bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A30: Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma
Authors: Kitadate Akihiro , Teshima Kazuaki , Ohshima Kouichi , Seto Masao , Sawada Kenichi , Tagawa Hiroyuki 
Published: August 2014

Abstract
The proto-oncogene BMI1 and its product, Bmi1, is overexpressed in various types of tumors, particularly in aggressive tumors and tumors resistant to conventional chemotherapy. BMI1/Bmi1 is also crucially involved in cancer-initiating cell maintenance, and is recurrently upregulated in mantle cell lymphoma (MCL), especially aggressive variants. Recently, side population (SP) cells were shown to exhibit tumor-initiating characteristics in various types of tumors. In this study, we show that recurrent MCL cases significantly exhibit upregulation of BMI1/Bmi1. We further demonstrate that clonogenic MCL SP shows such tumor-initiating characteristics as high tumorigenicity and self-renewal capability, and that BMI1 was upregulated in the SP from recurrent MCL cases and MCL cell lines. On screening for upstream regulators of BMI1, we found that expression of microRNA-16 (miR-16) was downregulated in MCL SP cells by regulating Bmi1 in the SPs, leading to reductions in tumor size following lymphoma xenografts. Moreover, to investigate downstream targets of BMI1 in MCL, we performed cross-linking/chromatin immunoprecipitation assay against MCL cell lines and demonstrated that Bmi1 directly regulated pro-apoptotic genes such as BCL2L11/Bim and PMAIP1/Noxa, leading to enhance anti-apoptotic potential of MCL. Finally, we found that a proteasome inhibitor bortezomib, which has been recently used for relapsed MCL, effectively induced apoptosis among MCL cells while reducing expression of Bmi1 and increasing miR-16 in MCL SP. These results suggest that upregulation of BMI1 and downregulation of miR-16 in MCL SP has a key role in the disease's progression by reducing MCL cell apoptosis. Our results provide important new insight into the pathogenesis of MCL and strongly suggest that targeting BMI1/Bmi1 might be an effective approach to treating MCL, particularly refractory and recurrent cases.
Citation Format: Akihiro Kitadate, Kazuaki Teshima, Kouichi Ohshima, Masao Seto, Kenichi Sawada, Hiroyuki Tagawa. Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A30.
Abstract A37: MicroRNA-26b potentiates cytotoxicity of malignant glioma cells by radiation
Authors: Lee David J. , Hwang Yeo-Hyun , Kim In Ah 
Published: August 2014

Abstract
MicroRNA-26b is known to be upregulated in high grade glioma and to play a crucial role in epithelial to mesenchymal transition (EMT). In this study, we evaluated the potential of targeting miRNA-26b to overcome the radioresistance of human malignant glioma cells. We also aimed to elucidate the mechanisms of radiosensitization by miR-26b.
U251 human glioma cells having activation of PI3K signaling due to deletion of PTEN were transfected with pre-miR-26b or control pre-miRNA. Ectopic overexpression of miR-26b attenuated the expression of p-AKT and enhanced the cytotoxicity of U251 cells by radiation. Overexpression of miR-26b prolonged radiation-induced gamma H2AX foci formation and attenuated the expression of p-DNA-PKcs. Increased expression of mature miR-26b also suppressed invasion, migration, vascular tube formation, and led to down-regulation of HIF-1alpha, VEGF and MMP-2 expression. In contrast, overexpression of miR-26b did not increased radiaton toxicity of normal human astrocytes.
Taken together, these findings suggest that miR-26b could be an attractive target for overcoming radioresistnace of human malignant glioma cells via unique modulation of the cancer pro-survival signaling and EMT.
Citation Format: David J. Lee, Yeo-Hyun Hwang, In Ah Kim. MicroRNA-26b potentiates cytotoxicity of malignant glioma cells by radiation. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A37.
Abstract B22: Modulation of insulin-like growth factor binding proteins expression in human prostate cancer cells in vitro by american cranberry (Vaccinium macrocarpon) extract
Authors: Hurta Robert , McKeown Brendan , Boddeti Ravi , Neto Catherine 
Published: August 2014

Abstract
American cranberry (Vaccinium macrocarpon) extract has been previously shown to affect cell cycle, apoptosis, and proliferative ability in prostate cancer cells in vitro. The insulin-like growth factors (IGFs) and their modulators the insulin-like growth factor binding proteins (IGFBPs) may play roles in these events. IGFBPs act by regulating IGF action but also exhibit many IGF-independent activities. IGFBP expression in response to cranberry extract [50 & 100 ug/mL for 3 and 24 hours] was determined via Western blot analysis in DU145 and in PC3 androgen-refractory human prostate cancer cells. Cranberry extract treatment decreased the expression levels of both IGFBP-2 and IGFBP-5 and increased the expression levels of IGFBP-4. IGFBP-3 protein expression levels were apparently unaffected by cranberry extract suggesting that IGFBP-3 is likely not involved in this cellular response to cranberry extract. A reduction in IGFBP-2/-5 expression suggests a reduction in IGF through loss of IGF-stabilization by the IGFBPs suggesting an inhibition of the cell cycle due to this restriction in IGF. Increases in IGFBP-4 levels in response to cranberry would also inhibit IGFs and thereby inhibit cellular growth and proliferation. Increased IGFBP-2/-5 expression has been associated with progression from androgen-sensitivity to androgen-insensitivity in prostate cancer cells. Decreased IGFBP-2/-5 expression levels in response to cranberry extract could counteract this progression in vitro. [funded by The Cranberry Institute (Wisconsin Board) and Jeanne & J.-Louis Levesque Foundation]
Citation Format: Robert Hurta, Brendan McKeown, Ravi Boddeti, Catherine Neto. Modulation of insulin-like growth factor binding proteins expression in human prostate cancer cells in vitro by american cranberry (Vaccinium macrocarpon) extract. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B22.
Abstract B26: Melanoma cells induce stem cells like fenotype of normal human keratinocytes
Authors: Kodet Ondrej , Lacina Lukas , Dvorankova Barbora , Kolar Michal , Strnad Hynek , Smetana Karel 
Published: August 2014

Abstract
Introduction: Nodular melanoma is one of the most life threatening tumors with frequently poor therapeutic outcome. Similarly to other the tumors, the intercellular interactions may be of crucial importance for biological properties of melanoma and course of the disease. This study is mapping the effect of melanoma cells and melanoma associated fibroblasts on keratinocytes as compared with effect of neural crest stem cells.
Methods: 100 samples removed during radical melanoma resection were analyzed by histology and 20 of them by immunohistochemistry and compared with in vitro models. For in vitro models of intercellular interactions we co-cultured in transwell systems melanoma cells or neonatal melanocytes or neural crest stem cells respectively with human normal keratinocytes. Further, we employed also melanoma associated fibroblasts and normal human dermal fibroblasts respectively in above mentioned culture system. Transcriptional analysis of these models was carried out in collaboration with the Institute of Molecular Genetics of the ASCR on the whole genome level by using Illumina microarrays.
Results: In tissue surrounding nodular melanoma we have observed significant hyperplasia of epithelial layer with aberrant suprabasal expression of keratin 14 (K14) along with absence of K10 - marker of differentiated epidermal keratinocytes. In vitro models revealed that melanoma cells, neural crest stem cells and also melanoma associated fibroblasts were able to influence expression of K14, but also expression of K19 and K8 as well as of vimentin in cocultured keratinocytes. Cytokines and growth factors such as FGF2, CXCL1, IL8 and VEGFA seem to participate in this activity of melanoma cell to keratinocytes.
Conclusion: Melanoma cells as well as melanoma associated fibroblasts are able to modify the landscape of tissue surrounding the proliferating malignant clone. These interactions result in maintenance of low differentiation status of keratinocytes in vivo as well as in vitro. This interaction further highlights the role of intercellular interactions in melanoma, but the functional significance for melanoma biology requires further analysis.
This study was supported by the Charles University project PRVOUK 27-1 and by the Grant Agency of the Czech Republic project no 304/121/333.
Citation Format: Ondrej Kodet, Lukas Lacina, Barbora Dvorankova, Michal Kolar, Hynek Strnad, Karel Smetana, Jr.. Melanoma cells induce stem cells like fenotype of normal human keratinocytes. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B26.
Abstract B29: Defining subclonal signaling heterogeneity in glioblastoma multiforme (GBM)
Authors: Lan Xiaoyang , Meyer Mona , Reimand Jüri , Zhu Xueming , Kushida Michelle , Head Renee , Clarke Ian , Bader Gary , Dirks Peter 
Published: August 2014

Abstract
Glioblastoma Multiforme (GBM, WHO grade IV) is the most common and malignant brain tumor of the adult central nervous system, with a median survival of between 12 and 15 months. Interestingly, the presence of genetically unique subclones in GBMs has been previously implicated in GBMs using Fluorescence in situ hybridization (FISH) and surgical multisampling approaches.1,2 The purpose of this study are to unequivocally demonstrate clinically relevant phenotypic heterogeneity in GBM subclones, and to identify genetic and phenotypic biomarkers predictive of subclonal drug responses. Previous work in the Dirks laboratory has allowed for the generation of 44 single-cell derived clonal cultures from 4 GBM tumors, by Fluorescence Activated Cell Sorting (FACS) and clonal expansion in vitro. Comparisons of clones derived from the same tumor uniquely allows for the identification and characterization of genetic and functional intratumoral diversity in GBM. We demonstrate that single-cell derived clonal cultures from the same primary tumor can differ in key phenotypes such as proliferation in vitro and responsiveness to the chemotherapeutic Temozolomide. Our work has also shown that expression of the oncogene EGFRvIII is exclusive to some clones within a tumor, and not others. Profiling of basal and activated EGFR signaling states also revealed subclonal variability in pERK and pS6 activity, suggesting subclonal differences in pathway dependencies which could be exploited for targeted therapies. Importantly, we observed clonal differences in sensitivity to the EGFR small molecule inhibitor Erlotinib, suggesting that clonal phenotypes can be correlated to differences in signaling activity between tumor subclones. The existence of inherently drug resistant clones in GBM tumors may lead to ineffective therapies and tumor relapses, and subclonal interrogation of patient specimens may lead to better treatment stratification.
References
1) Snuderl, M., L. Fazlollahi, et al. “Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.” Cancer Cell 20, 810-817(2011).
2) Sottoriva, A., I. Spiteri, et al. (2013). “Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics.” Proc Natl Acad Sci USA 110, 4009-4014(2013).
Citation Format: Xiaoyang Lan, Mona Meyer, Jüri Reimand, Xueming Zhu, Michelle Kushida, Renee Head, Ian Clarke, Gary Bader, Peter Dirks. Defining subclonal signaling heterogeneity in glioblastoma multiforme (GBM). [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B29.
Abstract B30: Identification of new regulator in p53-mediated cellular senescence
Authors: Shin Jae-Sik , Hong Seung-Woo , Lee Dae-Hee , Moon Jai-Hee , Kim Jeong Eun , Hong Yong Sang , Kim Kyu-pyo , Lee Jae-Lyun , Choi Eun Kyung , Lee Jung Shin , Jin Dong-Hoon , Kim Tae Won 
Published: August 2014

Abstract
The downstream events and target genes of p53 in senescence responses are not fully understood. Here, we identify a novel regulator, A-core gene, in p53-mediated cellular senescence. Overexpression of A-core in p53-deficient mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas A-core gene knockdown by small interfering RNA (siRNA) leads to escape from p53-mediated senescence in p53-expressing MEFs. A-core overexpression also increased intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-L-cysteine rescued A-core overexpression-induced senescence. Surprisingly, the elevated levels of ROS that accompanied A-core overexpression were paralleled by an increase in p21 expression. siRNA-mediated knockdown of p21 in A-core overexpressing MEFs abrogated the A-core-dependent increase in ROS levels, indicating that A-core acts through p21 induction and subsequent ROS elevation to trigger senescence. In addition, expression of the cell proliferation-related proteins cyclin E and B was decreased after A-core expression. Collectively, these results suggest that A-core is a downstream target of p53 that is sufficient to induce p21 expression and ROS production, and is necessary for p53-mediated senescence.
Citation Format: Jae-Sik Shin, Seung-Woo Hong, Dae-Hee Lee, Jai-Hee Moon, Jeong Eun Kim, Yong Sang Hong, Kyu-pyo Kim, Jae-Lyun Lee, Eun Kyung Choi, Jung Shin Lee, Dong-Hoon Jin, Tae Won Kim. Identification of new regulator in p53-mediated cellular senescence. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B30.
Abstract B31: Cell-based screening of novel anticancer molecules for prostate cancer
Authors: Santos Karen Cristina dos , Malavolta Isadora , Leitao Andrei 
Published: August 2014

Abstract
Metastatic and mutant androgen receptor prostate cancer are still of major concern for chemotherapy, lacking an efficacious approach to tackle this life threatening disease. This is so, because of the resilience to androgen ablation therapy. To accomplish with that, new molecules for prostate cancer have been tested in different in vitro models by academic groups and pharmaceutical entrepreneurs. In this work, novel molecules were tested in cell line that do not express androgen receptor (DU145) or cells harboring the mutant androgen receptor (LNCaP). Mouse fibroblast (Balb-c 3T3) cells were also tested in this cell-based screening to check for selectivity. These novel molecules came from previous studies using computational medicinal chemistry tools regarding mutant androgen receptor, surviving and mTOR inhibitors. All biological results were compared with the reference molecules bicalutamide, rapamycin, doxorubicin and YM155. The first screening comprised MTT colorimetric assay, further confirmed by flow cytometry studies, including cell cycle analysis and apoptosis indicators. Several novel molecules presented activity according to the screenings using prostate cancer cell lines. YM155 (a survivin inhibitor) was the only active molecule from the reference set when using the DU145 cells. Besides that, YM155 was the most selective molecule from the whole compound series (composed by reference and test sets). These phenotypic screenings provided the first evidence of anticancer molecules amenable for further chemical optimization.
Citation Format: Karen Cristina dos Santos, Isadora Malavolta, Andrei Leitao. Cell-based screening of novel anticancer molecules for prostate cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B31.
Abstract B41: EMC1 influences cellular calcium homeostasis and promotes breast cancer cell migration and proliferation
Authors: Molina Roberto Augusto Silva , Silva Rodrigo Ribeiro , Costa Roberta Ribeiro , Banzi Silmara Reis , Espreafico Enilza Maria 
Published: August 2014

Abstract
Endoplasmic Reticulum Membrane Complex protein 1 (EMC1), also named KIAA0090, was recently identified as part of a complex with six proteins (EMC1-EMC6) proposed to participate in the folding/maturation of membrane proteins, but the mechanisms remains unclear. High throughput studies reveal that EMC1 gene is up-regulated in many types of cancer and up-regulation correlates to poor survival rates. It has been known that there is a close relationship between proteins involved in the unfolded protein response (UPR) and tumor maintenance. Here, we investigated the involvement of EMC1 in breast cancer cell proliferation and migration. We showed by qPCR that EMC1 gene is overexpressed in breast cancer cell lines in comparison to immortalized epithelial breast cells. Next, we stably overexpressed EMC1 in MCF-7 and SKBR-3 cell lines. Overexpression led to an increase in proliferation rates, clonogenic capacity, and migration in wound-healing assays. Consistently, EMC1 knockdown in SKBR-3 cells led to a decrease of cell migration and clonogenic capacity. Furthermore, we assessed by Fluo3 the involvement of EMC1 in the regulation of intracellular calcium levels in SKBR-3 cells in response to thapsigargin treatment, which inhibits the endoplasmic reticulum Ca2+ ATPase. SKBR-3 control cells showed an expected increment in cytosolic calcium levels following thapsigargin addition. Interestingly, cytosolic calcium increments were about 50% higher in EMC1 overexpressing cells and nearly 10-fold lower in knockdown cells, suggesting a role for EMC1 in the control of cellular calcium homeostasis. EMC1 could function in the maturation/assembly of calcium channels or calcium pumps, thereby promoting breast cancer cell migration and maintenance.
Citation Format: Roberto Augusto Silva Molina, Rodrigo Ribeiro Silva, Roberta Ribeiro Costa, Silmara Reis Banzi, Enilza Maria Espreafico. EMC1 influences cellular calcium homeostasis and promotes breast cancer cell migration and proliferation. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B41.
Abstract B44: A role for endothelial αvβ3 integrin in breast tumor cell migration
Authors: Montenegro Cyntia Freitas , Durante Araceli Cristina , Micocci Kelli Cristina , Pereira Antonio Carlos Manucci , Selistre-de-Araujo Heloisa Sobreiro 
Published: August 2014

Abstract
Vascular endothelial growth factor (VEGF) and αvβ3 integrin are key molecules that actively participate in tumor angiogenesis and metastasis. Some integrin-blocking molecules are currently under clinical trials for cancer and metastasis treatment. However, the mechanism of action of such inhibitors is not completely understood and evasive resistance of antiangiogenic therapy has been reported. We have previously demonstrated the anti-angiogenic and anti-metastatic properties of DisBa-01, a recombinant His-tag RGD-disintegrin from Bothrops alternatus snake venom in experimental models. DisBa-01 blocks αvβ3 integrin binding to vitronectin and inhibits integrin mediated downstream signaling cascades and cell migration. Recently, we reported that DisBa-01 strongly decreases the expression of VEGF mRNA and of its receptors, vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2) in endothelial cells. Here, DisBa-01 was submitted to adhesion under flow and transmigration assays, both using different DisBa-01 concentrations and β3-siMDA-MB-231 cells. In the first assay, labeled tumor cells incubated with Disba-01 perfused for 5 minutes through a chamber containing endothelial cells as coat. In the second, labeled tumor cells incubated with DisBa-01 were attracted by complete medium and transmigrated through an endothelial cell coat. Individually, assays were photographed and the cells quantified. Results show that DisBa-01 dose-dependently inhibited adhesion of MDA-MB-231 cells to human endothelial cells under flow conditions, similarly to the effect observed by β3-siMDA-MB-231 cells. In addition, the disintegrin or β3-silencing inhibited the transmigration of tumor cells through endothelial cells in vitro. These results demonstrate that endothelial αvβ3 integrin has a key role in tumor cell adhesion and transmigration through the endothelium under flow conditions.
Support: Fapesp (grant no. 1998/14138-2), CNPq, and CAPES (Brazil)
Citation Format: Cyntia Freitas Montenegro, Araceli Cristina Durante, Kelli Cristina Micocci, Antonio Carlos Manucci Pereira, Jr., Heloisa Sobreiro Selistre-de-Araujo. A role for endothelial αvβ3 integrin in breast tumor cell migration. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B44.