bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3127: Cigarette smoke condensate (CSC) induces differential expression and promoter methylation profiles of critical genes involved in lung cancer in NL-20 lung cells in vitro: Short-term and chronic exposure
Authors: Lyn-Cook Lascelles E. , Word Beverly , Mwamba Bibi , Lyn-Cook Beverly D. , Hammons George 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer deaths in the United States. Smoking accounts for a large number of those deaths. Recently, the Food and Drug Administration has been given authority to regulate any new cigarette products coming to market and further demonstrate the harm caused by constituents in cigarettes or those chemicals created from smoking. Establishing early diagnostic markers are critical to effective prevention programs. This study examined the effects of cigarette smoke condensate on expression and promoter methylation profile of critical genes involved in various stages of lung cancer development, such as E-cadherin (ECAD), O6-mehyl-guanine-DNA methyltransferase (MGMT), and RASSF1A. NL-20 cells were treated with 0.1, 1, 10 or 100 µg/ml of CSC for 24, 48 and 72 hrs for short-term exposures. ECAD showed a significant decrease in expression after 72 hrs with both 10 and 100 µg/ml CSC. This decrease in expression correlated to hypermethylation of the ECAD promoter at both concentrations using MSP analysis. MGMT expression increased only with the concentration of 100 µg/ml CSC at all time points. This correlated to an unmethylated profile of the promoter at this concentration. RASSF1A promoter profile was methylated in the control samples. However, when treated with 10 or 100 µg/ml CSC, an unmethylated promoter profile was noted. This correlated to increased expression of RASSF1A at both the 10 and 100 µg/ml concentrations. No changes were noted at 0.1 or 1 µg/ml of CSC in NL-20 lung cells. For chronic studies, the cells were exposed for 30 days with 10 or 100 µg/ml CSC, with media changes every three days adding new CSC. After 30 days, cells showed morphological changes associated with transformation. Foci were noted. These cells were further analyzed for further changes in critical genes involved in lung cancer. This study provides critical data showing epigenetic regulation of critical genes involved in DNA repair, invasion and tumor suppressor with treatment of lung cells with CSC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3127. doi:1538-7445.AM2012-3127
Abstract 313: K-ras- and EGFR-mediated lung tumor formation require epithelial NF-κB signaling to modulate the inflammatory microenvironment
Authors: Ausborn Jamie A. , Sherrill Taylor , Zaynagetdinov Rinat , Polosukhin Vasiliy , McMahon Frank , Yull Fiona , Blackwell Timothy S. 
Published: August 2012

Abstract
The transcription factor nuclear factor-κB (NF-κB) is a key mediator of the inflammatory response, and its activation correlates with poor prognosis in non-small cell lung cancer patients. Oncogenic K-ras and epidermal growth factor receptor (EGFR) mutations occur frequently in lung adenocarcinoma and are associated with an inflammatory response in lung tumors. Recent papers have shown that inhibition of epithelial NF-κB signaling in a mouse model of K-ras-mediated lung tumorigenesis decreased tumor formation. However, the mechanisms linking NF-κB signaling to tumor formation remain unclear. We hypothesize that epithelial NF-κB signaling is a common requirement for lung tumorigenesis, causing activation and/or recruitment of inflammatory cells that promote lung tumor formation. For our studies, we used mice that inducibly express oncogenic K-rasG12D or EGFRT790M+L858R as well as a dominant negative inhibitor of κB signaling (DN-IκB) specifically in the lung epithelium. Mice expressing DN-IκB together with K-rasG12D or EGFRT790M+L858R developed significantly fewer tumors than mice expressing K-rasG12D or EGFRT790M+L858R alone after two months of doxycycline administration. However, two months of K-rasG12D or EGFRT790M+L858R expression did not significantly alter total inflammatory cell numbers in bronchoalveolar lavage fluid (BAL). EGFRT790M+L858R expression led to an increase in BAL neutrophils that was lost when NF-κB signaling was inhibited, while no changes in BAL macrophage, lymphocyte, or neutrophil subpopulations were observed in K-rasG12D-expressing mice with or without NF-κB signaling. At later time points, both K-rasG12D- and EGFRT790M+L858R-expressing mice demonstrated a profound inflammatory response, which was associated with an increased tumor burden. Using a model of long term alveolar macrophage depletion by intratracheal administration of liposomal clodronate, we found that depletion of alveolar macrophages decreased tumor burden in K-rasG12D-expressing mice. Together, these results suggest that, rather than causing a profound inflammatory influx, epithelial NF-κB signaling may be important for activating resident inflammatory cell populations that aid in K-ras- and EGFR-mediated tumor formation. From these studies, we hope to broaden understanding of the role of inflammatory signaling pathways in regulation of lung carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 313. doi:1538-7445.AM2012-313
Abstract 3130: Targeted DNA methylation reprogrammed differentiation and tumorigenesis of mesenchymal stem cells
Authors: Leu Yu-Wei , Hsiao Shu-Huei 
Published: August 2012

Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various sources and induced into different cell types. Although MSCs possess immune privilege and are more easily obtained, their propensity to tumorigenesis and immune responses they might bring to patients have not been fully explored. Epigenomic revolution like changes in DNA methylation and chromatin modification have been hypothesized to be critical in the determination of lineage-specific differentiation and tumorigenesis of MSCs but has not been forwardly proved. We identified the Polycomb group-governed loci in MSCs and tracked their differential methylation changes during the MSC-to-liver or MSC-to-adipocyte differentiation. These loci were also differentially methylated in breast cancer (n=93) and liver cancer (n=40). In an independent collection of liver cancer (n=100), the methylation states of these Polycomb-governed loci like Trip10, Casp8AP2, ENSA and ZNF484 were clustered together in contrast to the non-Polycomb targets like HIC1 and RassF1A. We then developed and applied a targeted DNA methylation method to methylate the Polycomb group protein-governed gene, Trip10, in MSCs which accelerated the cell fate determination of MSCs. Targeted methylation of Casp8AP2, another Polycomb group protein-governed gene, increased cellular survival and its resistance to drugs. The targeted methylation of ENSA and ZNF484 reveal the epigenomic evolution. Targeted methylation of HIC1 and RassF1A, both are tumor suppressors but not the Polycomb target genes, transformed MSCs into tumor stem cell-like cells. With this new method, we proved that DNA methylation within critical loci is sufficient to steer the cell fate of MSCs. (Supported in part by NSC 100-2320-B-194-001)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3130. doi:1538-7445.AM2012-3130
Abstract 3139: Frequent downregulation of NGB/GTPBP in lung cancer
Authors: Kim Donghwa , Park Sungman , Lee Sang Haak , Park Jong Y. , Cheng Jin Q. 
Published: August 2012

Abstract
GTP-binding protein NGB (GTPBP4) is located at chromosome 10p14-p15, a region common loss in various types of human malignancy. Here, we demonstrated that NGB expression was frequently down-regulated in human lung cancer cell lines and primary tumors. Furthermore, we found hypermethylation in NGB promoter region. Treatment with trichostatin A (TSA) and 5-Aza-2′-deoxycytidine (5-Aza) restored NGB expression. In addition, the reintroduction of NGB into the cells, in which it is downregulated, represses cell growth, colony formation, angiogenesis and tumor growth in nude mouse. These findings indicate that NGB is a putative tumor suppressor gene in lung cancer and could play a pivotal role in lung carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3139. doi:1538-7445.AM2012-3139
Abstract 3142: Hypermethylation of the tissue inhibitor of metalloproteinases-2 gene in multiple myeloma
Authors: Wilop Stefan , Jost Edgar , Schubert Claudia , Herman James G. , Brümmendorf Tim H. , Galm Oliver 
Published: August 2012

Abstract
Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the accumulation of malignant plasma cells in the bone marrow (BM) as well as abundant BM angiogenesis. Aberrant methylation of CpG islands near gene promoter regions is the most widely studied epigenetic abnormality in human malignancies and is associated with loss of gene function. There is increasing evidence for a role of the tissue inhibitor of metalloproteinases 2 (TIMP-2) gene as a tumor suppressor. Overexpression of TIMP-2 may result in decreased invasive potential, suppression of tumor growth and vascularization as well as inhibition of angiogenesis. We could previously show that TIMP-2 may become hypermethylated in association with transcriptional silencing in indolent and aggressive non-Hodgkin's lymphomas. Recently, downregulation of TIMP-2 was also reported in MM, and this is thought to contribute to increased BM angiogenesis. In this study, we determined the methylation status of the promoter-associated CpG island of TIMP-2 in primary MM samples and investigated correlations between TIMP-2 methylation and clinical parameters. Methylation of the promoter-associated CpG island of TIMP-2 was analyzed by methylation-specific polymerase chain reaction (MSP) in samples from 84 MM patients (median age 65 years [range 40-94]; 48 males, 36 females; 79 BM samples, 5 peripheral blood samples). Overall survival curves were plotted according to the method of Kaplan and Meier and compared using the log-rank test. Correlations between variables were analyzed using the Fisher's exact two-sided test and independent t-test, respectively. MSP analysis revealed aberrant methylation of the TIMP-2 promoter region in 4/84 MM patient samples. We found an association of TIMP-2 hypermethylation with plasma cell leukemia (p&lt;0.0001) and decreased platelet counts (111 G/l vs. 258 G/l; p=0.04). There was a trend towards an inferior overall survival in MM patients with a hypermethylated TIMP-2 gene, but this difference was not statistically significant (p=0.09). We conclude that promoter hypermethylation of TIMP-2 is a novel epigenetic event in MM that may contribute to disease progression and could serve as a prognostic biomarker. Further studies are warranted to elucidate the functional consequences of epigenetic dysregulation of TIMP-2 in the pathogenesis of MM. Additionally, the increasing evidence for the role of DNA methylation changes in MM may serve as a basis for the use of epigenetically targeted therapeutic approaches in malignant plasma cell disorders.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3142. doi:1538-7445.AM2012-3142
Abstract 3143: Epigenetic regulation of PTEN by miR-185 and miR-200b in liver cancer
Authors: Qadir Ximena V. , Han Chang , Wu Tong 
Published: August 2012

Abstract
PTEN is one of the most commonly lost tumor suppressors in human cancers. Deletion of PTEN in mice has been shown to induce steatohepatitis and the development of primary liver cancers (hepatocellular carcinoma and cholangiocarcinoma). This study provides novel evidence for epigenetic regulation of PTEN in both hepatocellular carcinoma and cholagniocarcinoma cells. Treatment of the hepatocellular carcinoma cell line (Huh-7) and cholangiocarcinoma cells line (TFK-1) with the DNA methyltransferase (DNMT) inhibitor, Decitabine (1 mM), and the histone deacetylase inhibitor, Trichostatin A (TSA, 10mM), increased the expression of PTEN protein. Methylation specific qPCR assay shows that Decitabine/TSA treatment significantly reduced the methylation of the CpG islands located at the PTEN gene promoter. Furthermore, we have shown that miR-185 and miR-200b target DNMT-1 and -3A/3B, respectively, thus upregulating the expression of PTEN in hepatic cancer cells. Forced overexpression of miR-185 or treatment with mimic miR-185 abolished the expression of DNMT1 protein and enhanced the level of PTEN protein in both Huh-7 and TFK-1 cells. Accordingly, miR-200b overexpression or mimic treatment significantly decreased DNMT3A and DNMT3B protein levels and enhanced the expression of PTEN. These results demonstrate a novel epigenetic regulation of PTEN by miR-185 and -200b which is critical in hepatic carcinogenesis
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3143. doi:1538-7445.AM2012-3143
Abstract 3144: A role for DOK2 methylation in platinum resistance and tumor suppression in ovarian cancer
Authors: Lum Elena , Vigliotti Michele , Cutter Noelle , Khan Sohail , Dimitrov Nevenka , Levine Douglas , Lucito Robert 
Published: August 2012

Abstract
Ovarian cancer is the 5th leading cause of cancer in women, affecting close to 22,000 women in the year 2011, of which nearly 15,500 will die. It is difficult to detect until it reaches advanced stages and becomes malignant. Currently, the standard treatment for ovarian cancer is platinum-based therapeutics, such as Carboplatin or Cisplatin, combined with Taxol. Unfortunately, approximately 25% of patients are inherently platinum-resistant and all patients who suffer from recurrence will have developed acquired platinum resistance. The genetic/epigenetic causes of this resistance are poorly understood. Epigenetic events are reversible and the identification of genes altered by this mechanism may lead to studies on how to reprogram the process leading up to resistance. To examine the ovarian epigenome, we utilized an array based method, Methylation Oligonucleotide Microarray Analysis (MOMA), to analyze a set of 50 primary ovarian tumors and 12 ovarian normal samples. We identified epigenetic differences that segregated with platinum response and then associated this with expression data to identify gene candidates transcriptionally repressed and methylated in patients resistant to platinum. Next, a pooled shRNA screen was performed on candidate genes to identify those that were functionally relevant to platinum resistance. One of the validated candidate genes identified through the pooled shRNA screen was DOK2, an adapter protein downstream of tyrosine kinase, which has been shown by others to be a lung cancer tumor suppressor. We show that suppression of DOK2 by short hairpin RNAs in ovarian cell lines conferred resistance to platinum treatment. To elucidate the mechanism for resistance, we measured the influx of platinum into the cells using C-14 tagged carboplatin. As a result, uptake of carboplatin was found to be decreased with DOK2 suppression. Consistent with DOK2 having tumor suppressor activity, knockdowns in ovarian cell lines increases growth and migration. Furthermore, loss of DOK2 induces invasive and tumorigenic phenotypes in ovarian cell lines. DOK2 is already a proven tumor suppressor in lung cancer, and our experiments indicate DOK2 has tumor suppressor features in ovarian cancer as well. We show that DOK2 is a tumor suppressor in ovarian cancer and that the loss of DOK2 also contributes to platinum resistance. Understanding DOK2 function will help us understand ovarian cancer development, progression as well as therapy resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3144. doi:1538-7445.AM2012-3144
Abstract 3154: Sequencing of the small RNA transcriptome in cytologically normal bronchial airway epithelium of smokers with and without lung cancer
Authors: Campbell Joshua D. , Luo Lingqi , Xiao Ji , Liu Gang , Aleksyev Yuriy , Elashoff David , Dubinett Steven M. , Lenburg Marc E. , Spira Avrum 
Published: August 2012

Abstract
Introduction: Based on the concept that cigarette smoke creates a molecular field of injury in epithelial cells throughout the respiratory tract, we have previously shown that mRNA expression differences in cytologically normal airway epithelial cells in patients with and without lung cancer can serve as a clinically-relevant lung cancer biomarker. MicroRNAs are short, non-coding RNAs that can each regulate the expression of hundreds of target genes and can be reliably detected in clinical samples with variable quality. The goal of this study is to generate a microRNA biomarker in the airway epithelium of smokers for the diagnosis of lung cancer. Methods: Cytologically-normal bronchial airway epithelial cells were collected via brushings of the mainstem bronchus of smokers undergoing fiberoptic bronchoscopy for suspicion of lung cancer (n=128). Subjects were followed after their bronchoscopy until a final diagnosis of lung cancer (n=75) or an alternate benign diagnosis (n=53) was made. The small RNA transcriptome (&lt;40 nucleotides) was sequenced using the Illumina HiSeq 2000 with multiplexing (8 samples/lane). Reads were aligned to hg19 using Bowtie allowing up to 3 mismatches and 10 locations to the genome. Linear models were used to associate expression profiles with disease-related phenotypes while controlling for differences in the total number of reads and other clinical covariates. Results: An average of 10.6 million reads was sequenced per sample with 77% of these reads having at least one alignment to the human genome. In addition, 75% of the aligned reads mapped to known microRNA precursors. 508 novel microRNA precursors were predicted using the miRDeep algorithm. 362 mature microRNAs were considered consistently expressed (Median Absolute Deviation &gt; 20). 98 of these microRNAs were differentially expressed between current and former smokers and 56 microRNAs differentially expressed in the airway epithelium of smokers with and without lung cancer (p&lt;0.05; 18 expected by chance at this threshold). Conclusions: We have sequenced the small RNA transcriptome in the cytologically-normal proximal airway epithelium of smokers and have identified microRNA expression profiles associated with smoking status and/or a final diagnosis of lung cancer. In the future, a microRNA biomarker will be developed on these samples using procedures outlined in the MicroArray Quality Control (MAQC)-II project and tested on an independent cohort in order to confirm their ability to serve as an early diagnostic tool for lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3154. doi:1538-7445.AM2012-3154
Abstract 3160: Expression of apoptosis-regulating miRNAs and target mRNAs in oral squamous cell carcinoma
Authors: Coutinho-Camillo Cláudia M. , Lourenço Silvia V. , Nishimoto Ines N. , Kowalski Luiz P. , Soares Fernando A. 
Published: August 2012

Abstract
Apoptosis is a genetically programmed form of cell death, which primarily functions to eliminate senescent or altered cells that are useless or harmful for the multicellular organism. In contrast, aberrations of the apoptotic mechanisms that cause excessive or deficient programmed cell death have been linked to a wide array of pathologic conditions. MicroRNAs (miRNAs) are approximately 22 nucleotide non-coding RNA molecules that regulate gene expression post-transcriptionally and recent studies have indicated the dysregulation of miRNAs involved in apoptosis. In this study, using Real Time RT-PCR we have analyzed the expression of apoptosis-regulating miRNAs (miR-15a, miR-16, miR-29a, miR-34a, miR-17-5p, miR20a, miR21) in a series of 20 oral squamous cell carcinoma samples and a pool of 5 normal oral mucosa tissue samples. Using TargetScan algorithms, target genes of these miRNAs were identified and the expression of mRNA transcripts of these target genes was also evaluated (Bcl-2, Caspase-2, Caspase-7, Bid, SMAC/DIABLO) in a series of 50 oral squamous cell carcinoma samples and a pool of 10 normal oral mucosa tissue samples. Considering up- or down-regulation as a 2-fold difference in expression relative to the normal tissue, we observed down-regulation of miR-15a, miR29a and miR34a in 50%, 75% and 70% of the samples, respectively. Normal-like expression was observed for miR-16, miR-17-5p, miR-20a and miR-21 in 80%, 75%, 90% and 60% of the samples, respectively. Down-regulation of the BCL-2 transcripts was observed in 60% of the samples and normal-like expression was observed for BID, CASPASE-2, CASPASE-7 and SMAC/DIABLO transcripts in 66%, 82%, 68% and 60% of the samples, respectively. Expression of BID, CASPASE-2 and CASPASE-7 might be regulated by miR-17-5p and miR-20a and we found no alteration in expression of both mRNAs and miRNAs. Expression of BCL-2 might be regulated by miR-15a, miR-16, miR-21 and miR-34. We found down-regulation of BCL-2 transcripts and miRNAs-15a and -34, suggesting that other mechanisms might be involved in the regulation of BCL-2. Expression of SMAC/DIABLO might be regulated by miR-29 and we found normal-like expression of SMAC/DIABLO transcripts and down-regulation of miRNA-29 also suggesting that other mechanisms might be involved in the regulation of SMAC/DIABLO. Our study provides evidence of alterations in the expression of apoptosis-regulating miRNAs and alterations in the expression of genes involved in the apoptotic pathway demonstrating that regulation of apoptosis is an important feature in OSCC behavior. FAPESP research grants 98/14335-2 and 07/50608-4.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3160. doi:1538-7445.AM2012-3160