bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2088: PU.1 enrichment to intronic enhancers is required for meis1 gene expression in both hematopoiesis and leukemogenesis
Authors: Li Yajun , Li Bo , Li Qiang , Zhang Lixia , Li Ping 
Published: August 2015

Abstract
Hematopoiesis is a tightly regulated process with multiple transcription factors (TFs) involved sequentially. Aberrant expression of the lineage specific transcription factors may disturb normal differentiation of hematopoietic cells and result in leukemia. Myeloid Ectropic viral Integration Site 1 (MEIS1), induces and maintains MLL transformation, and plays a rate-limiting regulatory role in MLL leukemogenesis. Meis1 gene is identified as the downstream targets of PU.1, another important hematopoietic transcription factor, which is inversely correlated with worse prognosis. Though multiple regulatory elements have been identified throughout the Meis1 locus, little is known about how PU.1 plays its role on Meis1 gene expression.
To gain insight into the transcriptional regulatory role of PU.1 during myeloid differentiation, we isolated the hematopoietic stem/progenitor cells (HSPC, Lin-kit+CD34+ cells) and matured myeloid cells (Lin+Gr1+cells) from bone marrows of C57 mice, performed ChIP sequencing assay, and analyzed PU.1 enrichment and histone modifications. The ChIP seq data was then confirmed with an induced differentiation model of mouse MLL-ENL leukemia cells. In addition to DNaseI hypersensitivity, the PU.1 binding elements were also characterized with H3K4me1 and H3K27ac modification. We studied the transcriptional activation role of one common PU.1 binding elements with luciferase assay. Insertion of PU.1 binding elements before the promoter increased the luciferase reporter activity, suggesting that the PU.1 binding region be the enhancer element of Meis1 gene. The association between PU.1 enrichment and Meis1 gene expression was studied in further with PU.1 knocking down assay in the MLL leukemia cells. Bioinformatics analysis results suggest that there were other transcription factors, including HOXA9 and MEIS1 itself enriched around the PU.1 binding sites. Our results suggest that PU.1 enrichment to the intronic enhancers of Meis1 gene is required for the proper expression during hematopoiesis. PU.1 together with histone modification and many other TFs, including MEIS1 itself, contributed to the hematopoietic expression of Meis1 gene. (The work is supported by National Natural Science Foundation of China (Grant number 81100380) to Y.L.)
Citation Format: Yajun Li, Bo Li, Qiang Li, Lixia Zhang, Ping Li. PU.1 enrichment to intronic enhancers is required for meis1 gene expression in both hematopoiesis and leukemogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2088. doi:10.1158/1538-7445.AM2015-2088
Abstract 209: A quantitative analysis of paclitaxel-induced mitotic catastrophe of MDA-MB-231 cells by high frequency ultrasound
Authors: Pasternak Maurice M. , Czarnota Gregory J. 
Published: August 2015

Abstract
In recent years, high-frequency ultrasound (HFUS) has shown promise of non-invasively detecting tumor death in response to chemotherapy. However, those studies have been limited to ultrasound B-mode and immunohistochemical image comparison over extended periods of time (≥24 hours). The purpose of this study was to evaluate the relationship of quantified HFUS spectral parameters to the dynamics of tumor cell death in MDA-MB-231 cell samples exposed to paclitaxel chemotherapy. Several ultrasound parameters were investigated, including the, attenuation, spectral slope, spectral y-intercept, midband fit, estimated scatterer diameter and estimated scatterer concentration. Changes in these spectral-based parameters were evaluated in their capacity to respond to various cell death events, including mitochondrial depolarization, caspase activation, phosphatidylserine exposition, and membrane selective permeability compromise, as determined by flow cytometry analysis. Standard histology and transmission electron microscopy (TEM) permitted further investigation of possible candidates responsible for the changes detected using ultrasound. Based on TEM, negative TUNEL staining, and cell cycle analysis it was found that paclitaxel at 1mM induces mitotic catastrophe as the main cell death modality. The spectral slope correlated strongly (r2 = 0.89) with the percentage of cells arrested at the G2/M checkpoint and exhibited an opposite trend to that of systems undergoing classical apoptosis, suggesting that it may be a prime biophysical marker for differentiating modalities of tumor cell death. Midband fit increases through time suggested an increase in the concentration of acoustic scatterers. The formation of condensed chromatin condensates of a 1 micron or greater diameter in the course of paclitaxel-induced mitotic catastrophe, as revealed by TEM, were hypothesized to act as large intracellular scatterers and correlated with the increase in ultrasound midband fit. Midband fit showed the strongest correlation of all parameters (r2 = 0.99) when plotted against the percentage of the cell population expected to possess these scattering structures, establishing the first quantitative correlation of ultrasound parameters to a cell death index. These findings support that HFUS spectral parameters may be used to quantify the degree of cell death and predict the efficacy of chemotherapeutic treatment within a short post-treatment timeframe.
Citation Format: Maurice M. Pasternak, Gregory J. Czarnota. A quantitative analysis of paclitaxel-induced mitotic catastrophe of MDA-MB-231 cells by high frequency ultrasound. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 209. doi:10.1158/1538-7445.AM2015-209
Abstract 2091: IL-8 mRNA gene expression up-regulated level in both primary culture cell and tissue biopsy from gastric cancer patient without Helicobacter pylori infection and down- regulated level predict clinical response after chemo
Authors: Limpakan (Yamada) Sirikan , Chakrabandhu ML.Bandhuphat , Kato Shunji , Wongsirisin Pattama 
Published: August 2015

Abstract
Background: There is some recent in vitro study reported that IL-8 mRNA gene had over expression when Helicobacter pylori was co- infected. In the Northern Thai population, we found independently IL-8 mRNA gene expression significantly rising level in gastric tissue biopsies when comparing to AGS cell line, and mainly in non-cag A H. pylori infection or without H. pylori infection.
Aim: The author aim to demonstrate the IL-8 mRNA gene expression level in vitro and in vivo study in the same host in order to see the change of its level in primary culture cell in same host gastric cancer patients, tissue biopsy, and AGS cell line. The comparative level before and after chemotherapy treatment were targeted for clinical response prediction.
Material and Methods: The control background of corpus normal epithelial and gastric adenocarcinoma biopsy tissues were treated for primary cell culture with single cell isolation technique. The histopathology, background atrophy, and H. pylori infection was confirmed. Biopsy tissues from tumor site also were collected at the same time before and after chemotherapy treatment in patient who received neo-adjuvant chemotherapy by FOLFOX IV regimen due to locally advance stage and unresectable tumor. The IL-8 mRNA gene expression was tested by relative quantitation real time RT-PCR.
Results: IL-8 mRNA gene expression can be significantly higher up-regulated level to 1.5-2.2 folds in gastric cancer tissue biopsy comparing to from 0.35-1.16 fold of primary culture cell without H. pylori infection when comparing to normal background of gastric epithelial tissue, and AGS cell line. The IL-8 mRNA gene expression down-regulated level is also remark decreased and/or undetected after chemotherapy treatment in correlation with patients who had well clinical response as a preliminary result.
Conclusion: We first demonstrated that the IL-8 mRNA gene expression is detected in primary gastric adenocarcinoma cell and its up-regulated level in tissue biopsies independently related to H. pylori infection in the same gastric cancer host background. The pilot sample size is needed to confirm in further clinical trial on chemotherapy as a new biomarker for advance gastric cancer treatment.
Citation Format: Sirikan Limpakan (Yamada), ML.Bandhuphat Chakrabandhu, Shunji Kato, Pattama Wongsirisin. IL-8 mRNA gene expression up-regulated level in both primary culture cell and tissue biopsy from gastric cancer patient without Helicobacter pylori infection and down- regulated level predict clinical response after chemo [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2091. doi:10.1158/1538-7445.AM2015-2091
Abstract 2093: Regulation of c-Myc expression by aspirin and salicylic acid in colon cancer cells through a novel pathway
Authors: Ai Guoqiang , Dachineni Rakesh , Muley Pratik , Tummala Hemachand , Gunaje Jayarama B. 
Published: August 2015

Abstract
Epidemiological studies have demonstrated a significant correlation between regular aspirin use and reduced colon cancer incidence and mortality; however, the exact pathway has not been identified. We hypothesized that aspirin's anti-cancer effect may occur through modulation of c-Myc gene expression. Being a transcription factor, c-Myc controls nearly 15% of the expression of all genes and its activity is highly regulated in normal cells. In many cancers including colon cancer, c-Myc is mutated and constitutively activated which leads to uncontrolled cell proliferation. In the present study, we demonstrate that aspirin and its primary metabolite, salicylic acid, significantly decrease the c-Myc protein levels in colon cancer cells. In total cell lysates, both drugs decreased the levels of c-Myc in a concentration dependent (250 μM to 2500 μM) fashion (up to 70%). Interestingly, greater inhibition was observed in the nucleus than the cytoplasm, and immuno-fluorescence studies further confirmed these observations. Pre-treatment of cells with lactacystin partially reversed the inhibitory effect of both aspirin and salicylic acid, suggesting that 26S proteasomal pathway is involved. Transfection of HCT-116 cells with DDK-tagged c-Myc produced abundant c-Myc protein; but, it was unaffected by aspirin and salicylic acid. In the same lysates, the endogenous c-Myc level were significantly decreased. HPLC analysis showed that aspirin taken up by cells was metabolized to salicylic acid in a time-dependent fashion. This further supports the finding aspirin's inhibitory effect on c-Myc occurs through formation of salicylic acid. Our result suggests that aspirin and salicylic acid regulate c-Myc level at both transcriptional and post-transcription level. Inhibition of c-Myc levels may represent an important pathway by which aspirin exerts its anti-cancer effect and decrease the occurrence of cancer in epithelial tissues.
Citation Format: Guoqiang Ai, Rakesh Dachineni, Pratik Muley, Hemachand Tummala, Jayarama B. Gunaje. Regulation of c-Myc expression by aspirin and salicylic acid in colon cancer cells through a novel pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2093. doi:10.1158/1538-7445.AM2015-2093
Abstract 2094: GSK-3 is a novel target of CREB and GSK-3-CREB signaling participates in cell survival in lung cancer
Authors: Park Sin-Aye , Lee Jong Woo , Herbst Roy S. , Koo Jaseok Peter 
Published: August 2015

Abstract
The transcription factor cyclic AMP-response element-binding protein (CREB) regulates diverse cellular processes, including cell differentiation, proliferation, survival, glucose metabolism, immune regulation, and synaptic plasticity associated with memory. Previously, we showed that CREB is critical on the regulation of mucous differentiation of normal human tracheobronchial epithelial (NHTBE) cells. In addition, the overexpression of CREB is associated with negative prognosis of patients with non-small cell lung cancer (NSCLC). Further studies showed that the knockdown of CREB suppresses the growth of lung cancer cells. It has been demonstrated that genes regulated by CREB have been reported to be involved in the suppression of apoptosis, induce cell proliferation, inflammation and tumor metastasis. However, the critical target genes of CREB in lung cancer have not been well understood. In this study, we identified GSK-3 as one of the CREB target genes critical for the growth and survival of lung cancer cells. The CREB knockdown significantly reduced the expression of GSK-3 and the direct binding of CREB on the promoter of GSK-3 was identified. Kaplan-Meier analysis with a public database showed a prognostic significance of aberrant GSK-3 expression in lung cancer. Inhibition of GSK-3 suppressed cell proliferation, colony formation and tumor growth. Although GSK-3 has been studied as a tumor suppressor in certain types of cancer, there is increasing evidence that GSK-3 plays an oncogenic role in various human cancers. Here, for the first time, we demonstrated that GSK-3 is regulated by CREB in lung cancer and is required for the survival of lung cancer cells. These findings implicate CREB-GSK-3 axis as a novel therapeutic target for lung cancer treatment.
Citation Format: Sin-Aye Park, Jong Woo Lee, Roy S. Herbst, Jaseok Peter Koo. GSK-3 is a novel target of CREB and GSK-3-CREB signaling participates in cell survival in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2094. doi:10.1158/1538-7445.AM2015-2094
Abstract 2097: Grainyhead-like 2 (GRHL2) regulates epithelial plasticity and stemness in oral cancers
Authors: Chen Wei , Mehrazarin Shebli , Shin Ki-Hyuk S , Lin Yi-Ling , Kim Reuben H. , Park No-Hee , Kang Mo K. 
Published: August 2015

Abstract
Purpose: Grainyhead-like 2 (GRHL2) is one of the three mammalian homologues of Drosophila Grainyhead involved in epithelial morphogenesis. GRHL2 also controls epithelial cell proliferation and differentiation. Our objective was to evaluate the role of GRHL2 in oral carcinogenesis and the underlying mechanism.
Experimental Design: GRHL2 expression was evaluated in multiple oral cancer cell lines and tissues of oral squamous cell carcinomas (OSCCs) by qRT-PCR, western blot assay, immunohistochemistry and laser-captured microdissection assay. The effects of shRNA-mediated GRHL2 knockdown were evaluated by tumor spheroid assay, colony formation assay, gene promoter luciferase assay and immunofluorescent staining and chromatin immunoprecipitation assay. In vivo the effect of GRHL2 loss on cancer cell tumorigenicity was evaluated by tumor xenograft assay.
Results: GRHL2 expression was elevated in cells and tissues of oral squamous cell carcinomas (OSCCs) compared with normal counterparts. Knockdown of GRHL2 resulted in the loss of in vivo tumorigenicity, cancer stemness, and epithelial phenotype of oral cancer cells. GRHL2 inhibition decreased oral cancer cell proliferation and colony formation. GRHL2 regulated the expression of miR-200 family and Octamer-binding transcription factor 4 (Oct-4) genes through direct promoter DNA binding. Overexpression of miR-200 genes in the oral cancer cells depleted of GRHL2 partially restored the epithelial phenotype, proliferative rate and cancer stemness.
Conclusion: GRHL2 plays pivotal role in the maintenance of the transformed phenotype in OSCCs. Downregulation of GRHL2 leads to the decrease of tumorigenicity, cancer stemness of oral cancer cell, in which miR-200 and Oct-4 genes partially mediate the tumorigenic effects of GRHL2 in OSCC. This study was supported in part by the grants R56DE024593 and Jack Weichman Endowed Fund.
Citation Format: Wei Chen, Shebli Mehrazarin, Ki-Hyuk S Shin, Yi-Ling Lin, Reuben H. Kim, No-Hee Park, Mo K. Kang. Grainyhead-like 2 (GRHL2) regulates epithelial plasticity and stemness in oral cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2097. doi:10.1158/1538-7445.AM2015-2097
Abstract 2104: Evidence for E2F/EWS-FLI1 oncoprotein synergism using systems biology
Authors: Schwentner Raphaela , Papamarkou Theodore , Kauer Maximilian , Stathopoulos Vassilios , Yang Fan , Bilke Sven , Meltzer Paul S. , Girolami Mark , Kovar Heinrich 
Published: August 2015

Abstract
Cell cycle deregulation and enhanced proliferation of cells is one of the hallmarks of oncogenesis. In Ewing Sarcoma, a highly aggressive pediatric cancer, the chimeric transcription factor EWS-FLI1 deregulates cell cycle by targeting several cell cycle regulators including the E2F family of transcription factors. ChIP-seq studies showed a significant overlap of EWS-FLI1 and E2F3/4 binding in Ewing sarcoma cells. We show that EWS-FLI1 is able to directly activate E2F3, followed by the combinatorial binding of EWS-FLI1 and E2F3 on their target genes synergistically activating their transcription. Furthermore we propose a model where EWS-FLI1 directly exchanges repressive E2F4/p130 by E2F3/pRB thereby driving cells into enhanced cell proliferation. However, so far we were unable to experimentally demonstrate a physical interaction of EWS-FLI1 with any E2F or pocket protein.
As an alternative approach to the study of functional synergy between EWS-FLI1 and E2F3, we used time resolved RNA and protein expression data as a basis for mathematical modeling of EWS-FLI1 dependent E2F target gene regulation. By Bayesian model selection, we were able to postulate the formation of a complex between EWS-FLI1 and E2F3 as the most likely explanation for the observed ETS/E2F synergy. This study therefore provides an example of how computational systems approaches can complement experimental data in the discovery of disease mechanisms.
This study was supported in part by the Austrian Science Fund (FWF), [grant 22328-B09], and by the 7th framework program of the European Commission, [grant 259348] (‘ASSET’).
Citation Format: Raphaela Schwentner, Theodore Papamarkou, Maximilian Kauer, Vassilios Stathopoulos, Fan Yang, Sven Bilke, Paul S. Meltzer, Mark Girolami, Heinrich Kovar. Evidence for E2F/EWS-FLI1 oncoprotein synergism using systems biology. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2104. doi:10.1158/1538-7445.AM2015-2104
Abstract 2116: HDAC9 and 11 contribute to UV resistance in melanoma cells
Authors: Chang Elizabeth T. , Parekh Palak R. , Yang Qingyuan , Carrier France 
Published: August 2015

Abstract
We have previously shown that the Histone Deacetylase Inhibitor (HDACi) trichostatin A (TSA) can sensitize cancer cells to UV radiation by facilitating the formation of Cyclobutane pyrimidine dimers (CPD) without increasing the levels of HDAC1. Here we show that HDAC9 and HDAC11 are upregulated in response to UV radiation in a number of human melanoma cell lines. Both HDAC9 and HDAC11 have an hnRNP A18 signature motif in their 3′UTR. hnRNP A18 is a new regulator of protein translation that can confer growth advantages to tumor cells by specifically increasing the stability and translation of mRNA transcripts harboring its signature motif. Our data indicate that HDAC9 and 11 levels correspond to hnRNP A18 level in response to UV radiation in several melanoma cell lines while hnRNP A18 and HDAC 9 and 11 are not upregulated in response to UV radiation in the normal human fibroblasts Malme cells or the normal melanocytes HEMa-LP. Moreover, clonogenic colony survival assays indicate that melanoma cells expressing higher hnRNP A18 endogenous levels are more resistant to UV radiation than cells expressing lower hnRNP A18 levels. In addition, down regulation of hnRNP A18 prevents HDAC 9 and 11 upregulation in response to UV radiation. Furthermore, overexpression of hnRNP A18 increases further the levels of HDAC 9 and 11 in response to UV radiation. These data suggest that upregulation of HDAC9 and 11 in response to hnRNP A18 activation contribute to UV resistance and may increase sensitization to UV-induced cell killing by HDACi.
Citation Format: Elizabeth T. Chang, Palak R. Parekh, Qingyuan Yang, France Carrier. HDAC9 and 11 contribute to UV resistance in melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2116. doi:10.1158/1538-7445.AM2015-2116