bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 799: Protein kinase C ϵ cooperates with Pten deficiency to regulate NF-κB pathway in prostate cancer progression
Authors: Garg Rachana , Blando Jorge , Perez Carlos J. , Benavides Fernando J. , Kazanietz Marcelo G. 
Published: August 2015

Abstract
Prostate cancer is one of the most commonly diagnosed malignancies and the second leading cause of cancer-related deaths among men in the United States. Protein kinase C epsilon (PKCϵ), a member of the PKC family of phorbol ester/diacylglycerol receptors, has emerged as an oncogenic kinase and shown to be up-regulated in human prostate cancer specimens. We recently demonstrated that PKCϵ is an upstream regulator of NF-κB activation in prostate cancer (JBC, 287:37570-37582, 2012) and that transgenic overexpression of PKCϵ in mice prostate under the control of the probasin promoter (PB-PKCϵ) leads to hyperplasia and PIN lesions but was insufficient to drive neoplastic changes (Cell Cycle, 10:268-277, 2011). Notably, when we intercrossed PB-PKCϵ mice with mice haploinsufficient for Pten, another common genetic alteration in human prostate cancer, the resulting compound mutant mice (PB-PKCϵ;Pten+/- mice) developed fully invasive adenocarcinoma with elevated NF-κB levels. In the present study, we aim to delineate the mechanism underlying the observed cooperativity between PKCϵ overexpression and Pten deficiency and to explore the consequences of this cooperativity on the transcription factor NF-κB signaling, a pathway known to be highly dysregulated in prostate tumorigenesis. To this end, we stably overexpressed PKCϵ in mouse prostate epithelial lines that are either heterozygous (P8) or homozygous (CaP8) for Pten deletion. We observed a striking synergism between PKCϵϵ overexpression and Pten loss in conferring enhanced proliferative, migratory and invasive phenotype. Moreover, LPS or TNFα stimulation of these cells led to increased NF-κB activation as evident from the elevated IκBα phosphorylation, NF-κB nuclear translocation and transactivation of a NF-κB luciferase reporter. These effects were much more pronounced in CaP8 cells. Of note, PKCϵ overexpression and Pten loss also cooperates to augment levels of the NF-κB regulated gene, COX-2. Stable overexpression of PKCϵ and Pten depletion in “normal” immortalized RWPE1 cells also resulted in significant enhancements in TNFα-induced NF-κB activation and COX-2 induction. Furthermore, NF-κB inhibition by parthenolide significantly retarded the growth of CaP8-PKCϵ tumors in athymic nude mice. Overall, our results identify NF-κB as a mediator of PKCϵ oncogenesis in prostate cancer, particularly in the context of Pten loss.
Citation Format: Rachana Garg, Jorge Blando, Carlos J. Perez, Fernando J. Benavides, Marcelo G. Kazanietz. Protein kinase C ϵ cooperates with Pten deficiency to regulate NF-κB pathway in prostate cancer progression. [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 799. doi:10.1158/1538-7445.AM2015-799
Abstract 800: Dysregulation of DLL4 gene expression in Li-Fraumeni syndrome and tumorigenesis
Authors: Yao Zhixing , Sherif Zaki A. 
Published: August 2015

Abstract
Li-Fraumeni Syndrome (LFS), a clinically and genetically rare heterogeneous cancer syndrome, is characterized primarily by a p53 (TP53) gene mutation. This study is an attempt to understand why 30-40% of LFS patients who do not harbor p53 mutation are nonetheless besieged by the same preponderance of primary cancers, die at an early age, and at the same rate as those with the p53 mutation. LFS provides powerful insights into our understanding of the somatic mutations present in sporadic cancers influenced by p53. The p53 protein is a transcription factor that guards against genomic instability by inducing target genes that mediate its functions. Utilizing cytogenetic techniques, we previously discovered a novel balanced reciprocal translocation t(11;15)(q23;q15) between chromosomes 11 and 15 in the normal skin fibroblasts of a patient with LFS who had bilateral breast cancer but was homozygous for wild-type p53. Analysis of the breakpoint regions of this translocation yielded a number of genes; of particular interest was DLL4 (Delta-like ligand 4, locus 15q15.1), which encodes a ligand that binds to Notch receptors. Notch signaling controls cell fate specification during embryonic and postnatal development. DLL4 is a putative regulator of T cell lineage and thymopoiesis. In this study, we analyzed DLL4 gene expression and regulation in tumorigenesis. We also analyzed the transcriptional regulation of the DLL4 promoter. Our data reveal that DLL4 expression is abrogated in the normal skin fibroblasts of all LFS patients under study and markedly down-regulated in breast cancer cells and neuroblastoma cells due to TP53 mutation, DNA methylation or gene disruption caused by a balanced reciprocal translocation between chromosomes 11q23 and 15q15. Immunohistochemistry (IHC) staining corroborated the down-regulation of DLL4 in cancer tissue samples from different organs. These findings taken together not only have possible implications for karyotype-phenotype correlation in carcinogenesis, specifically of breast cancer, but also shed light on the possible implication of DLL4 in LFS and breast cancer initiation and progression. The drastic reduction or absence in the expression of DLL4 in normal skin fibroblasts of LFS patients as well as breast and brain cancer cells is significant and supports the concept that this ligand may play a role in cancer immune-surveillance and its resuscitation in the tumor microenvironment may stimulate T-cell immunity and suppress tumor growth. This demonstrates that DLL4 may provide a strong platform as an immuno-therapeutic target in LFS and breast cancer patients.
Citation Format: Zhixing Yao, Zaki A. Sherif. Dysregulation of DLL4 gene expression in Li-Fraumeni syndrome and tumorigenesis. [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 800. doi:10.1158/1538-7445.AM2015-800
Abstract 805: Subcellular distribution of RAGE affects its functions in melanoma growth and progression
Authors: Reith Maike , Gebhardt Wolf-Henning , Tarnanidis Kathrin , Wagner Nikolaus B. , Ikenberg Kristian , Kehrel Coretta , Utikal Jochen , Gebhardt Christoffer 
Published: August 2015

Abstract
The receptor for advanced glycation end-products (RAGE) is known to act as a central driver of tumorigenesis by sustaining a chronic inflammatory tumor microenvironment. Until to date, RAGE has been exclusively described as a cell surface receptor being activated upon engagement with its various extra-cellular ligands, e.g. S100B, S100A8/A9, HMGB1, and others. This study aimed at elucidating the functional role of RAGE and its isoforms depending on their subcellular distribution in the context of melanoma development, growth and progression. Therefore, various in vitro models using melanoma cells or melanocytes and melanoma mouse models as well as tissue-microarrays representing human specimens of malignant melanoma and benign nevi were applied.
The expression analyses revealed an overexpression of RAGE in melanoma cells compared to melanocytes/nevocytes. Moreover, RAGE protein was found to be localized primarily in the nucleus of melanocytes/nevocytes whereas a predominant cell surface/cytoplasmic localization of RAGE is observed in melanoma cells. Nuclear translocation of RAGE depends on the nuclear transport machinery and site-directed mutagenesis of predicted DNA binding sites within the RAGE protein was applied in order to study its functional role in the nucleus. Furthermore, knockdown of RAGE indicated its central function in apoptosis induction.
In conclusion, RAGE and its isoforms are overexpressed and aberrantly localized in malignant melanoma cells compared to melanocytes/nevocytes. Our data point towards a novel tumor-protective function of RAGE in melanoma development depending on its nuclear localization.
Citation Format: Maike Reith, Wolf-Henning Gebhardt, Kathrin Tarnanidis, Nikolaus B. Wagner, Kristian Ikenberg, Coretta Kehrel, Jochen Utikal, Christoffer Gebhardt. Subcellular distribution of RAGE affects its functions in melanoma growth and progression. [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 805. doi:10.1158/1538-7445.AM2015-805
Abstract 812: Processing of core protein by signal peptide peptidase participates in propagation and pathogenesis of hepatitis C virus
Authors: Okamoto Toru , Aizawa Sayaka , Kouwaki Takahisa , Suzuki Tatsuya , Fukuhara Takasuke , Moriishi Kohji , Koike Kazuhiko , Matsuura Yoshiharu 
Published: August 2015

Abstract
Hepatitis C virus (HCV) is a major causative agent of chronic liver diseases including steatosis, cirrhosis and hepatocellular carcinoma (HCC). The HCV core protein is cleaved off from a precursor polyprotein by a signal peptidase and then further processed by signal peptide peptidase (SPP) within the transmembrane region. However, the biological significance of the processing of HCV core protein by SPP remains largely unknown. Transgenic mice expressing HCV core protein exhibit insulin-resistance, steatosis and finally develop HCC, suggesting that core protein plays crucial roles in pathogenesis of HCV. In this study we have established SPP-knockout (KO) mice and cell lines to examine the roles of SPP on the propagation and pathogenesis of HCV. SPP KO mice were embryonic lethal at around E13.5, therefore we prepared SPP-KO mouse embryonic fibroblast cells (MEFs). In SPP-KO cells, HCV core protein was quickly degraded by proteasome and propagation of HCV was severely impaired. Treatment of cells with LY-411575, an inhibitor for SPP, also induced degradation of HCV core protein and suppressed the production of infectious HCV particles. PA28γ or E6AP, which had been reported to degrade core protein, were not involved in SPP-mediated degradation, suggesting the other mechanisms were involved in SPP-induced core protein degradation. Furthermore, oral administration of LY-411575 into HCV core transgenic mice reduced expression of core protein and cured insulin-resistance. The deletion of one allele of SPP gene in core transgenic mice led to impair the expression of core protein and cure insulin-resistance. These results suggest that SPP is a novel drug target for chronic hepatitis C through suppression of viral propagation and liver failures.
Citation Format: Toru Okamoto, Sayaka Aizawa, Takahisa Kouwaki, Tatsuya Suzuki, Takasuke Fukuhara, Kohji Moriishi, Kazuhiko Koike, Yoshiharu Matsuura. Processing of core protein by signal peptide peptidase participates in propagation and pathogenesis of hepatitis C virus. [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 812. doi:10.1158/1538-7445.AM2015-812
Abstract 815: DTX1 is an epigenetically regulated tumor suppressor gene discovered by integrative analysis of epigenetic and transcriptional alterations in HNSCC
Authors: Gaykalova Daria A. , Zizkova Veronika , Tiscareno Ilse , Wei Yingying , Vatapalli Rajita , Hennessey Patrick T. , Ahn Julie , Danilova Ludmila V. , Khan Zubair , Bishop Justin A. , Koch Wayne M. , Westra William H. , Ochs Michael F. , Califano Joseph A. 
Published: August 2015

Abstract
Half a million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide. Given the advanced stage at diagnosis, 5 year survival after initial diagnosis is only 50% for HNSCC patients despite the current therapeutic strategies.
Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC, but given the high sensitivity of this methodology, these data require careful evaluation. To improve the detection of cancer-related changes in HNSCC we applied outlier statistics to high throughput DNA methylation and gene expression data, and identified 76 top-scoring candidate proto-oncogenes and tumor suppressor genes with significantly changed expression in tumors compared to normal tissues. We identified epigenetically regulated candidates with potential role in HNSCC by selecting genes with strong negative correlation between gene expression and DNA methylation of their promoters. Differential expression and methylation of selected candidates were confirmed with assays on an independent HNSCC cohort and on public domain high throughput data on TCGA-HNSCC cohort (The Cancer Genome Atlas). We further performed functional evaluation of a lead candidate - DTX1 and demonstrated that DTX1 is a negative regulator of cell migration. We confirmed that epigenetic-dependent downregulation of DTX1 enhanced invasiveness of head and neck cancer cells.
Outlier analysis integrated with high throughput expression and methylation can be used to identify an epigenetically- regulated tumor suppressor genes, including DTX1.
Citation Format: Daria A. Gaykalova, Veronika Zizkova, Ilse Tiscareno, Yingying Wei, Rajita Vatapalli, Patrick T. Hennessey, Julie Ahn, Ludmila V. Danilova, Zubair Khan, Justin A. Bishop, Wayne M. Koch, William H. Westra, Michael F. Ochs, Joseph A. Califano. DTX1 is an epigenetically regulated tumor suppressor gene discovered by integrative analysis of epigenetic and transcriptional alterations in HNSCC. [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 815. doi:10.1158/1538-7445.AM2015-815
Abstract 816: Persistent effects of radiation on intestinal stem cells: implications for colorectal carcinogenesis
Authors: Datta Kamal , Suman Shubhankar , Kumar Santosh , Fornace Albert J. 
Published: August 2015

Abstract
Adult stem cells, similar to somatic cells, are also subject to a similar array of insults and are therefore presumed to accrue radiation damage. Unlike somatic cells, however, lesions arising in the stem cell compartment are propagated both to daughter stem cells and to downstream lineages through the processes of self-renewal and differentiation. The impact of damage accrued in individual stem cells can thus have major ramifications for all levels of the developmental hierarchy leading to cancer initiation and promotion in human as well as in animal models of human colorectal cancer (CRC) such as in APCMin/+. Differentiation of intestinal stem cell (ISC) and ordered migration of differentiated cells along crypt-villus axis is essential for maintenance of intestinal homeostasis and provides a model system to study stem cell alterations after radiation. Furthermore, considering that tumors in animal models of CRC almost exclusively develop in the small intestine and increased intestinal tumor frequency was radiation quality dependent, we investigated persistent effects of radiation quality on ISC as well as on differentiated intestinal epithelial cells in mice. Mice (6 to 8 week; C57BL/6J) were exposed to γ (0.5 and 2 Gy) and 56-Fe (0.5 and 1.6 Gy) radiation, samples were collected 7 d and 2 m after radiation exposure, and carcinogenic precursor events such as persistent oxidative stress and DNA damage were assessed. Higher persistently increased oxidative stress and oxidative DNA damage was observed after 56-Fe relative to γ radiation. However, increased oxidative stress did not increase cell death implying that the oxidative stress was sub-lethal. Autophagy, a self-cannibalistic process of cell involved in removing damaged cell and cell constituents, was consistently downregulated in a radiation quality dependent manner even 2 m after exposure suggesting persistence of damage-bearing cells. We believe radiation-induced autophagy downregulation and sub-lethal oxidative stress is working in tandem to trigger proliferative signaling such as PI3K/Akt and mTOR in intestinal cells. Taken together our results provide insight into radiation quality dependent persistent cancer-related molecular events, which could have altered phenotypic behavior of ISC such as proliferation, differentiation, and migration.
Note: This abstract was not presented at the meeting.
Citation Format: Kamal Datta, Shubhankar Suman, Santosh Kumar, Albert J. Fornace. Persistent effects of radiation on intestinal stem cells: implications for colorectal carcinogenesis. [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 816. doi:10.1158/1538-7445.AM2015-816
Abstract 817: Lipid, glucose and global oxidation in relation to prostate cancer development
Authors: Wu Tianying 
Published: August 2015

Abstract
Oxidative stress has been implicated in the development of prostate cancer (PCa); however, no study has comprehensively examined the associations between lipid, glucose and global oxidation with the development of prostate cancer. Using a prospective study design, we collected blood and urine samples among participants who are free of cancer in Ohio area. These participants were followed up 14 years. We selected 24 men who developed PCa during this period and matched them with 24 healthy controls by age and race among these participants (who did not develop prostate cancer) during this period. We measured the following biomarkers in these 48 samples (24 PCa cases and 24 health controls). Biomarkers included urine F2-isoprostanes (a marker of lipid oxidation), plasma advanced glycation end products (AGEs; a marker of advanced glycation and glucose oxidation), and plasma fluorescent oxidation products (FlOPs; markers of global oxidation). We have found that only AGEs were significantly higher in PCa cases than in health controls (182 vs. 152 μg/ml, P &lt; 0.05). In the conditional logistic regression model, one standard deviation higher levels of AGEs were associated with increased risk of incident PCa (Relative risk = 1.79, 95% confidence interval = 1.00-3.21). In the model, one standard deviation higher levels of AGEs accounted for ∼8% variance of prostate cancer liability. Our results suggest that glycation and glucose oxidation but not lipid and global oxidation is an important etiology pathway for prostate cancer development. Lipid and global oxidation do not occur in parallel for the development of prostate cancer. If our results are confirmed by other studies, it may suggest a new pathway for prostate cancer prediction and treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Tianying Wu. Lipid, glucose and global oxidation in relation to prostate cancer development. [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 817. doi:10.1158/1538-7445.AM2015-817
Abstract 819: Fatty acid synthase, cycloxygenase-2 (COX-2) and osteoprotegerin (OPG) expression in invasive breast cancer: Implications in carcinogenesis
Authors: Goswami Sudeshna , Sharma-Walia Neelam 
Published: August 2015

Abstract
Breast cancer, the leading cause of death among women with an onset frequency of one in eight, is the most common type of cancer among women. However, despite the advancement in therapy, the mortality rate in breast cancer patients still remains high. The role of various different genes, directly or indirectly, regulating these processes have tremendously added to our knowledge of the complex process of proliferation, which has remained the most important prognostic factor so far. In our previous study, we established Osteoprotegerin (OPG)'s role in aneuploidy, cell proliferation and angiogenesis in breast cancer. We demonstrated that OPG is expressed and secreted at very high levels from the highly invasive breast cancer cell lines SUM149PT and SUM1315MO2 as compared to human normal mammary epithelial cells (HMEC). Here, we demonstrated by mass spectrometry that OPG pulls down fatty acid synthase (FASN), a key enzyme of the fatty acid biosynthetic pathway in breast cancer cells. We observed large number of lipid droplets in SUM149PT and SUM1315MO2 cells in comparison to HMEC by electron microscopy. Human breast cancer tissue samples showed high expression of FASN. Treatment with FASN inhibitor C75 decreased the number of lipid droplets/cell, altered expression of genes involved in cell proliferation, cell signaling (Akt/PI3K, ERK, GSK3β) apoptosis (caspase-3 and caspapse-9) and cell cycle. Treatment with C75 lowered the inflammatory pathway enzyme cyclooxygenase-2 (COX-2) expression and reduced secretion of its inflammatory metabolite prosataglandin E2 (PGE2). We reasoned that there might be crosstalk between OPG, FASN, and COX-2, that sustains the inflammatory pathways, and drives the progression of breast cancer. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 by recombinant human OPG. Collectively, our study indicates the crosstalk between FASN, COX-2 and OPG. Combinatorial drug treatment of these main players of carcinogenesis can be used as a potential therapeutic target to treat highly invasive breast cancer.
Citation Format: Sudeshna Goswami, Neelam Sharma-Walia. Fatty acid synthase, cycloxygenase-2 (COX-2) and osteoprotegerin (OPG) expression in invasive breast cancer: Implications in carcinogenesis. [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 819. doi:10.1158/1538-7445.AM2015-819