bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3173: Identification of miR-4423 as a primate-specific microRNA highly expressed in airway epithelium and associated with lung cancer
Authors: Perdomo Catalina , Campbell Joshua , Gerrein Joseph , Tellez Carmen , Gower Adam , Vick Jessica , Garrison Carly , Anderlind Christina , Jackson George R. , Schembri Frank , Gomperts Brigitte N. , Hayden Patrick , Belinsky Steven A. , Lenburg Marc E. , Lenburg Marc E. , Spira Avrum 
Published: August 2012

Abstract
Smoking is a significant risk factor for lung cancer, the leading cause of cancer-related deaths worldwide. Our group has previously shown that epithelial gene expression is altered throughout the airway of smokers and that some of these changes are regulated by microRNAs. Moreover, we have previously identified gene expression differences in cytologically normal bronchial airway epithelial cells between smokers with and without lung cancer that can serve as an early diagnostic biomarker for lung cancer. Here, we use next-generation sequencing of small RNAs to identify novel microRNAs expressed in airway epithelium and associated with lung cancer. We identify miR-4423 as a primate-specific microRNA highly expressed in the airway epithelium. In vitro, the expression of miR-4423 increases as Normal Human Bronchial Epithelial cells are differentiated into mucociliary epithelium at an Air Liquid Interface, while its mRNA targets decrease in expression. Furthermore, the expression of miR-4423 is reduced in lung tumors and in the cytologically normal bronchial airway epithelium of smokers with lung cancer. In gain-of-function experiments, ectopic expression of miR-4423 in lung cancer cell lines resulted in reduced colony formation in soft agar. Taken together, these data support the power of next-generation sequencing in identifying novel cell type- specific transcripts and provides evidence that this newly characterized microRNA may play a role in promoting the differentiation and/or maintenance of airway epithelium, and can reduce anchorage-independent lung cancer cell growth.
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 3173. doi:1538-7445.AM2012-3173
Abstract 3210: Glutamine synthetase is a genetic determinant of cell-type specific glutamine independence in breast epithelia
Authors: Kung Hsiu-Ni , Marks Jeffrey R. , Chi Jen-tsan Ashley 
Published: August 2012

Abstract
Although significant variations in the metabolic profiles exist among different cells, little is understood in terms of genetic regulations of such cell-type specific metabolic phenotypes and nutrient requirement. While many cancer cells depend on exogenous glutamine for survival to justify the therapeutic targeting of glutamine metabolism, the mechanisms of glutamine dependence and likely response and resistance of such glutamine-targeting strategies among cancers are largely unknown. In this study, we have found a systematic variation in the glutamine dependence among breast tumor subtypes associated with mammary differentiation: basal but not luminal-type breast cells are more glutamine dependent and may be susceptible to glutamine-targeting therapeutics. Glutamine independence of luminal-type cells is associated mechanistically with lineage-specific expression of glutamine synthetase (GS). Luminal cells can also rescue basal cells in co-culture without glutamine, indicating a potential for glutamine symbiosis within breast ducts. The luminal-specific expression of GS is directly induced by GATA3 and represses glutaminase expression. Such distinct glutamine dependency and metabolic symbiosis is coupled with the acquisition of the GS and glutamine independence during the mammary differentiation program. Understanding the genetic circuitry governing distinct metabolic patterns is relevant to many symbiotic relationships among different cells and organisms. In addition, the ability of GS to predict patterns of glutamine metabolism and dependency among tumors is also crucial in the rational design and application of glutamine and other metabolic pathway targeted therapies.
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 3210. doi:1538-7445.AM2012-3210
Abstract 3212: N-acetylcysteine protects melanoma cells from glucose depletion through unequal modulation of SOD1 and Copper chaperone for SOD1 depending on p53 mutational status
Authors: Chavez-Perez Valery , Strasberg-Rieber Mary , Rieber Manuel 
Published: August 2012

Abstract
BACKGROUND.-Cancer cells from solid tumors undergo metabolic stress, when nutrients become limiting, within poorly vascularized regions. Severe deprivation of glucose and serum-derived growth factors can promote cell death by metabolic stress, partly through excessive reactive oxygen species (ROS) production.OBJECTIVES.- To investigate whether survival in response to metabolic stress is influenced by N-acetylcysteine (NAC), an anti-oxidant glutathione precursor, and whether it is linked to modulation of superoxide dismutases (SOD1 and SOD2) that catalyze intracellularly the conversion of O2− to H2O2. EXPERIMENTAL- matched human melanoma cells with unequal p53 mutational status were exposed to overnight depletion of glucose with either 0.5% or 10% serum supplementation. Differential cell survival was assesed by crystal violet staining. Mechanisms influencing response to glucose limitation were studied by specific immune blotting. RESULTS.- A 24 hour glucose depletion suppressed cell survival in 0.5% dialyzed serum but this was counteracted by 2 mM NAC irrespective of cellular p53 status. A shorter glucose depletion in 0.5% serum revealed normoxic induction of hypoxia-inducible factor (HIF1α) reciprocal with concomitant down-regulation of SOD1 together with the Copper chaperone for SOD1 (CCS) and intact PARP, with no comparable effect on mitochondrial SOD2. Under these restrictive conditions, NAC addition partly restored SOD1 and PARP but not CCS expression in mutant p53(R175H) cells. No comparable NAC restoration of these proteins was evidenced in matched wt p53 melanoma under glucose depletion in 0.5 % dialyzed serum. However, SOD1 but not CCS was highest following glucose deprivation with 10% dialyzed serum in wt p53 melanoma cells, compared to identically treated mutant p53 cells. NAC addition increased CCS irrespective of p53 status with glucose depletion in 10% serum, and preferentially induced SOD1 in mutant p53 cells under comparable conditions. CONCLUSIONS.-human melanoma cells are protected from transient glucose depletion by anti-oxidants like NAC through differential modulation of SOD1 and CCS depending on serum availability and p53 mutational status.
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 3212. doi:1538-7445.AM2012-3212
Abstract 3220: The effects of cholesterol treatment drugs alone and in combination on prostate tumor xenograft growth
Authors: Masko Elizabeth M. , Solomon Keith R. , Valilis Nikolaos A. , Gaines Alexis R. , Muehlbauer Michael J. , Newgard Christopher B. , Dewhirst Mark W. , Pizzo Salvatore V. , Freedland Stephen J. 
Published: August 2012

Abstract
Background: Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer (PC), but not the incidence of the disease. This may occur by lowering levels of low-density lipoproteins (LDL). Statins and cholesterol-uptake inhibitors like ezetimibe lower serum LDL and are commonly prescribed for patients with high cholesterol. In this study, we determined the therapeutic role of simvastatin, ezetimibe, or both in vitro using several PC cell lines and in vivo using a LAPC-4 xenograft model. Methods: We treated 4 PC cell lines (LAPC-4, CWR22rv1, PC-3, and DU145) with varying concentrations of simvastatin (0-1000nM) or ezetimibe (0-100μM) for 0-5 days. MTS assays were performed to determine cell proliferation, and the IC50 was calculated using BioDataFit 1.02. For our in vivo study, a total of 90 athymic male nude mice were fed a high-fat, high-cholesterol diet (HFHC; 40% fat, 17% protein, 43% carbohydrates, 1.25% cholesterol), subcutaneously injected with 1 x 10^5 LAPC-4 cells, and randomized 2 weeks later to 1 of 4 treatments: vehicle control, 11mg/kg/day simvastatin (delivered via osmotic pump), 30mg/kg diet ezetimibe (delivered in the food), or simvastatin + ezetimibe. Mice remained on study for 42 days post-randomization, at which point they were harvested and samples analyzed. Results: In vitro, simvastatin directly reduced PC cell proliferation in a dose-dependent, cell line-specific manner, but ezetimibe had no inhibitory effect. In vivo, treatment of low continuous dosing of simvastatin or ezetimibe for 42 days had no effect on tumor growth compared to control. However, relative to control, the combination of simvastatin and ezetimibe accelerated tumor growth (p=0.01). The simvastatin-ezetimibe mice also showed lower fat infiltration in the liver and lower serum cholesterol, but higher tumor cholesterol levels than control. Conclusions: Our results suggest that low continuous dosing of simvastatin or ezetimibe may have no effect on PC growth in a slow-growing LAPC-4 xenograft model, but the combination of simvastatin and ezetimibe may accelerate PC growth, possibly by stimulating cholesterol uptake within the tumor. This novel finding may be important in implementing new treatments for men with slow growing PC and high cholesterol.
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 3220. doi:1538-7445.AM2012-3220
Abstract 324: The integrin-linked kinase (ILK) / Rictor complex is required for TGFβ-1-induced epithelial to mesenchymal transition (EMT)
Authors: Serrano-Martinez Isabel , McDonald Paul C. , Dedhar Shoukat 
Published: August 2012

Abstract
Epithelial to mesenchymal transition (EMT) causes fibrosis, cancer progression and metastasis. Integrin-linked kinase is a focal adhesion adaptor and serine/threonine protein kinase that regulates cell proliferation, survival, and EMT. Elucidating the molecular mechanisms necessary for the development and progression of human malignancies is critical to predict the most appropriate targets for cancer therapy. Here we used transforming growth factor beta-1 (TGFβ-1) to promote EMT and migration in mammary epithelial cells. We demonstrate a requirement of ILK activity for TGFβ-1 mediated EMT in mammary epithelial cells. In addition to nuclear translocation of Snail and Slug, TGFβ-1 treatment also induced expression of the mTORC2 component Rictor as well as its phosphorylation on Thr1135. Interestingly, TGFβ-1 treatment also induced an interaction between ILK and Rictor. All of these TGFβ-1-induced processes were significantly suppressed by inhibiting ILK activity or by disrupting the ILK-Rictor complex using siRNA-mediated knockdown. Furthermore, we identified formation of the ILK/Rictor complex formation in cancer but not normal cell types, and this was accompanied by ILK-dependent phosphorylation of Rictor on residue Thr1135. Inhibition of ILK partially reversed the basal mesenchymal phenotype of MDA-MB-231 cells and prevented EMT in MCF10A cells following TGFβ-1 treatment. These data demonstrate a requirement for ILK function in TGFβ-1-induced EMT in mammary epithelial cells and identify the ILK/Rictor complex as a potential molecular target for preventing/reversing EMT.
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 324. doi:1538-7445.AM2012-324
Abstract 3241: Analysis of transcription factor activation by the embryonic microenvironment in metastatic breast cancer cells
Authors: Tarasewicz Elizabeth , Aviles Misael , Shea Lonnie D. , Jeruss Jacqueline S. 
Published: August 2012

Abstract
Introduction: The embryonic microenvironment is an important source of signals that program multipotent cells to adopt a particular fate. Numerous studies have shown that components of the embryonic stem cell microenvironment can induce a reversion of cancer cell phenotype from a more aggressive to less aggressive state through mechanisms that are largely unknown. We have examined the phenotypic transformation associated with the culture of metastatic breast cancer cells in mouse embryonic stem cell conditioned media and have implemented a novel cell array technology to characterize the signaling pathways associated with this transformation. Methods: We used phase contrast microscopy to determine the time course of structure formation in MDA-MB-231 cells cultured in 3D with control or conditioned mouse embryonic stem cell media. Cell proliferation of study cells stably expressing Gaussia Luciferase was quantified by measuring Gluc production over time. Cell migration was measured for treated and untreated cells using a transwell migration assay. A live cell array was implemented to quantify changes in activity of 19 cancer-related transcription factors over a period of 8 days. Results: MDA-MB-231 cells cultured in stem cell conditioned media showed decreased area covered by spindle-like projections over a period of 10 days. Study cells cultured in stem cell conditioned media, but not in control media or mouse embryonic fibroblast conditioned media, had decreased proliferation over time. Cells cultured in stem cell conditioned media had decreased cell migration relative to cells cultured with regular media. Using a cell array to report on TF activity, cells cultured in conditioned stem cell media, when compared to control media, had varied activity in 7 of the 19 constructs investigated, including metastasis-related factors SP1 and GATA1. Conclusion: Our findings support the normalizing influence provided by the stem cell microenvironment through decreased MDA-MB-231 spindle-like projections, cell proliferation, and cell migration. Of the 19 transcription factor reporter constructs tested using the novel live cell array, GATA1 and SP1 emerged as 2 of the transcription factors impacted by the embryonic microenvironment. These factors may reflect potential paracrine signaling pathways stimulated by the microenvironment that can influence transformation and may be targets for therapeutic intervention.
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 3241. doi:1538-7445.AM2012-3241
Abstract 3250: Chondroitin sulfate-mediated regulation of Wnt/β-catenin signaling in breast cancer
Authors: Willis Catherine M. , Klüppel Michael 
Published: August 2012

Abstract
Breast cancer is among the leading causes of cancer related deaths in women in the U.S. Aberrant activation of the Wnt/β-catenin signaling pathway plays a critical role in breast cancer progression; however, activating mutations in core pathway components are not frequently observed. Molecules that reside in the cellular microenvironment, including glycosaminoglycans, are known to regulate tumor progression. The glycosaminoglycan chondroitin sulfate, as part of proteoglycan molecules, resides at the cell surface or in the extracellular matrix, and has been proposed to regulate the activities of several signaling pathways. We show here that the balance of chondroitin sulfation is a critical regulator of Wnt/β-catenin signaling in breast cancer cells. Overexpression of the chondroitin sulfotransferase C4ST-1 in vitro can significantly reduce several parameters of Wnt/β-catenin signaling activity, including Wnt3a-stimulated total β-catenin levels, TOPFLASH reporter activity, and proliferation, suggesting that the specific chondroitin sulfation pattern conferred by C4ST-1 can negatively regulate Wnt/β-catenin signaling in breast cancer cells. Interestingly, we show that Wnt3a stimulation increases C4ST-1 mRNA and protein levels, thus forming a negative feedback loop to attenuate Wnt/β-catenin signaling output. Accordingly, treatment with the C4ST-1 product CS-E interferes with Wnt/β-catenin signaling activity, LRP6 phosphorylation, β-catenin nuclear localization, and Wnt3a-mediated biological events in vitro. These data identify a novel chondroitin sulfate-based control mechanism for the Wnt/β-catenin pathway, and provide evidence for a potential therapeutic use of CS-E as an inhibitor of Wnt/β-catenin signaling in breast 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 3250. doi:1538-7445.AM2012-3250
Abstract 3252: Divergence of activin and TGFβ-induced SMAD-independent signaling in colon cancer
Authors: Bauer Jessica , Jung Barbara H. 
Published: August 2012

Abstract
Introduction: Activin and TGFβ are members of the TGFβ superfamily with growth suppressive and pro-migratory properties. While growth suppressive SMAD 2/3/4 signaling is shared, we have evidence of diverging SMAD-independent migratory signaling involving the CDK inhibitor p21. Here, we dissect the participation of respective mitogenic pathways in activin and TGFβ-specific SMAD-independent signaling in colon cancer. Methods: Colon cancer cell lines with and without SMAD4 were assessed for SMAD, PI3K and MEK pathway influences on activin or TGFβ signaling and associated effects using pharmacologic inhibition, knock-down, co-immunoprecipitation, Western blotting, and functional assays of migration. Results: Irrespective of SMAD4 status, activin-induced migration was PI3K-dependent and associated with PI3K-induced p21 downregulation, while TGFβ-induced migration was MEK1/2-dependent. Activin but not TGFβ lead to colocalization of ACVR1, ACVR2's primary binding partner, with p85, the regulatory subunit of PI3K, in an ACVR1-dependent SMAD-independent manner. Further, activin-induced p21 downregulation was PI3K dependent and associated with proteasomal degradation, while TGFβ stabilized p21 via MEK/ERK. Inhibition of proteasomal degradation of p21 lead to a decrease in migration with activin implicating p21 downregulation in activin-induced migration but not in TGFβ-induced migration. Conclusion: Activin and TGFβ diverge in their pro-migratory SMAD-independent signaling in colon cancer affecting distinct targets to include p21 and employing diverse mitogenic signals. Dissecting ligand-specific functions in colon cancer may be exploited for risk stratification or therapeutic intervention in the near future.
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 3252. doi:1538-7445.AM2012-3252
Abstract 3387: Secreted exosomes from cultured bladder cells are enriched for distinct miRNAs detected in circulation of metastatic bladder cancer patients
Authors: Ostenfeld Marie S. , Jeppesen Dennis , Morth Jens P. , Khanh Huy B. , Theodorescu Dan , Borre Michael , Dyrskjøt Lars , Ørntoft Torben 
Published: August 2012

Abstract
Exosomes are small nanovesicles (30-100 nm) secreted from the cell surface of most cell types. The vesicles are secreted at increased levels by cancer cells and can be detected in body fluids of cancer patients. Exosomes function in paracrine delivery of proteins, RNA, and DNA into recipient cells. By this, exosomes are speculated to be involved e.g. in pre-metastatic niche formation at distant sites. Here we present a characterization of exosome vesicles isolated from bladder cancer cells as examined by electron microscopy, dynamic light scattering and by western blotting of common exosome protein markers. The expression of 671 unique human miRNAs by qPCR was analyzed in both exosomes and donor cells from: 1) cultivated normal urothelial cells (NHU), 2) T24 bladder carcinoma cell line (non-metastatic) and its metastatic isogenic derivates FL3 and SLT4 and 3) UMUC3 bladder carcinoma cell line (moderate metastatic) and its highly metastatic isogenic derivative LUL2. Several miRNAs were detected in the vesicles yet absent in their parental donor cell indicating a possible preferential vesicular packaging. miRNAs miR92a, -106a, -20a, -21, -16, and let-7a/b/d/e were detected among the top100 ranked miRNAs in all vesicles. Among the top30 enriched exosomal miRNAs, miR-223 and-383 were detected in all cancer vesicles, and miR-921 in the highly metastatic vesicles (FL3, SLT4, LUL2). The release of miRNAs (miR-21, -16, and let7b) from FL3 cells into the culture media was time-dependent and a fraction of these miRNAs were stable to RNaseOne degradation indicating possible protection inside the vesicles. Examination of miRNAs in human plasma samples also suggested resistance towards endogenous RNAse degradation as well as towards repetitive freeze/thawing. The profiling of miRNA expression by Affymetrix microarray analysis of crude exosome-containing fractions of human plasma samples (10 healthy controls and 10 cases of metastatic bladder cancer) showed significant upregulation in cancer plasma of e.g. miR-92a, -106a, -23a, -20a, -21, some of which were the same as the miRNAs highly expressed in the tumor vesicles. The significant increase was confirmed by q-RT-PCR for miR-92a and -23a and validated on an independent set of plasma samples (8 healthy controls and 8 metastatic cancer cases). Our results suggest that specific miRNAs are encapsulated into exosomes in bladder cancer and that these may be detected in circulation in advanced stages of bladder 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 3387. doi:1538-7445.AM2012-3387