bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4115: Depletion of unsaturated fatty acids by stearoyl-coA desaturase inhibition results in endoplasmic reticulum stress-mediated tumor cell death
Authors: Roongta Urvashi V. , Pabalan Jonathan G. , Wang Cindy , Ryseck Rolf-Peter , Fargnoli Joseph , Henley Benjamin , Yang Wen-Pin , Zhu Jun , Madireddi Malavi , Lawrence Michael , Wong Tai W. , Rupnow Brent A. 
Published: August 2012

Abstract
Over the past few years, a more detailed picture of the importance of metabolic pathways to the maintenance and progression of human cancers has begun to emerge. In particular, recent studies have implicated lipid biosynthesis and desaturation as a requirement for tumor cell survival. The endoplasmic reticulum-resident Stearoyl CoA Desaturase (SCD) is the rate limiting enzyme that catalyzes conversion of saturated fatty acids to monounsaturated fatty acids, a key step in the fatty acid metabolic network. In the studies reported here, we show that inhibition of SCD1 by siRNA or a small molecule antagonist results in strong induction of apoptosis and growth inhibition when tumor cells are cultured in reduced (2%) serum conditions but has little impact on cells cultured under normal (10%) serum conditions. Consistent with the observed dependence on SCD1, levels of SCD1 protein increased in response to decreasing serum levels. Both induction of SCD1 protein and sensitivity to growth inhibition by SCD1 inhibition could be reversed by supplementing growth media with unsaturated fatty acids. Transcription profiling of cells treated with an SCD inhibitor revealed strong induction of markers of endoplasmic reticulum stress. This finding was confirmed using siRNA specifically targeting SCD1. Underscoring its importance in cancer, SCD1 protein was found to be highly expressed in a large percentage of human cancer specimens. SCD inhibition resulted in tumor growth delay in a human gastric cancer xenograft model. Altogether, these results suggest that unsaturated fatty acids are required for tumor cell survival and that SCD may represent a viable target for the development of novel agents for cancer therapy.
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 4115. doi:1538-7445.AM2012-4115
Abstract 4128: miR203 induces mesenchymal to epithelial transition via repressing SNAI2 and activating P-cadherin in prostate cells
Authors: Qu Yi , Zhang Jigang , Li Wen-Cheng , Hellem Margrete R. , Rostad Kari , Liu Run-hui , Zhang Wei-dong , Oyan Anne Margrete , Kalland Karl H. , Ke Xi-Song 
Published: August 2012

Abstract
MicroRNAs play critical roles in tumorigenesis and metastasis. Here we report the functions of miR203 in prostate cancer based upon an experimental cell culture model. While highly expressed in prostate epithelial cells, miR203 became completely repressed following their epithelial to mesenchymal transition (EMT). Forced re-expression of miR203 in the mesenchymal cells induced many epithelial features, including morphological change in 2D and 3D culture, decreased abilities of invasion and migration, as well as increased epithelial markers and decreased mesenchymal markers. By computer prediction combined with microarray profiling and luciferase reporter target assays, we identified SNAI2 as target of miR203. Knock-down of SNAI2 can mimic the epithelial phenotypes induced by miR203. Most of the affected genes by miR203 were also found to be changed with the same pattern by knock-down of SNAI2. Furthermore, P-cadherin (CDH3), an important epithelial adhesion component, was identified as the downstream target of SNAI2. CDH3-promoter-Luc reporter assay demonstrated that 3 E-boxes in the CDH3 promoter mediated direct targeting by SNAI2. Decreased and increased expression of CDH3 were found in culture cells with overexpression and knock-down of SNAI2, respectively. We concluded that miR203 represses SNAI2, thus activating P-cadherin in induction of epithelial features.
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 4128. doi:1538-7445.AM2012-4128
Abstract 4140: MicroRNA expression in Osteosarcoma: potential role of miR-1 and miR-133b
Authors: Pazzaglia Laura , Novello Chiara , Cingolani Chiara , Conti Amalia , Quattrini Irene , Magagnoli Giovanna , Manara Maria Cristina , Benassi Maria Serena 
Published: August 2012

Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults. Conventional therapy for OS has reached a plateau of 60-70%, a 5-year survival rate that has remained almost unchanged in two decades, highlighting the need for new therapeutic approaches by finding new targets. This study presents a comparative analysis of miRNA expression profile in clinical OS samples and paired normal tissues with microarray approach. The Unsupervised Hierarchical Clustering, performed on log2(Hy3/Hy5) ratios, revealed 100 miRNAs with the highest standard deviation across all samples. The Supervised Hierarchical Clustering showed that 40 miRNAs were differentially expressed with a p-value &lt;3,95E-5, and 80% of these were underexpressed in OS samples when compared with normal tissues. In particular, the 5-fold underexpression of miR-1 and miR-133b (p&lt;3.95E-5) was confirmed by Real Time PCR. When U2OS OS cells were transfected with miRNA precursor molecules, we demonstrated that the ectopic expression of miR-1 and miR-133b respectively decreased to 75% and 68% the cell proliferation as compared with negative control, concomitantly with strong slowing down of cell migration and invasion and reduced expression of Met protein that it is considered a potential target of both miRNAs. It is well known that miR-1 and miR-133b are expressed in skeletal muscle and are transcriptionally regulated by myogenic differentiation factors. Our data demonstrate a deregulation of miRNA profiling in OS clinical specimens and highlight the function of miR-1 and miR-133 in the control of OS cell growth and invasiveness. Further studies should be addressed to investigate the role of these miRNAs and their targets as potential prognostic and therapeutic markers.
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 4140. doi:1538-7445.AM2012-4140
Abstract 4146: The expression of exosomal microRNA in serum of patients with esophageal squamous cell carcinoma
Authors: Tanaka Youhei , Watanabe Masayuki , Kamohara Hidenobu , Kurashige Junji , Mima Kousuke , Okabe Hirohisa , Baba Hideo 
Published: August 2012

Abstract
Background: Exosomes are 40 -100 nm membrane vesicles secreted by various cells such as T cells, platelets, and epithelial cells by exocytosis. Exosomes are found in blood, urine, amniotic fluid, and malignant ascites, and contain distinct subsets of microRNAs (miRs) depending upon the tumor from which they are secreted. Exosomes play a major role in cell-to-cell communication, targeting cells to transfer exosomal molecules including proteins, mRNAs, and microRNAs by an endocytosis-like pathway. Recent reports imply that miRNAs can be stably detected in circulating plasma and serum since miRNAs are packaged by exosomes to be protected from RNA degradation. We have previously reported that overexpression of miR-21 was observed in patients with esophageal squamous cell carcinoma. miR-26a is also known to be overexpressed in esophageal cancer. Objective: Aim of this study is to clarify the expression levels of miR-21 and miR-26a in exosomes from the serum of esophageal cancer patients. Patients and method: We extracted exosomes from serum of 20 esophageal cancer patients (ESCC group) and of 20 benign disease cases without inflammation (control group) by September, 2010 from October, 2009. We separated exosomes from serum, and then extracted total RNA including microRNA from exosome. Furthermore, using quantitative quantitative RT-PCR, we analyzed expression of miR-21, miR-26a where overexpression was confirmed in esophageal cancer in a past report. Results: The expression levels of miR-21 in exosomes were significantly higher in ESCC than those in control (P &lt;0.001), while miR-26a expression levels in ESCC were tended to be higher than those in controls. Furthermore, we analyzed the supernatant which extracted exosomes from serum. There was almost no expression of both miRs in the supernatant after extraction of exosomes. When we compared exosomal and serum levels of miR-21, no correlation was observed between them. Conclusion: We have confirmed the elevated levels of exosomal miR-21 in the serum of patients with ESCC compared with the control. Although further analysis is needed to clarify the biological meaning of the elevated exosomal miR in the serum, the exosomal miR may become new biomarkers for ESCC.
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 4146. doi:1538-7445.AM2012-4146
Abstract 4151: Real-time imaging of inter-cellular communication via exosomes
Authors: Homma Kimi , Suetsugu Atsushi , Ochiya Takahiro , Hoffman Robert M. 
Published: August 2012

Abstract
Growing evidence suggests that extracellular microRNAs (miRNAs) stably exist in human body fluids, including plasma, saliva and urine, although ribonucleases (RNases) also circulate throughout the body. Therefore, miRNAs are excreted in RNase-resistant lipid vesicles, such as exosomes and apoptotic bodies, which can deliver gene-silencing signals between living cells in vitro and in vivo. However, very little is known about the exosome-mediated intra-cellular communication machinery. Here we demonstrate with labeling of exosomes with green fluorescent protein (GFP) linked to CD63, the transfer and incorporation of exosomes into recipient cells via indirect or direct contact with cells in a co-culture system. These findings suggest that secretory exosomes are transfered from cell to cell, transferring genetic information that can affect a wide array of biological events.
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 4151. doi:1538-7445.AM2012-4151
Abstract 4154: Exosomal microRNAs: mediators for cell-cell communications
Authors: Singh Ramesh , Mo Yin Yuan 
Published: August 2012

Abstract
Background: Exosomes are 30-100nm membrane vesicles of endocytic origin, mediating diverse biological functions including tumor-cell invasion, cell-cell communication and antigen presentation through transfer of proteins, mRNAs and microRNAs to neighboring or distant cells. MicroRNAs are small regulatory non-coding RNA molecules that regulate protein-coding genes. Recent evidence suggests that microRNAs can be released through ceramide-dependent secretory machinery regulated by neutral sphingomyelinase 2 (nSMase2) enzyme expressed by smpd3 gene that triggers exosome secretion. In this study, we investigated the exosome-mediated microRNA transfer among various types of cells, the regulation of exosome-mediated microRNA secretion and functional role of these exosomal microRNAs inside the recipient cell after uptake. Methods: Exosomes were isolated from culture media of cells by serial centrifugation, filtration and ultracentrifugation method. Isolated exosomes were stained with PKH26 dye and then observed for cellular uptake in different cells by confocal microscopy after counterstaining with Hoechst stain. In addition, this uptake was also shown by exosome isolated from stable 293T cell line overexpressing the pCDH-CD63-GFP fusion protein. To determine the effect of nSMase2 on exosome secretion, stable cell lines were established with smpd3 gene. Levels of microRNAs secreted in media were determined by real time PCR. To validate the function of exosomal microRNA in the recipient cells, we determined the protein level of microRNA target genes by western blot. Results: We first showed that exosomes can be transferred among different cell lines through direct uptake. We found that miR-10b is highly expressed in metastatic breast cancer MDA-MB-231 cells as compared to non-metastatic breast cells; it is actively secreted into medium. For example, nSMase2 promoted the exosome-mediated miR-10b secretion whereas ceramide inhibitor suppressed this secretion. Importantly, western blot revealed that upon uptake, miR-10b can still reduce the protein level of its target genes such as Bim, indicating its functional significance. Conclusion: We found that the exosomes secreted from cancer cells containing microRNA can be taken up by other cells and have functional role in the recipient cells suggesting the importance of exosome-mediated microRNA transfer in tumor microenvironment. Our results collectively suggest that a set of specific microRNAs may play an important role in modulating tumor microenvironment through exosomes. Thus, a better understanding of this process may aid in the development of novel therapeutic agents.
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 4154. doi:1538-7445.AM2012-4154
Abstract 4156: Interaction between the rabphillin-3A-like gene and phosphorylation of mammalian target of rapamycin (mTOR) in colorectal cancer
Authors: Katkoori Venkat R. , Choudhary Sandeep , Butler Abraham R. , Shanmugam Chandrakumar , Bovell Liselle L. , Samuel Temesgen , Athar Mohammed , Grizzle William E. , Manne Upender 
Published: August 2012

Abstract
Background: Recently, we demonstrated that, for colorectal carcinomas (CRCs), genetic alterations in the rabphillin-3A-like (RPH3AL) gene are associated with aggressive tumor phenotypes and poor patient survival. The mammalian target of rapamycin (mTOR) pathway regulates tumor growth by integrating diverse signals of growth factors, nutrients, and energy sufficiency. Therefore, we determined the effects of wild-type (w+) and mutated (67w-, 175w-, 290w-) RPH3AL on the mTOR signaling pathway in CRC tissues and in a line of colon cancer cells (LoVo). Materials and Methods: Ninety five prospectively collected, frozen CRC tissues and their matching control tissues were analyzed for the mutational status of RPH3AL using the cDNA polymerase chain reaction and direct sequencing. Expression constructs of RPH3AL w+ and the mutant variants were developed using eukaryotic expression vectors. LoVo cells were stably transfected with the w+ and w- forms of RPH3AL. Western blot analyses were performed on lysates of CRC tissues and LoVo cells to assess expression of p53, p27, and PCNA and proteins in the mTOR pathway. Results: Mutational analysis of RPH3AL detected four missense mutations: at codon 67 (Val &gt; Met) in 2 CRCs, at codon 175 (Pro &gt; Ser) in 1 CRC, and at codon 290 (Arg &gt; Lys) in 1 CRC. Western blot analyses demonstrated that over-expression of wt RPH3AL in LoVo cells or CRC tissues with wt RPH3AL led to decreases in total mTOR and to phosphorylation of Rictor p-mTOR (S2481), Raptor p-mTOR (S2448), p70S6K1, and p70S6K. In contrast, in CRC tissues or LoVo cells with over-expression of mutant forms of RPH3AL, there were higher levels of total mTOR and greater phosphorylation of the Rictor, raptor, P70S6K1 and p70S6K. Additionally, CRC w+ RPH3AL and LoVo cells that over-expressed w+ RPH3AL demonstrated higher levels of p27, and lower levels of PCNA, and p53. In contrast, the CRC tissues or LoVo cells with over-expression of RPH3AL mutants exhibited lower levels of p27 and higher levels of PCNA. Conclusion: The results demonstrate that the RPH3AL gene has a tumor-suppressing effect involving changes in the mTOR pathway and suggest that these changes inhibit progression of CRCs. This work was supported by grants from the NCI/NIH (2U54-CA118948-06, R01-CA98932, and R03-CA139629).
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 4156. doi:1538-7445.AM2012-4156
Abstract 4159: PTEN nucleo-cytoplasmic protein compartmentalization and gene status are correlated with aggressiveness of pulmonary neuroendocrine tumors
Authors: Collaud Stephane , Tischler Verena , Perren Aurel , Komminoth Paul , Schraml Peter , Moch Holger , Weder Walter , Soltermann Alex 
Published: August 2012

Abstract
Introduction: Lung neuroendocrine tumors (NET) comprise typical (TC) and atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). Phosphatase and tensin homolog (PTEN) protein is a known cytosolic tumor suppressor with recently described novel nuclear functions. We investigated this differential PTEN protein compartmentalization together with its genomic status in pulmonary NETs. Patients and Methods: A retrospective multicenter cohort of 192 patients with lung NET was investigated on a tissue microarray (TMA, surgical resections = 183/autopsies = 9) by immunohistochemistry (IHC, cytoplasm and nucleus) and fluorescence in-situ hybridization (FISH, nucleus). Results were correlated with markers of neuroendocrine differentiation (synaptophysin, chromogranin A), proliferation (mib-1), cell cycle (p27, cyclin D1) and survival data. Results: The histotypes represented were TC in 58 patients, AC in 42, LCNEC in 32 and SCLC in 60. All NETs showed higher PTEN immunoreactivity in the cytoplasm than in the nucleus, whereby the greatest nucleo-cytoplasmic difference was found for SCLC. In both compartments, immunoreactivity was higher in the carcinoids than in LCNEC and SCLC. Loss of cytosolic or nuclear PTEN protein was correlated with increased mitotic rate, with low synaptophysin or chromogranin A and with PTEN genomic deletion. Loss of nuclear PTEN protein correlated with high nuclear TTF1, whereas loss of cytosolic protein correlated with low p27 and low cyclin D1 (all p-values &lt;0.05). Patients with PTEN genomic deletion or low PTEN immunoreactivity had poorer survivals. Conclusion: PTEN genomic deletion or PTEN protein loss is linked to dedifferentiation and poor prognosis of lung NET. Nucleo-cytoplasmic shuttling of PTEN protein could play a role in the different PTEN inactivation mechanisms.
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 4159. doi:1538-7445.AM2012-4159
Abstract 4165: Identification of flotillin-1 as a regulator of H-Ras activation in lipid raft
Authors: Yong Hae-Young , Son Hwajin , Kim Eun-Sook , Hwang Jin-Sun , Kim Myeong-Ok , Choi Wahn Soo , Noh Dong-Young , Hwang Ki-Tae , Kim Ki-Bum , Lee Jae-Seon , Kim Hyung Joon , Kim Hong-Hee , Choi Yoomi , Kim Eun Joo , Park So Yeon , Kim Hyeong-Reh Choi , Jeon You Rim , Moon Aree 
Published: August 2012

Abstract
Metastatic spread is the major cause of death from breast cancer. We previously showed that H-Ras, but not N-Ras, induces invasive/migratory phenotypes of MCF10A human breast epithelial cells, while both H-Ras and N-Ras induce proliferation/transformation. Here, we identified flotillin-1 as an H-Ras-induced lipid raft protein through comparative proteome profiling of lipid raft proteins. Flotillin-1 interacts with H-Ras in lipid raft at a higher affinity than with N-Ras. Small interfering RNA(siRNA)-mediated flotillin-1 knockdown significantly reduced H-Ras activation and H-Ras-mediated motility/invasion in MCF10A cells engineered to express active H-Ras as well as in Hs578T breast carcinoma and T24 bladder carcinoma cells that express endogenous active mutant of H-Ras. These results suggest a positive signal amplification loop between flotillin-1 and H-Ras for the invasive signaling program. Flotillin-1 was crucial for the activation of the Ras-GRF1 exchange factor and its interaction with H-Ras in lipid rafts. Using a xenograft tumor model, we show that knockdown of flotillin-1 reduces the tumor growth in vivo. Importantly, tissue microarrays of 289 breast cancer patients revealed that flotillin-1 expression in the plasma membrane positively correlates with HER2/neu expression(p&lt;0.001) and high histologic grade(p=0.014). Although infrequent, the membranous flotillin-1 expression is significantly associated with poor disease-free survival of patients(p=0.005), suggesting the clinical importance of predicting the characteristics of a small subpopulation of malignant breast cancer. Taken together, our findings provide new insight into the molecular basis of the Ras isoform-specific signaling mechanism leading to cell invasion that depends on the lipid-based sorting platforms.
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 4165. doi:1538-7445.AM2012-4165
Abstract 4166: Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation
Authors: Deschênes-Simard Xavier , Gaumont-Leclerc Marie-France , Bourdeau Véronique , Moiseeva Olga , Forest Valérie , Mallette Frédérick A. , Lessard Frédéric , Saad Fred , Mes-Masson Anne-Marie , Ferbeyre Gerardo 
Published: August 2012

Abstract
We report that ERK/MAPK signaling mediates tumor suppression. Oncogenic forms of ras are found in approximately 25% of all human cancers and are generally associated with uncontrolled proliferation of cancer cells. However, expression of oncogenic ras in normal cells is associated with cellular senescence. In primary cells expressing oncogenic ras, ERK knockdown by shRNA prevented the activation of the DNA damage response, p53, p16INK4a/Rb and senescence and cooperated with hTERT in transformation. In human prostate neoplasms, high levels of phosphorylated-ERK were found in benign lesions while in malignant lesions lower levels correlated with a higher Gleason score and earlier disease relapse after treatment. Mechanistically, the antitumor effects of ERK/MAPK signaling included the selective proteasome-dependent degradation of proteins required for cell cycle progression, mitochondrial functions and cell signaling and the inhibition of the phosphoinositide-3-kinase/AKT (PI3K/AKT) signaling pathway. We thus show for the first time that the outcome of ERK/MAPK signaling can be controlled at the level of ERK1/2, the final members of the pathway. A quantitative control at the end of the pathway provides a mechanism for specific modulation of ERK/MAPK signaling since controlling the input may also affect the numerous signaling pathways activated by membrane receptors. The data also indicate that the levels of the ERK kinases control a binary switch between cell proliferation and senescence and explain the maintenance of the senescence phenotype despite the presence of constitutively activated growth factor signaling pathways. Since inhibitors of the ERK pathway are under consideration for clinical use, we caution that they may trigger the escape of dormant senescent cells leading to malignant tumors.
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 4166. doi:1538-7445.AM2012-4166