bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3128: Mxd3 is required for proliferation of human neuroblastoma cells.
Authors: Barisone Gustavo , Satake Noriko , Lewis Carly , Duong Connie , Chan Cathy , Lam Kit , Nolta Jan , Diaz Elva 
Published: August 2014

Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Up to 45% of the cases are high risk at diagnosis, representing very aggressive, usually metastasized tumors that are refractory or recurrent after all available therapies. Prognosis for these patients is very poor with only 30% survival. MXD3 is a transcription factor previously shown in our lab to be a novel member of the Hedgehog (Hh) pathway (Yun, Rust, Ishimaru, Diaz, Mol Cell Biol, 2007) in granule neuron precursors. In these cells, overexpression of MXD3 results in higher MYCN expression, suggesting a functional interaction between the two transcription factors. MXD3 phenocopies MYCN expression in mouse models of medulloblastoma; we have also shown that it is expressed in human medulloblastoma and that its knockdown reduces proliferation of human medulloblastoma cell lines (Barisone et al., PLoS One, 2012). More than 20% of NBs have MYCN amplification, which is considered a marker of poor prognosis. In the current study, we investigated a possible role for MXD3 in NB cell proliferation. Using qRT-PCR we observed high levels of MXD3 mRNA expression in 5 NB cell lines: SK-N-DZ, IMR-32, SH-SY5Y, SK-N-BE and SK-N-SH. Immunoblot analysis with anti-MXD3 monoclonal antibodies confirmed that the protein was present in these cells. Furthermore, immunohistochemistry analysis showed strong immunoreactivity in a cohort of 16 primary NB tissue specimens. We investigated the role of MXD3 in NB cell proliferation by silencing MXD3 in the SK-N-DZ cell line. We used lentiviral delivery to knockdown MXD3 using an RNA interference approach. Upon transduction by the viral vector, MXD3 knockdown was confirmed at both the RNA and protein level. Within 48 hours, MXD3 protein levels were reduced &gt;90% in cells infected with the shMXD3 virus but not with the control virus. MXD3 knockdown resulted in decreased proliferation in NB cells, supporting our hypothesis that it may be involved in the maintenance of NB. We analyzed cell cycle progression after knockdown using flow cytometry. We observed no significant differences in the G0/G1, S or G2/M populations between experimental and control samples. Our results suggest that MXD3 is important for NB cell proliferation, possibly by acting as an anti-apoptotic factor. Therefore, MXD3 is a potential candidate for targeted therapies against neuroblastoma.
Citation Format: Gustavo Barisone, Noriko Satake, Carly Lewis, Connie Duong, Cathy Chan, Kit Lam, Jan Nolta, Elva Diaz. Mxd3 is required for proliferation of human neuroblastoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3128. doi:10.1158/1538-7445.AM2013-3128
Abstract 3129: COX2 overexpression increases malignant potential of human glioma cells through Id1.
Authors: Xu Kaiming , Shu Hui-Kuo G. 
Published: August 2014

Abstract
Increased COX2 expression directly correlates with glioma grade and is also associated with shorter survival in malignant glioma patients. Id1 is similarly overexpressed in higher grade gliomas. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. Recent studies indicate that Id1 may be involved in the genesis/progression of gliomas. Here, we find that COX2 overexpression in human glioma cells correlates with increased Id1 protein levels. We further find that forced expression of COX2 and Id1 enhances soft agar colony formation. In cell invasion assay, both COX2 and Id1 expression in LN229 human glioma cells (LN/COX2 and LN/Id1) increase migration through matrigel. These cells also showed more tumorigenic potential with development of significantly larger subcutaneous tumors compared with controls. Of note, tumors expressing COX2 or Id1 had higher microvessel density than control tumors. Next, the effect of COX2 and Id1 overexpression was assessed in an orthotopic intracranial model. Here, nude mice injected with LN/COX2 or LN/Id1 cells had significantly decreased survival times compared with corresponding controls (Table 1). To assess the role of Id1 induction on the malignant potential of COX2-expressing glioma cells, LN/COX2 cells with shRNA against Id1 were intracranially injected and found to have a statistically significant increase in survival compared to those injected with control shRNA LN/COX2 cells (Table 1). Finally, to test a COX2-targeting therapy, we used the COX2 inhibitor celecoxib in our xenograft model and found inhibition of growth of flank tumors derived from glioma cells overexpressing COX2. In conclusion, COX2 overexpression in human glioma cells results in elevated Id1 protein level, which, in turn, enhances the transformation and invasiveness of human glioma cells, promotes microvessel formation and enhances xenograft tumor growth subcutaneously and intracranially.
Table 1. Survival of nude mice injected intracranially with the indicated glioma cells. Expt. 1 Expt. 2 Expt. 3 Cell type N Median Survival (days) N Median Survival (days) N Median Survival (days) LN/Ctrl 10 71 8 78 LN/COX2 10 40 9 53 LN/Id1 9 22 11 21 LN/COX2 shCtrl 10 75 LN/COX2 shId1 10 56 p-value by logrank &lt;0.001 &lt;0.001 0.011
Citation Format: Kaiming Xu, Hui-Kuo G. Shu. COX2 overexpression increases malignant potential of human glioma cells through Id1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3129. doi:10.1158/1538-7445.AM2013-3129
Abstract 313: ATDC drives bladder cancer formation by promoting methylation of the PTEN promoter and inhibition of p53 function.
Authors: Palmbos Phillip , Wang Lidong , Yang Huibin , Detzler Taylor , Ney Gina , Hart Justin , Daignault-Newton Stephanie , Kunju L. Priya , Kumar-Sinha Chandan , Liebert Monica , Ljungman Mats , Simeone Diane 
Published: August 2014

Abstract
Bladder cancer is the 5th most common malignancy and a significant cause of morbidity and mortality, but the molecular events leading to its development are incompletely understood. We have identified an oncogene, Ataxia-Telangiectasia Group D Complementing (ATDC) gene, which drives formation and progression of pancreatic and bladder tumors. To better characterize the oncogenic function of ATDC, we generated transgenic (tg) mice which overexpress ATDC and the predominant phenotype of these mice was the development of non-invasive and muscle-invasive urothelial carcinomas. Tg bladder tumors were histologically identical to human tumors and displayed a similar gene expression signature to human invasive bladder tumors. ATDC expression was assessed in a tissue microarray and was highly up-regulated in 70% of human invasive bladder tumors (173/252). High expression of ATDC correlated with more advanced stage disease and worse survival after chemotherapy (p = 0.002). ATDC knockdown in human bladder cancer cell lines correlated with increased sensitivity to chemotherapy in vitro and decreased proliferation and invasion both in vitro and in vivo in a human bladder cancer xenograft model. To understand the mechanism of ATDC-mediated tumor formation, we modulated ATDC expression in normal and bladder cancer cells lines. ATDC overexpression down-regulated PTEN levels via DNA promoter methylation by DNMT3A in both tg mouse tumors and human cell lines. IHC analysis of ATDC, PTEN and DNMT3A expression in human bladder tumors specimens demonstrated similar findings. ATDC was also found to bind to p53 and inhibit p53 mediated functions. These findings establish ATDC as a novel determinant of bladder cancer initiation, progression and resistance to treatment which mediates tumorigenesis by down-regulation of PTEN expression and inhibition of p53.
Citation Format: Phillip Palmbos, Lidong Wang, Huibin Yang, Taylor Detzler, Gina Ney, Justin Hart, Stephanie Daignault-Newton, L. Priya Kunju, Chandan Kumar-Sinha, Monica Liebert, Mats Ljungman, Diane Simeone. ATDC drives bladder cancer formation by promoting methylation of the PTEN promoter and inhibition of p53 function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 313. doi:10.1158/1538-7445.AM2013-313
Abstract 3137: Functional analysis of the chr13q22.1 pancreatic cancer risk locus suggests allele-specific effects on DIS3 expression.
Authors: Hoskins Jason , Ibrahim Abdisamad , Jia Jinping , Collins Irene , Parikh Hemang , Petersen Gloria M. , Amundadottir Laufey 
Published: August 2014

Abstract
Pancreatic cancer is the 10th most common cancer and 4th most common cause of cancer mortality in the United States. A genome wide association study has revealed pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. The chr13q22.1 region contains the most significant of all risk SNPs, rs9543325, (P= 3.27 x 10−11) which is located in a gene desert. The nearest genes are KLF5, KLF12, PIBF1, DIS3 and BORA, which range in distance from 265kb to 586kb, respectively, from the most significant variants. Given the high linkage disequilibrium across this risk locus, there are many candidate functional variants to consider. Imputation in the region did not improve the signal but gave a set of highly correlated SNPs which likely includes the functional variant(s). In an effort to identify the functional variant(s) we performed eQTL analyses to test the association between the genotypes of these candidate SNPs and expression of nearby genes. Among 100 normal pancreatic tissue samples, DIS3 showed the strongest association with SNPs in our risk locus (P-values as low as 0.0004). Mutations in DIS3 have been identified in acute myeloid leukemia and multiple myeloma, and its expression has been correlated with metastatic potential in colorectal cancer, suggesting this gene could be important in pancreatic cancer biology. Chromosome Conformation Capture (3C) was performed to test for physical interactions between the risk locus and nearby genes. This assay confirmed the three dimensional proximity of the risk locus and DIS3 promoter. Sub-regions of the risk locus were then cloned upstream of a minimal promoter controlling luciferase expression to assay for potential allele specific enhancer/silencer activity. This assay revealed a sub-region downstream of rs9543325 that causes allele-specific silencing. These results suggest that a sub-region of the chr13q22.1 risk locus has allele-specific effects on DIS3 expression, which may have implications in the susceptibility to pancreatic cancer.
Citation Format: Jason Hoskins, Abdisamad Ibrahim, Jinping Jia, Irene Collins, Hemang Parikh, Gloria M. Petersen, Laufey Amundadottir. Functional analysis of the chr13q22.1 pancreatic cancer risk locus suggests allele-specific effects on DIS3 expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3137. doi:10.1158/1538-7445.AM2013-3137
Abstract 3138: Development of a tetracycline-inducible lentiviral system for RNAi screen in PDX tumors.
Authors: Chen Lei , Geng Yi , Fruhling Dave , Zhong Wenyan , Diesl Veronica , Pan Jing , Loreth Christine , Wang Elizabeth , Bulynko Yaroslava , Arndt Kim , Follettie Maximillian 
Published: August 2014

Abstract
Patient-derived xenograft (PDX) tumors are believed to be more clinically relevant pre-clinical models for cancer target identification and validation. We used a tetracycline-inducible lentiviral vector that delivers shRNA expression which is tightly linked to a GFP reporter in PDX cells. Using shRNAs against PLK1 (polo-like kinase 1) as positive controls, we demonstrated that three of the four PLK1 hairpins resulted in growth inhibition of HT29 and A549 cells upon dox induction. Correspondingly, these 3 hairpins showed significant knockdown of PLK1 mRNA. To facilitate RNAi in PDX tumors, we have established an in vitro system to culture PDX tumor cells. Gene expression and IHC study demonstrated that tumors regenerated from colon PDX cells grown in vitro retained features of their parental tumors. PDX cells cultured in vitro also remained tumorigenic. When GFP/shRNA-transduced colon PDX cells were re-implanted in mice to form tumors, approximately 30% of the new tumor cells was GFP-positive, enabling us to capture shRNA-expressing cells by flow cytometry. Initial shRNA drop-out screens were carried out in HT29 and colon PDX cells transduced with a pool of ∼600 shRNAs targeting a set of potential cancer associated genes. Included amongst the hairpins demonstrating statistically significant depletion in HT29 were the exact same three PLK1 shRNAs previously functionally validated. These results demonstrated that we have established a robust in vivo shRNA drop-out screening platform in PDX tumors for identification of novel cancer drug targets.
Citation Format: Lei Chen, Yi Geng, Dave Fruhling, Wenyan Zhong, Veronica Diesl, Jing Pan, Christine Loreth, Elizabeth Wang, Yaroslava Bulynko, Kim Arndt, Maximillian Follettie. Development of a tetracycline-inducible lentiviral system for RNAi screen in PDX tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3138. doi:10.1158/1538-7445.AM2013-3138
Abstract 3139: Identification and functional studies of p53 mutants detected in breast cancers after chemotherapy treatment.
Authors: Huun Johanna , Berge Elisabet O. , Lillehaug Johan R. , Lonning Per Eystein , Knappskog Stian 
Published: August 2014

Abstract
Background: Approximately 4300 different TP53 mutations have been reported in human cancers. TP53 mutations, in particular those affecting the L2/L3 domains, are associated with resistance to anthracycline or mitomycin treatment in breast cancer patients. While many mutations have been characterised functionally, novel TP53 mutations are continuously reported. Here, we characterise 10 p53 protein variants encoded by mutated TP53 (5 within and 5 outside L2/L3) detected in locally advanced or metastatic breast cancers. Each tumour was previously characterised for response to therapy, allowing comparison between in vivo and in vitro findings.
Methods: Mutated p53 variants were analysed for their ability to oligomerise with the wild-type protein and their subcellular localisation by immunoprecipitation and immunofluorescence, respectively. Their ability to induce transcription of target genes was determined by qPCR. Cellular growth rate, apoptosis and senescence were monitored by WST-1, TUNEL and beta-galactosidase assays, respectively.
Results: Immunoprecipitation assays revealed each mutant protein to retain binding capacity for wild-type p53, thus potentially acting in a dominant negative manner. Even though each p53 variant located predominantly in the nucleus, the percentage of cells with only nuclear p53 localisation varied between 60-90%. None of the p53 variants were able to induce target genes to levels similar to wild-type p53, nor where they able to reduce cellular growth rate, induce apoptosis or senescence similar to wild-type p53 after anthracycline treatment in vitro.
Conclusions/General Significance: Our data add further information characterising the effects of somatic TP53 mutations on p53 protein function and anthracycline resistance in breast cancer.
Citation Format: Johanna Huun, Elisabet O. Berge, Johan R. Lillehaug, Per Eystein Lonning, Stian Knappskog. Identification and functional studies of p53 mutants detected in breast cancers after chemotherapy treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3139. doi:10.1158/1538-7445.AM2013-3139
Abstract 3143: A functional interaction between alpha-fetoprotein and miRNA-29 modulates the HCC epigenome.
Authors: Parpart Sonya , Roessler Stephanie , Dong Fei , Rao Vinay , Loffredo Christopher , Wang Xin Wei 
Published: August 2014

Abstract
Globally, hepatocellular carcinoma (HCC) accounts for 70-85% of primary liver cancers and ranks second in the leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally expressed during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors may differ biologically and have different prognosis in HCC patients. Using microarray-based global microRNA and mRNA profiling, we found that members of the miR-29 family are the most significantly (p&lt;1E-5) down-regulated miRs in AFP+ tumors (n=242). Physiologically, during mouse embryonic development, miR-29 family expression is low but gradually increases after birth, contrary to AFP expression which dramatically decreases after birth. In addition, a member of the DNA methyltransferase (DNMT) family, DNMT3A, is one of the most significantly (p=8E-6) up-regulated genes in AFP+ HCC. Interestingly, there is a significant inverse correlation (p&lt;1E-4) between miR-29 and DNMT gene expression, suggesting that they may be functionally antagonistic, which is consistent with the finding showing that DNMT3A and DNMT3B are direct targets of miR-29. Experimentally, we found that increased AFP expression or the addition of AFP+ media to AFP- cells inhibits miR-29a expression in HCC cell lines. We also found that AFP transcriptionally regulates the promoter of miR-29a. Moreover, global DNA methylation array profiling reveals increased methylation in HCC patients with high levels of serum AFP. These results support our hypothesis that AFP inhibits miR-29, which modulates epigenetic changes that contribute to poor outcome. Taken together, this study elucidates the mechanisms that link AFP and miR-29 expression to epigenetic alterations and may aid in the development of novel therapeutic agents to improve survival of HCC patients.
Citation Format: Sonya Parpart, Stephanie Roessler, Fei Dong, Vinay Rao, Christopher Loffredo, Xin Wei Wang. A functional interaction between alpha-fetoprotein and miRNA-29 modulates the HCC epigenome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3143. doi:10.1158/1538-7445.AM2013-3143
Abstract 3150: Characterizing the effects of somatic mutations in splice factors on the transcriptome.
Authors: Brooks Angela N. , Wan Youzhong , Choi Peter , Jing Rui , DeLuca David S. , Sougnez Carrie , Chmielecki Juliann , Imielinski Marcin , Getz Gad , Wu Catherine J. , Meyerson Matthew 
Published: August 2014

Abstract
Recent studies have identified recurrent somatic mutations in splice factors, including SF3B1 and U2AF1, in myelodysplastic syndromes, chronic lymphocytic leukemias, breast cancer, and lung adenocarcinoma. In one study, 91 tumor and matched normal whole-exomes were sequenced from patients with CLL and the second most frequently mutated gene was SF3B1. Analysis of 187 whole-exomes in lung adenocarcinoma and matched normals revealed recurrent somatic mutations in the splice factor U2AF1 in 3% of cases. In addition to U2AF1 mutations, recurrent truncating mutations were observed in a putative splice factor, RBM10, in 4% of lung adenocarcinomas. The recurrence of somatic mutations in splice factors in multiple tumor types suggests that alterations in RNA splicing may play an important role in tumorigenesis.
Although these mutations have been identified in cancer genomes, the effect on the cancer transcriptome has yet to be fully explored; therefore, we do not understand how mutations in splice factors can contribute to tumorigenesis. We hypothesize that somatic mutations in splice factors cause alterations in mRNA splicing of important cancer genes.
We are using a computational tool called JuncBASE to identify alternative splicing in tumor transcriptomes from RNA-Seq data. We are then associating somatic mutations in splice factors, found from whole-exome sequencing, with splicing signatures identified through RNA-Seq.
Preliminary results on the identification of splice events associated with SF3B1 mutations in CLL reveal novel isoforms of multiple genes specifically expressed in SF3B1 mutant samples. Additionally, we examined the effects of SF3B1, U2AF1, and RBM10 mutations on tumor transcriptomes using RNA-Seq data from The Cancer Genome Atlas.
Citation Format: Angela N. Brooks, Youzhong Wan, Peter Choi, Rui Jing, David S. DeLuca, Carrie Sougnez, Juliann Chmielecki, Marcin Imielinski, Gad Getz, Catherine J. Wu, Matthew Meyerson. Characterizing the effects of somatic mutations in splice factors on the transcriptome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3150. doi:10.1158/1538-7445.AM2013-3150
Abstract 3156: New candidate oncogenes discovered in microsatellite unstable colorectal cancer.
Authors: Gylfe Alexandra E. , Kondelin Johanna , Turunen Mikko , Ristolainen Heikki , Katainen Riku , Pitkänen Esa , Kaasinen Eevi , Rantanen Ville , Tanskanen Tomas , Lehtonen Heli J. , Palin Kimmo , Taipale Minna , Taipale Jussi , Renkonen-Sinisalo Laura , Järvinen Heikki , Böhm Jan , Mecklin Jukka-Pekka , Ristimäki Ari , Tuupanen Sari , Karhu Auli , Kilpivaara Outi , Vahteristo Pia , Aaltonen Lauri A. 
Published: August 2014

Abstract
Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI). A characteristic high passenger mutation load has discouraged systematic mutation screens in MSI CRCs. To systematically search for novel MSI CRC oncogenes, the exomes of 25 MSI CRC-normal pairs were sequenced as the discovery set. Observed hot spots were confirmed by Sanger sequencing and further validated in a set of 86 MSI CRCs. Mutational hot spots were confirmed in 15 genes and three genes showed additional hot spot mutations in the validation set. These three sites were highly conserved across species. The hot spot sites of these three genes were screened in 75 microsatellite stable CRCs and 12 MSI CRC cell lines with negative results. Next, we analyzed the subcellular localization of wild-type and mutant proteins. The findings of this study support the idea that cancer genomes are heterogeneous and characterized by few, frequently mutated “mountains” (e.g. BRAF and KRAS) and numerous, less frequently mutated “hills”. The identified mutational hot spots may prove important in developing personalized tumor profiling and therapy.
Citation Format: Alexandra E. Gylfe, Johanna Kondelin, Mikko Turunen, Heikki Ristolainen, Riku Katainen, Esa Pitkänen, Eevi Kaasinen, Ville Rantanen, Tomas Tanskanen, Heli J. Lehtonen, Kimmo Palin, Minna Taipale, Jussi Taipale, Laura Renkonen-Sinisalo, Heikki Järvinen, Jan Böhm, Jukka-Pekka Mecklin, Ari Ristimäki, Sari Tuupanen, Auli Karhu, Outi Kilpivaara, Pia Vahteristo, Lauri A. Aaltonen. New candidate oncogenes discovered in microsatellite unstable colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3156. doi:10.1158/1538-7445.AM2013-3156