bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3526: The mTORC2 component RICTOR plays a key role in lung cancer cell growth
Authors: Cheng Haiying , Zou Yiyu , Borczuk Alain , Qiu Wanglong , Piperdi Bilal , Kim Mimi , Halmos Balazs , Perez-Soler‎ Roman 
Published: May 2015

Abstract
RICTOR (Rapamycin-insensitive companion of mTOR protein) is a key component of mTORC2 (the mammalian target of rapamycin complex 2). One of the most-recognized targets for RICTOR-mTORC2 is AKT (Ser473). RICTOR also carries functions independent of mTORC2. RICTOR signaling has been suggested to play key roles in regulating cancer cell migration, invasion and metastasis in breast, ovarian, colorectal cancers and gliomas. The potential roles of RICTOR in lung cancer remain to be elucidated. We first examined the expression profile of RICTOR in primary lung tumor specimens and in lung cancer cell lines by immunohistochemistry. Among 125 FFPE patients' specimen, ninety nine were stained positive for RICTOR (intensity 1+ to 3+). More interestingly, the RICTOR IHC expression is stronger in squamous cell lung cancer in comparison to adenocarcinoma. Furthermore, twenty four out of 36 lung cancer cell lines showed positive RICTOR IHC staining. Thus, RICTOR is expressed in most lung tumors. To investigate the role of RICTOR in lung cancer cell growth, we found that RICTOR knockdown by siRNA reduced colony formation in A549, HCC827 and Calu3 cells, regardless of KRAS or EGFR mutational status (A549 is KRAS mutated whereas HCC827 is EGFR mutated). Western blot confirmed RICTOR knockdown and also decreased level of its downstream pAKT S473. We further blocked RICTOR signaling by utilizing inducible shRNAs of RICTOR. Similar inhibition of lung cancer cell growth was observed. Moreover, to test the in vivo role of RICTOR, we preformed xenograft mouse experiments. When RICTOR was inducibly knockdown by the presence of doxycycline, the growth of A549 lung tumor xenografts was markedly reduced by 60% (P&lt;0.05). Taken together, our study provides the rational basis for a potential RICTOR-targeted therapy in lung cancer.
Citation Format: Haiying Cheng, Yiyu Zou, Alain Borczuk, Wanglong Qiu, Bilal Piperdi, Mimi Kim, Balazs Halmos, Roman Perez-Soler‎. The mTORC2 component RICTOR plays a key role in lung cancer cell growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3526. doi:10.1158/1538-7445.AM2014-3526
Abstract 3530: The parathyroid hormone-related peptide region likely features seven discrete breast cancer susceptibility loci
Authors: Freeman Adam N. , Martin Terence ‘Jack’ , Henderson Michael , Makalic Enes , Schmidt Daniel F. , Kapinski Miroslaw K. , Southey Melissa C. , Giles Graham G. , Hopper John L. 
Published: May 2015

Abstract
Parathyroid hormone-related protein (PTHrP), the product of the PTHLH gene, has long been implicated in the mechanism by which breast cancers establish and grow as metastases in bone. Paradoxically, a prospective clinical study clinical suggests that its production early in breast cancer in a cancer is actually protective. Multiple recent Genome-Wide Association Studies (GWAS) have confirmed a single susceptibility locus immediately upstream of the PTHLH gene to be associated with breast cancer. In this study we compare the findings of two GWAS, the ABCFS and the MCCS, along with a large imputed meta-analysis combining the ABCFS, BBCS, DFBBCS, MARIE, SASBAC, HEBCS, GC-HBOC, UK2, BPC3, BCFR and SardiNIA data. To better discern the signals of association with common variant Single Nucleotide Polymorphisms (SNPs) in the PTHLH gene region, we compare results from a conventional marginal analysis performed by plink with those from DepTH, a novel bootstrap permutation-based method that considers multiple contiguous SNPs. These are plotted on the genome and analysed in conjunction with hapmap, encode expression and regulation, genome-wide epistasis, eQTLs, and genetic data. Whereas the classic approach identifies only one SNP (“top hit”), our analysis suggests there are at least 7 discrete regions in and around PTHLH in which there are susceptibility variants, rare or common, with potentially independent functions on disease risk. In addition, exhaustive genome-wide epistasis demonstrates statistical interactions between PTHLH and multiple other gene regions including calcitonin and the vitamin D receptor in breast cancer.
Citation Format: Adam N. Freeman, Terence ‘Jack’ Martin, Michael Henderson, Enes Makalic, Daniel F. Schmidt, Miroslaw K. Kapinski, Melissa C. Southey, Graham G. Giles, John L. Hopper. The parathyroid hormone-related peptide region likely features seven discrete breast cancer susceptibility loci. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3530. doi:10.1158/1538-7445.AM2014-3530
Abstract 3534: Epigenetic control of the tumor suppressive microRNA miR-34a in bladder cancer
Authors: Huang Wen-Yu , Chen Pi-Che , Yeh Chia-Ming , Cheng Frank H.C. , Hsieh Hsiao-Yen , Shen Cheng-Huang , Hsu Cheng-Da , Chan Michael W. 
Published: May 2015

Abstract
Bladder cancer is the sixth most common cancer in the world and the incidence is particularly high in southwestern Taiwan. One of the hypotheses suggests that cancers arise from cancer stem-like cell (CSC) with surface antigen CD44. MicroRNAs (miRNAs) are endogenous, non-protein-coding RNAs that can regulate the expression of their target mRNAs. Up to 90% of human genes can be regulated by this mechanism. However, the role of miRNAs in the regulation of CSC in bladder cancer is not fully explored. Bioinformatics prediction identified that miR-34a regulates the expression of CD44. In this study, we aimed to investigate how miR-34a are regulated in bladder cancer. Expression analysis showed that miR-34a was down-regulated in UMUC3 bladder cancer cells. COBRA assay and bisulphite pyrosequencing demonstrated extensive DNA methylation of miR-34a in this cell. Treatment of DNMT inhibitor, 5-aza restored miR-34a expression in UMUC3 cells thus suggesting that miR-34a is epigenetically silenced in UMUC3 cells. Over-expression of miR-34a resulted in a reduction of chemo-resistance to cisplatin in UMUC3 cells. This may be due to a down-regulation of CD44 and another predicted miR-34a target, c-myc in this cell. Recently, additional mechanism namely, competitive endogenous RNA (ceRNA) hypothesis in controlling the function of miRNAs are demonstrated. To test this hypothesis in bladder cancer, we overexpressed 3′UTR of CD44 in TSGH8301 bladder cancer cells which expressed miR-34a, and resulted in an up regulation of another target of miR-34a, c-myc in this cells. Since amplification of chromosome 8q24 where c-myc resides is frequently observed in bladder cancer, we investigated the relationship between expression of c-myc and CD44 in a publicly available expression array data set (GDS1479) using 60 bladder cancer patients. Interestingly, a positive correlation was found between the expression of c-myc and CD44 (P=0.0016) in this data set. In conclusion, aberrant promoter methylation and ceRNA mechanism may contribute to attenuate the function of miR-34a in bladder cancer. The tumor suppressive role of miR-34a in controlling CSC phenotype in bladder cancer deserves further investigation.
Citation Format: Wen-Yu Huang, Pi-Che Chen, Chia-Ming Yeh, Frank H.C. Cheng, Hsiao-Yen Hsieh, Cheng-Huang Shen, Cheng-Da Hsu, Michael WY Chan. Epigenetic control of the tumor suppressive microRNA miR-34a in bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3534. doi:10.1158/1538-7445.AM2014-3534
Abstract 3541: HOTAIR modulates β-catenin signaling pathway through NLK and NFAT5 in human glioblastoma
Authors: Zhou Xuan , Ren Yu , Han Lei , Kang Chunsheng 
Published: May 2015

Abstract
Background
Glioblastoma (GBM) is the most common malignant tumor of human central nervures system with poor prognosis. A new class of transcripts, long noncoding RNAs (lncRNAs), has been recently found to be pervasively transcribed in the genome. Recent progress suggests that the involvement of lncRNAs in human cancers could be far more prevalent than previously appreciated. HOTAIR, lncRNA Hox transcript antisense intergenic RNA, has been characterized as a novel hall marker to predict poor prognosis in glioma. HOTAIR serves as a modular scaffold by interacting with the polycomb repressive complex 2 (PRC2) and the lysine-specific demethylase 1 (LSD1) corepressor for element-1-silencing transcription factor (CoREST) complex to silence the HOXD loci in trans. Constitutive activation of the Wnt/β-catenin pathway is a common feature of human cancers and contributes to its development, progression and metastasis.
Methods
RNA sequencing and qPCR were used to determine HOTAIR expression status in GBM samples. TOP/FOP flash luciferase assays and western blot were employed to identify the effect of HOTAIR's function on the Wnt/β-catenin pathway activity. In addition, FCM, transwell assay, clone formation assay were used to examine HOTAIR's biological function in regulating GBM cell phenotype.
Results
We show β-catenin pathway is associated to HOTAIR expression by RNA sequencing in GBM cell lines and large scale glioma samples. Besides, increasing NLK and NFAT5 expression, PKM2 and β-catenin pathway inhibition is induced by HOTAIR knockdown in vivo and in vitro. Moreover, HOTAIR knockdown can partially overcome hypoxia stimulation to U87 and U87VIII cells, block cell cycle at G1 phase, and attenuate GBM cell invasion or EMT like transformation. And EZH2 domain may contribute to HOTAIR's biological function.
Conclusion
Our data indicate that HOTAIR expression is correlated with the overexpression ofβ-catenin pathway activation in both GBM cell lines and tissues. And HOTAIR can serve as a therapeutic target in gliobalstoma, relating its oncogenic effects to activation of β-catenin pathway.
Citation Format: Xuan Zhou, Yu Ren, Lei Han, Chunsheng Kang. HOTAIR modulates β-catenin signaling pathway through NLK and NFAT5 in human glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3541. doi:10.1158/1538-7445.AM2014-3541
Abstract 3555: LncRNA-21a is a potential tumor suppressor in breast cancer
Authors: Singh Ramesh , Mo Yin-yuan 
Published: May 2015

Abstract
Long non-coding RNA (lncRNA)-21A is a polymerase III driven non-coding RNA consisting of 324 nucleotides in length. LncRNA-21A was originally identified through in silico analysis and its expression was then confirmed in human cell lines. Further study suggested that lncRNA-21A can control the proliferation of human tumor cell lines, possibly through regulation of CENP-F expression. However, little is known whether lncRNA-21A plays a role in breast cancer. In this study, we reported that lncRNA-21A is downregulated in breast cancer, as detected by RT-PCR analysis of breast cancer tissue scan, suggesting its possible role as a tumor suppressor. In consistent with this finding, lncRNA-21A promotes apoptosis and attenuates cell invasion ability in breast cancer cells. Western blot revealed that overexpression of lncRNA-21A can reduce the phosphorylation of Akt in MCF-7 cells. To determine its underlying mechanism, we performed RNA precipitation assays with the synthetic biotin labeled lncRNA-21A RNA probe followed by mass spectrometry analysis, and we identified hnRNP U and EWS as binding partners for lncRNA-21A. Suppression of EWS by RNAi leads to a reduced level of phosphorylated Akt, suggesting its role in lncRNA-21A-medited Akt activity. Of great interest, we found that like microRNAs, lncRNA-21A can also be secreted through exosomes into conditioned medium. Furthermore, the secreted lncRNA-21A from normal breast epithelial cells can be functionally taken up by recipient metastatic breast cancer cells, suppressing the cell invasion. Together, these results suggest that as a potential tumor suppressor, lncRNA-21A may be used by the host through exosome-mediated gene transfer as a defense mechanism against invasive tumor cells.
Citation Format: Ramesh Singh, Yin-yuan Mo. LncRNA-21a is a potential tumor suppressor in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3555. doi:10.1158/1538-7445.AM2014-3555
Abstract 3562: Building workflows for gene fusion detection by RNA-seq
Authors: Gross Stephen , Watson Lisa , Pathak Smita , Khrebtukova Irina , Schroth Gary 
Published: May 2015

Abstract
Many cancers are associated with chromosomal rearrangements, which in some cases yield fusions between disparate genes and impact cancer phenotypes. Rapid discovery of gene fusions in cancer can facilitate a deeper understanding of specific cancers and may become an important diagnostic tool in clinical settings informing decisions on cancer treatment. An attractive and cost-effective method to identify and study gene fusions is by massively-parallel RNA sequencing (RNA-seq), which provides rich transcriptome profiling data and, with appropriate computational analysis, can discover fusions between transcribed genes. Herein we present data exploring the robustness of gene fusion detection by RNA-seq on Illumina sequencing platforms with TopHat-Fusion, a RNA-seq read aligner specifically designed to detect expressed gene fusions. Using a set of synthetic fusion transcripts to spike in to human RNA samples, we demonstrate quantitative detection of gene fusions by RNA-seq. Additionally, we report the sensitivity of gene fusion discovery across different RNA-seq library preparation methods, including mRNA enrichment by poly-A selection, rRNA-depletion, and exome enrichment by targeted capture. This data helps build workflow recommendations for the detection and study of gene fusions by RNA-seq.
Citation Format: Stephen Gross, Lisa Watson, Smita Pathak, Irina Khrebtukova, Gary Schroth. Building workflows for gene fusion detection by RNA-seq. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3562. doi:10.1158/1538-7445.AM2014-3562
Abstract 3563: New tools for RNA-sequencing of FFPE tumor samples
Authors: Watson Lisa , Pathak Smita , Gross Stephen , Khrebtukova Irina , Schroth Gary 
Published: May 2015

Abstract
Next generation RNA sequencing is an ideal platform to leverage archival formalin-fixed paraffin-embedded (FFPE) tissue samples for cancer research, as it offers extensive functional genomic information including transcriptome expression profiling, differential expression analysis and fusion detection. However, both RNA degradation from the formalin fixation process as well as limited sample material, pose major challenges for RNA sequencing of FFPE samples. Here we describe a novel method for generating whole-transcriptome RNA sequencing libraries from moderate to poor quality FFPE samples starting with as low as 20ng total RNA. This approach provides increased transcriptome coverage and robust measurement of gene expression levels compared to currently available FFPE RNA sequencing methods. Furthermore, we demonstrate that we can detect both known and novel gene fusions in clinical tumor samples that are potential drivers of disease. We anticipate this new technology will enable functional genomic studies on numerous FFPE tumor samples that would not previously be possible, providing invaluable information for developing cancer diagnostics and therapeutics.
Citation Format: Lisa Watson, Smita Pathak, Stephen Gross, Irina Khrebtukova, Gary Schroth. New tools for RNA-sequencing of FFPE tumor samples. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3563. doi:10.1158/1538-7445.AM2014-3563
Abstract 3569: Transcriptional signatures in human melanoma epitope MART-127-35 specific TCR-engineered T cells
Authors: Singh Prashant , Chakraborty Nitya G. , Farooq Umar , Hegde Upendra P. , Everson Richard , Dorsky David I. , Mukherji Bijay 
Published: May 2015

Abstract
Adoptive Cell Therapies (ACT) with T cell receptor-engineered (TCReng) T cells have shown promising results. Unfortunately, for a fuller understanding of their biology, currently available immunological assays have proven inadequate. Given that RNA-Seq using Next Generation Sequencing (NGS) offers substantial opportunities, we carried out NGS of the MART-127-35 specific TCReng human primary CD8+ and CD4+ T-cells following cognate stimulation, to obtain a comprehensive understanding of the transcriptional signatures underlying their biology.
Data analyses revealed approximately 30,000 transcripts, a sizeable number of which showing up- or down-regulation covering virtually all relevant aspects of T cell biology (i.e., effector function, differentiation, proliferative activities, apoptosis, etc.) when stimulated by the cognate epitope. The transcriptional profiles of the TCReng CD8+ and CD4+ T cells were found to be remarkably similar. Additionally, 72,000 known isoforms and about 20,000 previously undescribed isoforms were detected. Interestingly, a number of long noncoding RNAs (lncRNA) - some with known functions (e.g., NEAT1 and MALAT1, both implicated in RNA editing, were up-regulated in the two cell types), and others with unknown function (e.g., GAS5, MIAT, and FTX showing modulations in expression), were also detected in both cell types. Although a comprehensive knowledge of the transcriptional signatures and a clear understanding of the spliced variants, the novel isoforms, and the lncRNAs in T cell biology will require further work, our study shows that NGS of specific epitope reactive T cells will be a very useful tool in deciphering the transcriptional controls underlying the function and the fate of epitope specific anti-tumor T cells.
Citation Format: Prashant Singh, Nitya G. Chakraborty, Umar Farooq, Upendra P. Hegde, Richard Everson, David I. Dorsky, Bijay Mukherji. Transcriptional signatures in human melanoma epitope MART-127-35 specific TCR-engineered T cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3569. doi:10.1158/1538-7445.AM2014-3569
Abstract 4447: Generation of a conditional S194A mutant RalA allele in mice
Authors: Crowe Matthew S. , Counter Christopher M. 
Published: May 2015

Abstract
The Ras family of small-GTPases represent the most frequently mutated oncogene in human cancer. Oncogenic Ras activates RalGEFs, which converts the Ras like small GTPases RalA and RalB to their active GTP-bound state to promote tumorigenesis. Despite being highly related, RalA generally tends to be more important in tumor growth while RalB has been implicated in metastasis. In regard to a mechanism underlying these functional differences, we note that RalA, but not RalB, is phosphorylated by the mitotic kinase AuroraA at Serine 194, and this phosphorylation is necessary for Ras-driven tumorigenesis. This phosphorylation has been found to result in an accumulation of RalA in mitochondrial fractions and an increase in mitochondrial fission and segregation during cytokinesis. Despite these encouraging observations, the role of this seemingly critical phosphorylation event in an actual in vivo setting was completely unknown. Thus, to determine the physiological consequence of this phosphorylation in vivo, we generated a mouse with a Cre-inducible S194A conditional Rala allele. We now report that these mice express wild-type RalA in the absence of Cre, but upon Cre-mediated recombination, convert wild-type exon 5 of Rala to one encoding the S194A mutant version. We propose to next investigate the consequences of blocking this critical posttranslational modification on normal development and on oncogenic Kras-driven tumorigenesis.
Citation Format: Matthew S. Crowe, Christopher M. Counter. Generation of a conditional S194A mutant RalA allele in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4447. doi:10.1158/1538-7445.AM2014-4447
Abstract 4452: Regulation of histone deacethylase 8 expression by inhibitory GTP binding proteins signaling via JNK pathway in H1299 non-small-cell lung cancer cells
Authors: Hahn Hwa-jeong , Juhnn Yong-Sung 
Published: May 2015

Abstract
Histone deacetylases (HDACs) have been reported to regulate the cell growth, proliferation, and apoptosis, and HDAC8 seems to be involved in tumor growth and progression. Inhibitory heterotrimeric GTP-binding proteins (Gαi) are activated by seven transmembrane receptors, and regulate cell proliferation by regulating the activity of adenylate cyclase, phospholipase C beta, and ion channels. This study investigated the effects of Gαi signaling system on the expression of HDAC8 and the underlying mechanism in lung cancer cells. When Gi signaling system was activated by expressing Gαi1Q204L, a constitutively active mutant Gαi1, the expression of HDAC8 protein and mRNA was increased in H1299 non-small-cell lung cancer (NSCLC) cells. Inhibition of transcription by treatment with Actinomycin D did not block the increase in mRNA, and the degradation of HDAC8 mRNA was facilitated in Gαi1Q204L -expressing cells, suggesting Gαi1 signaling system increases HDAC8 expression by stabilizing mRNA. In addition, treatment with adenosine or an adenosine receptor agonist, CCPA (2-chloro-N(6)-cyclopentyladenosine), which activate Gαi-coupled receptors, also increased HDAC8 mRNA and protein levels. The effect of adenosine was blocked by treatment with DPCPX (8-Cyclopentyl-1,3-dipropylxanthine), an adenosine A1 receptor antagonist. JNK phosphorylation was inhibited by treatment with the adenosine and CCPA. Treatment with a JNK inhibitor, SP600125 increased HDAC8 expression. Adenosine inhibited the activation of MKK4 and CDC 42, which act upstream of JNK. Activation of Gαi signaling stimulated proliferation of H1299 cells, and the stimulating effect was abolished by knockdown of Gαi1. Thus, we conclude that Gαi signaling increases HDAC8 expression via JNK pathway, resulting in stimulation of cell proliferation of H1299 lung cancer cells. This study suggests that Gαi signaling may be involved in epigenetic control of gene expression by regulating HDAC8 expression.
Citation Format: Hwa-jeong Hahn, Yong-Sung Juhnn. Regulation of histone deacethylase 8 expression by inhibitory GTP binding proteins signaling via JNK pathway in H1299 non-small-cell lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4452. doi:10.1158/1538-7445.AM2014-4452