bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1878: Inhibition of the Transforming Growth Factor beta pathway in human glioblastoma cell lines induces apoptosis and inhibits anoikis escape
Authors: Gallo-Oller Gabriel , Dotor Javier , Fan Xing , Castresana Javier S. 
Published: July 2016

Abstract
Glioblastoma Multiforme (GBM) is the most prevalent malignant brain tumor accounting for 60-70% of all gliomas. Current achieved median patient survival ranges only 12-15 months, and improvements in survival over the last century can be measured only in weeks. A hallmark of this malignancy is the intrinsic resistance to current therapies. The Transforming Growth Factor beta (TGF-beta) signaling pathway plays a key role in GBM. Several inhibitors of different elements and regulators of the TGF-beta pathway have entered to clinical trials.
Here, we analyzed the potential effect of P144, a TGF-beta pathway inhibitor peptide, over cell proliferation and apoptosis in commercial GBM cell lines (A172 and U-87 MG). We found that treatment with P144 significantly decreased cell proliferation of both cell lines analyzed. In addition, different apoptosis determinations such as ELISA and Acridine Orange/Ethidium Bromide (AO/EB) staining, confirmed a significant increase in apoptosis in both cell lines.
Quantification of SMAD2 phosphorylation status and its nuclear translocation, by western blot, confirmed the inhibition of TGF-beta signaling by P144. These data support the correlation between TGF-beta pathway inhibition and the apoptotic process induction.
Anoikis escape sustains invasiveness and metastatic potential in GBM, and has been established as a clear target against tumor progression. Due to P144 clear effect on apoptosis, we analyzed its influence on anoikis escape. The inhibition of anoikis escape by P144 was confirmed in A172 and U-87 MG cell lines under in vitro anchorage-independent culture conditions. The significant upregulation of BAX, Lamin A and Lamin C produced by P144 confirmed the induction of this apoptotic subtype process in the analyzed cell lines.
We can conclude that P144 increases apoptosis and induces anoikis through inhibition of the TGF-beta signaling pathway. Our results highlight the therapeutic potential of P144 for the treatment against GBM. However, previous to further clinical development, additional studies are required in order to confirm the effect of P144 over GBM in the brain environment, as well as to explore the therapeutic potential of P144 in combination with current and emerging molecular based therapies.
Citation Format: Gabriel Gallo-Oller, Javier Dotor, Xing Fan, Javier S. Castresana. Inhibition of the Transforming Growth Factor beta pathway in human glioblastoma cell lines induces apoptosis and inhibits anoikis escape. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1878.
Abstract 1879: Structural and biochemical characterization of farnesylated and methylated KRAS-membrane interactions
Authors: Van Que , Gillette William K. , Esposito Dominic , Ghirlando Rodolfo , Heinrich Frank , Stephen Andrew G. 
Published: July 2016

Abstract
KRAS4b, which is frequently mutated in pancreatic, colon and lung cancers, is processed in several enzymatic steps that results in the addition of a farnesyl and a methyl group to the terminal cysteine residue. Plasma membrane localization of KRAS4b requires this processing along with a polybasic stretch of lysines within the hypervariable region. KRAS4b can bind to RAF-RBD in solution but membrane bound KRAS4b is required for RAF-kinase activation. In order to determine why membrane interaction of KRAS4b is required for MAPK signal transduction we under took a structural and biochemical analysis of KRAS4b-membrane interactions. We have developed methods using an engineered baculovirus for the insect cell production of farnesylated and methylated KRAS4b (KRAS4b-FME) and this material was used in these studies. We have demonstrated that the stable interaction of KRAS4b-FME to lipid Nanodiscs and tethered lipid bilayers is dependent on the presence of anionic phospholipids. Using analytical ultracentrifugation we have evaluated the binding stoichiometry of KRAS4b-FME with Nanodiscs. In addition we have used neutron reflectivity to determine the orientation of KRAS4b-FME on tethered lipid bilayers.
Citation Format: Que Van, William K. Gillette, Dominic Esposito, Rodolfo Ghirlando, Frank Heinrich, Andrew G. Stephen. Structural and biochemical characterization of farnesylated and methylated KRAS-membrane interactions. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1879.
Abstract 1883: Treatment with histone deacetylase (HDAC) and BRAF inhibitors upregulates the expression of the plasma membrane Ca2+ pump, PMCA4b and alters intracellular Ca2+ handling in BRAF mutant melanoma cells
Authors: Hegedus Luca , Garay Tamas , Molnar Eszter , Varga Karolina , Padanyi Rita , Paszty Katalin , Hegedus Balazs , Wolf Mathias , Grusch Michael , Kallay Eniko , Enyedi Agnes 
Published: July 2016

Abstract
The aim of our study was to test the effects of histone deacetylase (HDAC) and BRAF inhibitors on the expression and activity of the plasma membrane Ca2+ pump isoform 4b (PMCA4b) in BRAF mutant melanoma cell lines. Remodeling of Ca2+ homeostasis during malignancy is caused by the rearrangement of the Ca2+ signaling machinery, including Ca2+ pumps, Na+/Ca2+ exchangers and channels. Plasma membrane calcium ATPases (ATP2B - or PMCA) maintain the resting low intracellular calcium concentration by pumping out excess calcium from the cytosol. Changes in PMCA expression during malignant transformation have been described previously in colorectal and breast cancer cells, and most recently by our group in melanomas. We found that in BRAF mutant melanoma cells the PMCA 4b protein level was markedly elevated by BRAF inhibitor treatment. Overexpression of PMCA4b suppressed motility and metastatic potential. Previously, it was shown that HDAC inhibitors-induced differentiation up-regulated PMCA4b expression in gastric, colon and breast cancer cells. In the present study we treated BRAF mutant and BRAF wild type melanoma cells with HDAC inhibitors (SAHA (suberanilohydroxamic acid) or valproic acid) and tested the changes in abundance, localization and function of PMCA4b. Expression levels of the PMCA proteins were analyzed by qRT-PCR and Western Blotting. Subcellular localization of the PMCAs and the effects of treatments on cytosolic Ca2+ signaling were analyzed by confocal microscopy. We found that treatment with the HDAC inhibitors increased the level of PMCA4b expression at both mRNA and protein levels in both BRAF wild type and BRAF mutant cell types. The increased PMCA4b level was coupled with enhanced plasma membrane localization and with a faster Ca2+ clearance after stimulation. Our results show that in melanoma cells the expression of PMCA4b is under epigenetic control and HDAC inhibitors efficiently enhanced PMCA4b expression independent of the BRAF status of cells.
Citation Format: Luca Hegedus, Tamas Garay, Eszter Molnar, Karolina Varga, Rita Padanyi, Katalin Paszty, Balazs Hegedus, Mathias Wolf, Michael Grusch, Eniko Kallay, Agnes Enyedi. Treatment with histone deacetylase (HDAC) and BRAF inhibitors upregulates the expression of the plasma membrane Ca2+ pump, PMCA4b and alters intracellular Ca2+ handling in BRAF mutant melanoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1883.
Abstract 1894: Understanding the role of microRNA-206 in breast cancer
Authors: Adorno-Cruz Valery , Liu Huiping 
Published: July 2016

Abstract
MicroRNAs are short non-coding RNA sequences that that can modify genes in post transcriptional manner and are often de-regulated in cancer. Cancer stem cells, a subset of cancer cells with stem cell properties, are considered the root of tumorigenesis and seeds of metastasis. In this study we are interested in elucidating the role of miR-206 in breast cancer stem cell-mediated tumorigenesis and metastasis. We have observed that microRNA-206 (miR-206) regulate the metastatic traits of breast cancer cells, both in vitro and in vivo. Our studies have elucidated a signaling cascade that culminates in the silencing of cytokine (such as interleukin) and integrin expression. Knockdown of the interleukin and integrin genes by siRNAs mimics the phenotype of miR-206 expression in breast cancer cells. DNA content analysis using propidium iodide staining revealed that knockdown of miR-206 targets as well as over-expression of miR-206 in MDA-MB-231 cells regulates cell cycle arrest. Our results indicate that miR-206 mediates its regulatory effects through inhibiting multiple targets. MiR-206 may serve as a new therapeutic candidate for the future treatment of breast cancer.
Citation Format: Valery Adorno-Cruz, Huiping Liu. Understanding the role of microRNA-206 in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1894.
Abstract 1908: Lung tumorigenesis and metastasis is suppressed by the miR-200-GATA4/6-BMP4 axis
Authors: Kim Jeong Seon , Kurie Jonathan M. , Ahn Young-Ho 
Published: July 2016

Abstract
MicroRNA-200 (miR-200) family members suppress the epithelial-mesenchymal transition of various cancer cells, including lung adenocarcinoma cells. Previously, we found that forced expression of miR-200 decreased bone morphogenetic protein 4 (BMP4). In this study, we explored the mechanism and role of BMP4 depletion by miR-200 in murine lung adenocarcinoma cells. miR-200 down-regulated BMP4 via direct targeting of the GATA4 and GATA6 transcription factors that stimulate Bmp4 transcription. Bmp4 knockdown suppressed cancer cell growth, migration, and invasion and inhibited tumorigenesis and metastasis of lung cancer cells when injected into syngeneic mice. In addition, BMP4 was required for normal sphere formation in Matrigel 3-D culture, which might be mediated by MYH10, a downstream target of BMP4. These findings suggest that BMP4 functions as a pro-tumorigenic factor in a murine lung cancer model, and its transcription is regulated by miR-200 and GATA4/6.
Citation Format: Jeong Seon Kim, Jonathan M. Kurie, Young-Ho Ahn. Lung tumorigenesis and metastasis is suppressed by the miR-200-GATA4/6-BMP4 axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1908.
Abstract 1910: Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 in prostate cancer
Authors: Kato Mayuko , Kurozumi Akira , Goto Yusuke , Matsushita Ryosuke , Fukumoto Ichiro , Okato Atsushi , Nishikawa Rika , Sakamoto Shinichi , Ichikawa Tomohiko , Seki Naohiko 
Published: July 2016

Abstract
BACKGROUNDS:
Most patients with prostate cancer (PCa) initially respond to androgen-deprivation therapy, but eventually becomes hormone-insensitive and progress to castration-resistant prostate cancer (CRPC). CRPC is difficult to treat, and most clinical trials for advanced PCa have shown limited benefits, with disease progression and metastasis to the skeleton or other sites. Therefore, understanding the molecular mechanisms of CRPC and the metastatic pathways underlying PCa using genomic approaches would help to prevent and improve therapies for the disease. Our previous studies showed that three tumor-suppressive microRNAs (miRNAs), miR-26a/b, miR-29a/b/c and miR-218, significantly inhibited cancer cell migration and invasion. Therefore, we hypothesized that these miRNAs-regulated target genes deeply contributed to cancer metastasis.
METHODS:
Genome-wide gene expression analysis and in silico analysis were applied to investigate molecular targets regulated by miR-26a/b, miR-29a/b/c and miR-218 in PCa cells. A luciferase reporter assay was carried out to determine whether 3’ UTR of target genes have actual biding sites for these miRNAs. To investigate the functional role of target genes in PCa cells, loss-of-function studies by using siRNAs of targets genes were performed.
RESULTS:
Our in silico analysis and luciferase reporter assays showed that lysyl oxidase-like 2 (LOXL2) was directly regulated by tumor-suppressive miR-26a/b, miR-29a/b/c and miR-218 in PCa cells. Overexpression of LOXL2 was observed in PCa clinical specimens by immunohistochemical staining. Moreover, downregulating the LOXL2 gene significantly inhibited cell migration and invasion in PCa cells. The function of the LOXL2 is covalent crosslinking of collagen and/or elastin in the ECM. Aberrant expression of LOXL2 has been reported in several diseases, including cancers.
CONCLUSIONS:
Our present data showed that the gene promoting metastasis, LOXL2, was epigenetically regulated by tumor-suppressive microRNAs, miR-26a/b, miR-29a/b/c and miR-218 providing important insights into the molecular mechanisms of PCa metastasis. Elucidation of tumor-suppressive miRNAs regulated molecular pathways and targets could provide new information on potential therapeutic strategies in PCa.
Citation Format: Mayuko Kato, Akira Kurozumi, Yusuke Goto, Ryosuke Matsushita, Ichiro Fukumoto, Atsushi Okato, Rika Nishikawa, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki. Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1910.
Abstract 1913: Inhibition of S-Adenosylmethionine-dependent methyltransferase resists TGF-β1-induced EMT of pancreatic cancer via microRNA alterations
Authors: Govindarajan Rajgopal , Modi Hardik 
Published: July 2016

Abstract
Identification of epigenetic reversal agents for use in combination chemotherapies for human pancreatic ductal adenocarcinomas remains an unmet clinical need. Pharmacological inhibitors of EZH2 are emerging as potential epigenetic reversal agents in various solid tumors and leukemia, however, the surprisingly small set of mRNA transcripts identified with EZH2 knockdown suggests novel mechanisms to govern their anti-tumorigenic effects. Here, we report 3-deazaneplanocin-A, an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, to significantly reprogram the noncoding miRNA expression, including a subset of PDAC-downregulated miRNAs, to dampen TGF-β-induced EMT signals in pancreatic cancer. Particularly, we identify epigenetic silencing of miR-663a and -4787-5p in PDAC tissues and cell lines that are reactivated by 3-deazaneplanocin-A to directly target TGF-β1 for RNA interference. Lentiviral overexpression of miR-663a and -4787-5p partially phenocopied 3-deazaneplanocin-A's EMT resisting effects in pancreatic cancer cells, whereas locked nucleic acid antimiR-663a and -4787-5p mitigated them. In vivo, 3-deazaneplanocin-A, miR-663a and -4787-5p significantly reduced tumor burden and metastasis in an orthotopic mouse pancreatic tumor model with miR-663a displaying more potency than miR-4787-5p in curtailing TGF-β1 signaling pathway. These findings reveal tumor miRNA reprogramming as a novel approach for controlling TGF-β-induced EMT in human PDAC and uncover a list of putative miRNA targets that may guide further selection and development of synthetic histone methylation reversal agents for clinical use.
Citation Format: Rajgopal Govindarajan, Hardik Modi. Inhibition of S-Adenosylmethionine-dependent methyltransferase resists TGF-β1-induced EMT of pancreatic cancer via microRNA alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1913.
Abstract 1915: microRNA-320a inhibits cancer cell migration and invasion through targeting LAMP1 in castration-resistant prostate cancer
Authors: Okato Atsushi , Goto Yusuke , Kurozumi Akira , Kato Mayuko , Matsushita Ryosuke , Kojima Satoko , Sakamoto Shinichi , Ichikawa Tomohiko , Seki Naohiko 
Published: July 2016

Abstract
BACKGROUND:
In early-stage prostate cancer (PCa), more than 90% of patients initially respond to the therapeutic use of androgen deprivation; however, many cases become refractory and progress to castration resistant prostate cancer (CRPC). CRPC is difficult to treat, and most clinical trials for advanced PCa with metastasis to bones or other sites have shown limited benefits. Therefore, understanding the molecular mechanisms of metastatic pathways of CRPC underlying current genomic approaches would help to improve therapies for this disease.
Our recent studies of microRNA (miRNA) expression signatures of CRPC revealed that microRNA-320a (miR-320a) was significantly reduced in cancer tissues, suggesting miR-320a acts as a tumor-suppressor in CRPC cells. The aim of this study was to investigate the functional significance of miR-320a in CRPC cells and to identify miR-320a-mediated target genes involved in oncogenesis and metastasis of the disease.
METHODS:
Gain-of-function studies were performed using transfection of mature miR-320a into cancer cells (DU145 and PC3). Genome-wide gene expression analysis and in silico analysis were applied to identify molecular targets regulated by miR-320a in PCa cells. A luciferase reporter assay was carried out to determine regulation of miR-320a. Loss-of-function studies using siRNA were performed to investigate the functional role of target genes.
RESULTS:
The expression levels of miR-320a were significantly reduced in PCa tissues and the cell lines. Restoration of mature miR-320a in cancer cells led to significant inhibition of cell migration and invasion activities in PCa cell lines. Lysosomal-associated membrane protein 1 (LAMP1) was identified as a direct target of miR-320a in this assays. Silencing of LAMP1 significantly inhibited cell proliferation, migration and invasion in PCa cells. Moreover, overexpression of LAMP1 was observed in PCa and CRPC clinical specimens.
CONCLUSIONS:
To the best of our knowledge, this is the first report demonstrating that tumor-suppressive miR-320a directly regulated LAMP1 in PCa cells. The identification of novel target gene regulated by tumor-suppressive miRNAs may lead to a better understanding of molecular mechanisms of CRPC metastatic pathways.
Citation Format: Atsushi Okato, Yusuke Goto, Akira Kurozumi, Mayuko Kato, Ryosuke Matsushita, Satoko Kojima, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki. microRNA-320a inhibits cancer cell migration and invasion through targeting LAMP1 in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1915.
Abstract 1916: Targeting a MAPK-miR-124-Sox9 axis radiosensitizes human glioblastoma cells
Authors: Sabelstrom Hanna , Jandial Rahul , Shchors Ksenya , Masic Selma , Yuan Edith , Fenster Trenten , Saxena Supna , Ho Allen , Nicolaides Theodore P. , Wong Robyn , Yakovenko Stanislava , Berger Mitchel H. , Snyder Evan Y. , Jakobsson Johan , Weiss William A. , Persson Anders I. 
Published: July 2016

Abstract
Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor. Although genetic alterations and overexpression of genes in the RTK/RAS/MEK/ERK pathway (MAPK) is known to drive GBM aggressiveness, less is known about down-stream effector genes. We confirmed that EGFR amplified human GBMs display high levels of the transcription factor SOX9, a known barrier to neurogenesis and target of microRNA-124 (miR-124). Surprisingly, a subpopulation of SOX9-negative tumor cells expressed markers of mature neurons. Here, we demonstrate that the MEK inhibitor PD325901 depletes SOX9, reduces proliferation, and induces neurogenesis in a mouse GBM model and human GBM cells. We find that MAPK signaling regulates a large cluster of miRNAs in mouse neurosphere cultures, including miR-124. In addition, PD325901 effectively induced miR-124 levels in SOX9-expressing human GBMs. Using a doxycycline-regulable approach, we demonstrate that miR-124 overexpression depletes SOX9 levels and induces neurogenesis in a concentration- and time-dependent manner in human GBM tumorsphere cultures. Doxycycline treatment of athymic nude mice intracranially xenografted with human GBM cells resulted in reduced tumor growth, robust neuronal differentiation, and increased overall survival. Finally, we demonstrate that a brief 3-day treatment with PD325901 or doxycycline effectively radiosensitizes human GBM cells and extends overall survival of xenografted mice. Our work shows that the miR-124-SOX9 axis is a down-stream effector pathway that drives GBM aggressiveness. Long-term exposure to PD325901 is associated with adverse side-effects in patients. We propose that a priming regimen of the clinically relevant MEK inhibitor PD325901 should radiosensitize SOX9-expressing tumors in patients and result in reduced side-effects compared to continuous treatment protocols.
Citation Format: Hanna Sabelstrom, Rahul Jandial, Ksenya Shchors, Selma Masic, Edith Yuan, Trenten Fenster, Supna Saxena, Allen Ho, Theodore P. Nicolaides, Robyn Wong, Stanislava Yakovenko, Mitchel H. Berger, Evan Y. Snyder, Johan Jakobsson, William A. Weiss, Anders I. Persson. Targeting a MAPK-miR-124-Sox9 axis radiosensitizes human glioblastoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1916.