June 2012

Abstract
CD151 has been suggested to promote cancer invasion and metastasis by regulating adhesion-dependent signaling events through its association with laminin-binding α3β1/α6β1 integrins. Previously, we have demonstrated that homophilic interactions of CD151 stimulate integrin-dependent signaling to c-Jun through the FAK-Src-MAPKs pathways in human melanoma cells. In this study, we found that CD151 plays a role in recruiting Ras, Rac1, and Cdc42, but not Rho, to the membrane region, leading to formation of α3β1/α6β1 integrins-CD151-small GTPases complexes. Adhesion receptor complexes-associated small GTPases were found to be activated by β1 integrins-CD151 complexes-stimulating adhesion events such as interactions of integrins with laminin and homophilic interactions of CD151 on two contacting cells, implicating CD151-mediated signaling network between cell-matrix and cell-cell adhesions. Adhesion-dependent activation of small GTPases appeared to be mediated by the FAK-Src pathways. Meanwhile, EGF and phorbol ester treatment further enhanced CD151-β1 integrin complexes-induced cell motility and MMP-9 expression, along with activation of p38 MAPK and JNK, indicating a positive signaling cross-talk between CD151-β1 integrin adhesion receptor, EGF receptor, and PKC. Using siRNAs and dominant-inhibitory mutant expression constructs for various intracellular signaling mediators, we found that integrin-linked kinase (ILK), PAK1-interacting exchange factor beta (β-PIX), and p21-activated protein kinase 1 (PAK1) were involved in CD151-β1 integrin adhesion receptor complex signaling pathways. Also, MEK3/6 and MEK7 were found to participate in CD151-β1 integrin signaling cascades, upstream of p38 MAPK and JNK, respectively. Taken together, our data strongly suggest that β1 integrin-CD151 adhesion receptor complexes activate c-Jun AP-1 factor via the signaling cascades involving the FAK-Src, ILK-β-Pix, small GTPases-PAK1, MEK3/6-p38 MAPK, and MEK7-JNK pathways, leading to increased cell motility and MMP-9 expression in human melanoma cells.
Key words: tetraspanin, CD151, integrin, adhesion receptor, cell signaling
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3124. doi:10.1158/1538-7445.AM2011-3124