bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2127: HnRNP Q1 contributes to tumorigenesis through the translational regulation of Aurora-A in colorectal cancer
Authors: Hung Liang-Yi 
Published: August 2015

Abstract
HnRNP Q1 is a RNA-binding protein which belongs to hnRNP Q family and involves in pre-mRNA splicing, mRNA transport, translation and turnover. Data from Oncomine, which is a cancer microarray database, indicates that hnRNP Q1 is overexpressed in colorectal cancer. According the literatures, hnRNP Q1 can increase the translational efficiency through binding to the 5′-untranslated region (5′-UTR) of target genes. From RNA-IP assay following the next generation sequencing (NGS), we found that hnRNP Q1 regulates a group of cell cycle-related genes. Among them, Aurora-A is one of the targets of hnRNP Q1. Aurora-A is a cell-cycle dependent kinase involved in regulating centrosome duplication, maturation, and spindle assembly during mitosis. Abnormally elevated Aurora-A will cause mitotic defect and aneuploidy, which might lead to genomic instability and tumorigenesis. In addition, overexpression of hnRNP Q1 is positively correlated with overexpressed Aurora-A in clinical colorectal cancer tissues. Our previous report demonstrated that Aurora-A can be translational up-regulated in colorectal cancer. In this study, we demonstrated that hnRNP Q1 can bind to Aurora-A 5′-UTRs and also mapped the interacting domain between Aurora-A 5′UTR and hnRNP Q1 has been mapped by Biacore analysis, RNA-IP and biotin pull-down assay. Overexpressed hnRNP Q1 enhances the Aurora-A protein expression but doesn't alter its mRNA level. In contrast, repressed expression of hnRNP Q1 decreases the translation of Aurora-A. Importantly, we found that Aurora-A 5′UTR has IRES-dependent translational activity in a cell cycle regulated manner. Overexpression of hnRNP Q1 can up-regulate the IRES-dependent translation of Aurora-A during cell cycle progression, and promotes the cells proliferation. Taken together, our data indicate hnRNP Q1 is a novel trans-acting factor that binds on the Aurora-A 5′-UTRs and regulates it's translation, which may increase the cell proliferation and contribute to the tumorigenesis of colorectal cancer.
Citation Format: Liang-Yi Hung. HnRNP Q1 contributes to tumorigenesis through the translational regulation of Aurora-A in colorectal 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 2127. doi:10.1158/1538-7445.AM2015-2127
Abstract 2131: The Arkadia-ESRP2 axis suppresses tumor progression: Analyses in clear cell renal cell carcinoma
Authors: Mizutani Anna , Koinuma Daizo , Seimiya Hiroyuki , Miyazono Kohei 
Published: August 2015

Abstract
Tumor-specific alternative splicing is implicated in the progression of cancer, including clear cell renal cell carcinoma (ccRCC), a major subtype of kidney cancer accounting for 70-80% of all kidney cancer patients. Using ccRCC RNA-sequencing data from The Cancer Genome Atlas, we found that epithelial splicing regulatory protein 2 (ESRP2), one of the key regulators of alternative splicing in epithelial cells, is expressed in ccRCC, while ESRP1 is decreased in most of the ccRCC as previously reported. ESRP2 mRNA expression did not correlate with the overall survival rate of ccRCC patients, but the expression of some ESRP-target exons, including ENAH exon 11a, ITGA6 exon 27, and SLK exon 13, correlated with the good prognosis and with the expression of Arkadia (also known as RNF111) in ccRCC. Arkadia, a RING-type E3 ligase, that is known to enhance TGF-β signaling activities, physically interacted with ESRP2, induced polyubiquitination, and modulated its splicing function. Arkadia and ESRP2 suppressed ccRCC tumor growth in a coordinated manner. Lower expression of Arkadia correlated with advanced tumor stages and poor outcomes in ccRCC patients. This study thus reveals a novel tumor-suppressive role of the Arkadia-ESRP2 axis in ccRCC.
Citation Format: Anna Mizutani, Daizo Koinuma, Hiroyuki Seimiya, Kohei Miyazono. The Arkadia-ESRP2 axis suppresses tumor progression: Analyses in clear cell renal cell carcinoma. [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 2131. doi:10.1158/1538-7445.AM2015-2131
Abstract 2133: Investigating the molecular interaction between KRAS mRNA and RNA binding protein CRD-BP
Authors: Mackedenski Sebastian J. , Lee Chow H. 
Published: August 2015

Abstract
The Coding Region Determinant-Binding Protein (CRD-BP) is an RNA-binding protein which, among other functions, provides a protective effect for select target mRNA transcripts against degradation, effectively increasing their half-life leading to elevated level of gene expression. CRD-BP was first identified due to its inherent ability to bind to a specific coding region of c-myc mRNA. It has further been demonstrated to convey a protective effect to target transcripts, including GLI1, MITF, CD44, and KRAS as well as a host of other mRNAs. CRD-BP is normally under strict spatiotemporal regulation; expressed only during early developmental stages where rapid growth is necessary. However, CRD-BP re-expression has been reported to occur in a number of human cancers, suggesting its roles as an onco-protein. Abnormal expression or function of KRAS, a CRD-BP target, is implicated in some cancers; roughly 90% of pancreatic cancers, 60% of colorectal, and 50% of lung cancers, making KRAS an attractive target for cancer therapies and highlighting the significance of understanding the CRD-BP-KRAS mRNA interaction. To help understand the CRD-BP-RNA interaction, we have previously mutated the first glycine of the G-X-X-G motif in the KH domains of CRD-BP to an aspartate. Using electrophoretic mobility shift assay, we showed that mutation at any two KH domains, except the KH3 and KH4 di-domains, completely abrogated CRD-BP-c-myc and CD44 RNAs interactions. To understand the CRD-BP-KRAS RNA interaction, we used the identical site-directed KH mutants of CRD-BP to assess their binding profiles to a 185-nt KRAS RNA corresponding to a specific coding region of KRAS mRNA. Using EMSA, additional binding assessments were carried out in a systematic fashion to determine the smallest region of KRAS mRNA bound by CRD-BP. In addition, plasmids carrying these variants of FLAG-CRD-BP were transfected into HeLa cells. Immuno-precipitation (IP) using anti-FLAG was performed, followed by RT-qPCR to measure the relative amounts of KRAS mRNA associated with each of the variants as compared to the controls. The in vitro EMSA and IP cell data were all consistent with the notion that all KH domain(s) are critical for CRD-BP-KRAS RNA interaction. These experiments and their results will be discussed in further detail upon presentation.
Citation Format: Sebastian J. Mackedenski, Chow H. Lee. Investigating the molecular interaction between KRAS mRNA and RNA binding protein CRD-BP. [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 2133. doi:10.1158/1538-7445.AM2015-2133
Abstract 214: Characterization of the near-infrared fluorescent protein iRFP for plate-based assays and animal imaging
Authors: Gong Haibiao , Kovar Joy L. , Urlacher Teresa 
Published: August 2015

Abstract
Fluorescence imaging has been extensively used in biological research because of its high sensitivity, signal stability, and simplicity of multiplexing. Compared to fluorophores in the visible spectral region, fluorophores with excitation (Ex) and emission (Em) maxima in the near-infrared (NIR) region (700-900 nm) are desirable in many applications. Cells, buffers and plastic materials generate less background fluorescence in the NIR region. As a result, NIR fluorescence imaging offers higher sensitivity and better signal-to-background ratio (SBR) compared to visible fluorescence. In addition, due to the reduced light absorption and scattering in animal tissues, NIR fluorescence is particularly suitable for in vivo imaging studies. In this study, we characterized the NIR fluorescent protein iRFP for plate-based assays and animal imaging. HEK293 cells stably expressing iRFP were established and designated as HEK293-iRFP. Serial dilutions of HEK293-iRFP cells were seeded in 96-well plate and scanned on the Odyssey CLx Imaging System. A good linear relationship between fluorescence signal intensity and cell number was obtained. The lower limit-of-detection was determined as 763 cells. To evaluate the performance of iRFP for animal imaging, the iRFP-expressing plasmid was delivered into mouse liver cells using a hydrodynamic injection method. A dose- and time-dependent pattern of fluorescence signal was observed after plasmid injection. At 8 h post-injection of 10 μg of iRFP plasmid, a SBR of 41 was observed by live animal imaging. Analysis of liver tissue lysates revealed a SBR of 148. Other tissues, including kidney, spleen, heart and lung, showed very little fluorescence signal. Our results demonstrate that iRFP is a good reporter for both plate-based assays and animal imaging studies.
Citation Format: Haibiao Gong, Joy L. Kovar, Teresa Urlacher. Characterization of the near-infrared fluorescent protein iRFP for plate-based assays and animal imaging. [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 214. doi:10.1158/1538-7445.AM2015-214
Abstract 2144: Kinetic mechanism of the lysine methyltransferase SMYD3 using MAP3K2 protein substrate
Authors: Riera Thomas V. , Wigle Tim J. , Gureasko Jodi , Boriack-Sjodin P. Ann , Copeland Robert A. 
Published: August 2015

Abstract
Dysregulation of DNA and histone methylation has been shown to play fundamental roles in carcinogenesis. Recently however, protein methylation in the cytoplasm has been linked to oncogenic Ras signaling. Mazur and colleagues demonstrated that SMYD3 (SET and MYND domain containing protein 3), a primarily cytoplasmic protein methyltransferase, can methylate MAP3K2 using S-adenosyl-L-methionine (SAM) as a cofactor (Mazur et al. 2014. Nature 510(7504):283-7). Methylation by SMYD3 preserves the active, phosphorylated state of MAP3K2 sustaining activation of the Ras/Raf/MEK/ERK/ signaling module and potentiating formation of Ras-driven cancers. Here, we characterized the kinetic mechanism of SMYD3 using MAP3K2 protein as a substrate. SMYD3 activity was measured with a radiometric assay using 3H-SAM. Initial velocity, product and dead-end inhibitor studies indicate that SMYD3 uses a random kinetic mechanism where both SAM and MAP3K2 can bind apo-SMYD3. This was supported by substrate and ligand binding assays using SPR. Together, these studies elucidate the kinetic mechanism of SMYD3 with MAP3K2 and provide a context for inhibitor development.
Citation Format: Thomas V. Riera, Tim J. Wigle, Jodi Gureasko, P. Ann Boriack-Sjodin, Robert A. Copeland. Kinetic mechanism of the lysine methyltransferase SMYD3 using MAP3K2 protein substrate. [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 2144. doi:10.1158/1538-7445.AM2015-2144
Abstract 2154: ERK/MAPK pathway inhibits tumorigenesis and cellular reprogramming of pancreatic cancer cells
Authors: le Calvé Benjamin , Deschenes-Ximard Xavier , Kottakis Filippos , Bourdeau Véronique , Lessard Frédéric , Moineau-Vallée Karine , Saint-Germain Emmanuelle , Fitamant Julien , Perera Rushika Miriam , Bardeesy Nabeel , Ferbeyre Gerardo 
Published: August 2015

Abstract
Reprogrammation of cancer cells into stem-like state is one the most important mechanisms implicated in tumor initiation, metastasis and resistance to chemotherapies. Acquisition of stem-like cell property is directly correlated with the level of activation of the ERK/MAPK pathway. Our study focuses on the implication of the downregulation of this pathway during the transition of pancreatic benign neoplasms to pancreatic ductal adenocarcinoma. This transformation is directly correlated with the acquisition of stem-like cells properties. Conversely, hyperactivation of the ERK pathway using phosphatase inhibitors abrogates the stem-like cell phenotype.
We analyzed the variation of genes expression by microarrays analysis between cells obtained from pancreatic intraepithelial neoplasias and pancreatic cancer. These analyses implicate the expression of DUSPs and genes related to stem cell biology in tumor progression during pancreatic cancer.
Citation Format: Benjamin le Calvé, Xavier Deschenes-Ximard, Filippos Kottakis, Véronique Bourdeau, Frédéric Lessard, Karine Moineau-Vallée, Emmanuelle Saint-Germain, Julien Fitamant, Rushika Miriam Perera, Nabeel Bardeesy, Gerardo Ferbeyre. ERK/MAPK pathway inhibits tumorigenesis and cellular reprogramming of pancreatic cancer 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 2154. doi:10.1158/1538-7445.AM2015-2154
Abstract 2158: PDK1-dependent activation of RSK is an absolute requirement for PI3K oncogenic activity in the thyroid gland
Authors: Orlacchio Arturo , Di Cristofano Antonio 
Published: August 2015

Abstract
Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway plays a key role in thyroid tumorigenesis, particularly in follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC). Accordingly, conditional deletion of Pten in the mouse thyroid epithelium induces constitutive activation of the PI3K/AKT pathway, and causes thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. This phenotype is dramatically accelerated by simultaneous deletion of Trp53, leading to the development of ATC, or activation of Kras, leading to poorly differentiated carcinomas.
The PDK1 kinase plays a central role in the PI3K signaling cascade, acting as a master regulator of PI3K downstream effectors belonging to the AGC kinases family, such as AKT and S6K1. Additional AGC kinases are controlled by PDK1 independent of PI3K activity.
PDK1 possesses a substrate docking site, the “PIF pocket”, required for the phosphorylation of most AGC kinases (including S6K, PKC, SGK, and RSK) but not of AKT. The L155E PDK1 mutant disrupts the PIF pocket and impairs AGC kinase activation, without any effect on AKT activation.
Thanks to this differential mechanism of substrate activation, we are defining the relative contribution of AKT and other PDK1 targets to the neoplastic transformation process in Pten-/- thyrocytes.
Surprisingly, in vivo disruption of the PIF-pocket completely abrogates neoplastic transformation of Pten-/- thyroids, even in the face of AKT constitutive activation. This finding supports the hypothesis that the linear PI3K-AKT pathway is not sufficient to drive thyroid transformation and that concomitant activation of additional PDK1-dependent pathways is absolutely required.
We now show that RSK family members (RSK1-3) are essential components of this PDK1-dependent accessory pathway. Remarkably, RSK3 levels in the thyroid are increased in the absence of Pten, and RSK activity in thyroid cells is abrogated when PDK1 PIF-pocket is mutated.
Genetic and pharmacological inhibition of RSK drastically impairs [Pten,Trp53]-/- ATC cell proliferation both in vitro and in vivo, in syngeneic allograft models.
Taken together, our data identify a new signaling cascade that is essential for neoplastic transformation of thyroid epithelial cells, and thus a new critical candidate for drug development.
Citation Format: Arturo Orlacchio, Antonio Di Cristofano. PDK1-dependent activation of RSK is an absolute requirement for PI3K oncogenic activity in the thyroid gland. [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 2158. doi:10.1158/1538-7445.AM2015-2158
Abstract 2160: PTEN deletion is associated with metastatic disease and worse prognosis in pancreatic cancer
Authors: Wartenberg Martin , Centeno Irene , Zlobec Inti , Lugli Alessandro , Perren Aurel , Karamitopoulou Eva 
Published: August 2015

Abstract
Background: PTEN is a tumor suppressor gene encoding a phosphatase. PTEN inactivation is a frequent event in cancer, occurring through various genetic and epigenetic alterations. Here we investigate the role of PTEN alterations in the microenvironment of ductal pancreatic adenocarcinoma (PDAC).
Methods: Presence of PTEN was investigated by immunohistochemistry and mRNA-in-situ-hybridization (mRNA-ISH) by using multi-punch tissue microarrays (TMAs)containing at least 4 punches per tumor, in a set of 120 well characterized PDACs with full clinicopathological information. Expression was assessed separately in tumor and stromal cells. Multiplex ligation-dependent probe amplification (MLPA) of DNA probes to identify loss of heterozygosity (LOH) of the PTEN gene was additionally performed in 61 cases. Results were correlated with clinicopathological features including survival of the patients.
Results: Loss of PTEN protein (i.e. average immunohistochemical expression in &lt;10% of the neoplastic cells across all tumor punches) was found in 62% of PDAC cases, mostly paralleled by the results of mRNA-ISH. In 22.2% of the cases PTEN protein and/or mRNA loss was additionally observed in the tumor stroma. Interestingly, protein loss in the stromal cells was associated with distant metastasis (p = 0.0045). MLPA identified PTEN LOH (all exons or only exon 1) in 51% of all examined cases and in 73.5% of the cases with PTEN protein/mRNA loss. The occurrence of PTEN LOH was slightly more frequent among cases with concomitant PTEN protein loss in tumor and stromal cells (80%). PTEN LOH as identified by MLPA was associated with higher tumor grade (p = 0.0412), vascular invasion (p = 0.0176), presence of distant metastases (p = 0.0082) and decreased overall survival (p = 0.0127). In 26.5% of the cases with PTEN protein/mRNA loss, no PTEN deletion could be found suggesting occurrence of other genetic changes or epigenetic mechanisms.
Conclusion: PTEN LOH is a major cause of PTEN loss in PDAC and is associated with aggressive tumor characteristics and worse patient prognosis. This is intensified by concomitant PTEN loss in tumor and stromal cells.
Citation Format: Martin Wartenberg, Irene Centeno, Inti Zlobec, Alessandro Lugli, Aurel Perren, Eva Karamitopoulou. PTEN deletion is associated with metastatic disease and worse prognosis in pancreatic 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 2160. doi:10.1158/1538-7445.AM2015-2160
Abstract 2166: Analyses of protein expression of PI 3-kinase/AKT signaling in response to altered expression of motor protein MYO1C
Authors: Visuttijai Kittichate , Ejeskär Katarina , Behboudi Afrouz 
Published: August 2015

Abstract
In the previous work, a minimal region of recurrent deletion distal to the Tp53 gene was identified in BDII rat model for endometrial adenocarcinoma and the MYO1C gene was singled out as the tumor suppressor candidate in this region. Myo1c can bind to PIP2, the substrate of PI3-kinase, as well as to the mTOR complex, indicating a role for MYO1C in the PI3-kinase pathway. In this study, we assessed protein levels of 12 members of PI3-kinase/AKT signaling pathways in transient transfected HeLa cells expressing increasing amounts of MYO1C using Western blotting and densitometry analyses. Results revealed decreased protein levels of PTEN, AKT, and phosphorylated AKT, at both residues T308 and S473, and an increased expression of p110α protein in the cells transfected with the MYO1C gene expression constructs compared to the control cells transfected with empty plasmid. We next investigated potential effect of MYO1C protein depletion on serum-induced activation (phosphorylation) of AKT in the MCF10A cells that has de novo expression of MYO1C protein. Following serum stimulation, AKT was rapidly phosphorylated in its residue S473 (pAKTS473) in the cells transfected with MYO1C-siRNA, but with significantly lesser extent in the control cells. Overall, a negative correlation between the protein expression of MYO1C and AKT expression/activation was suggested, signifying a role for MYO1C as a negative regulator of PI3-kinsase/AKT signaling pathway. This is in agreement with the initial hypothesis of involvement of MYO1C in tumorigenesis pathways through its potential tumor suppressor activity. Further studies are required to fully understand the functional contribution of MYO1C to tumor development.
Citation Format: Kittichate Visuttijai, Katarina Ejeskär, Afrouz Behboudi. Analyses of protein expression of PI 3-kinase/AKT signaling in response to altered expression of motor protein MYO1C. [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 2166. doi:10.1158/1538-7445.AM2015-2166
Abstract 2168: BC-BET: an online bladder cancer biomarker evaluation tool
Authors: Dancik Garrett 
Published: August 2015

Abstract
Cancer is a genetic disease whose biology is driven by mutated and abnormally expressed genes. In the past ∼15 years, the identification of diagnostic and prognostic biomarkers from genomic data has increased our understanding of cancer biology and has led to advances in the personalized treatment of many cancers. Despite these advances, however, there are no clinically approved biomarkers for the treatment of bladder cancer, which is the fourth most common cancer in males in the United States and one of the most expensive cancers to treat.
Although gene expression profiles of bladder cancer patients are publicly available, their analysis is time-consuming and requires computational resources and bioinformatics expertise often not available to biologists or clinician-researchers. Here we describe BC-BET, an online Bladder Cancer Biomarker Evaluation Tool for evaluating candidate diagnostic and prognostic biomarkers in bladder cancer.
The BC-BET database contains gene expression data collected from 11 publicly available patient cohorts (N = 1041). For a chosen gene, BC-BET evaluates whether the gene is differentially expressed (P &lt; 0.05) between normal cells and tumors, between low-grade (LG) and high-grade (HG) tumors, and between non-muscle invasive (NMI) and muscle invasive (MI) tumors. Survival analysis is carried out to evaluate whether gene expression is significantly associated with survival in all patients, or in clinically important subsets of patients with NMI, LG tumors, or in patients with MI, HG tumors. Results are summarized graphically and can be downloaded in an Excel spreadsheet. A user can also look at the relative expression of a gene or the correlation between the expression of two genes across 40 bladder cancer cell lines.
This tool is freely available to the cancer research community and will be updated as additional bladder cancer biomarker data becomes available. BC-BET is available from http://bioinformatics.easternct.edu.
Citation Format: Garrett Dancik. BC-BET: an online bladder cancer biomarker evaluation tool. [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 2168. doi:10.1158/1538-7445.AM2015-2168