bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4117: Increased pancreatic adipocyte hypertrophy in EL-Kras/PEDF null mice with versus without pancreatic cancer
Authors: Samiei Arash , Fitchev Philip S. , Bentrem David J. , Melstrom Laleh G. , Adrian Kevin , Cornwell Mona L. , Crawford Susan E. , Grippo Paul J. 
Published: August 2012

Abstract
Understanding non-parenchymal contributions to disease etiology and factors that assess risk and prognosis are currently key points of interest in pancreatic cancer research. One such focus is in regards to fat, where obesity and increased visceral fat enhance risk and predict worse prognosis for pancreatic cancer patients. Pigment epithelium-derived factor (PEDF), initially identified for its potent anti-angiogenic activity, has been recently implicated in metabolism and adipogenesis, and loss of PEDF in mice promotes pancreatic hyperplasia and visceral obesity. In an attempt to create a model of pancreatic cancer that emulates metabolic features related to fat content, we generated PEDF knockout mice with KrasG12D-induced pancreatic neoplasia, where oncogenic Kras can also induce adipogenesis (typically observed as lipoatrophy). We have recently shown that EL-KrasG12D/PEDF null mice developed invasive pancreatic cancer associated with increased peripancreatic fat with adipocyte hypertrophy and pancreatic steatosis. Indeed, the stroma within the pancreas of these mice demonstrated higher levels of tail interacting protein 47 (TIP47, Perilipin 3) and adipose differentiation-related protein (ADRP, Perilipin 2), two lipid droplet associated proteins. In this study, we expanded upon this work to demonstrate that in most EL-Kras/PEDF null mice, there appeared to be greater number of neoplastic lesions near neighboring fat stores. In addition, there was a significant increase in the size of adipocytes (greater adipocyte hypertrophy) in EL-Kras/PEDF null mice with invasive cancer as opposed to age-matched mice with an identical genotype without the presence of cancer. Despite increased adipocytes in mice with cancer, there was no significant difference in overall body weight between these cohorts of animals. Future work aims at identifying if neoplastic lesions near adipocytes have a greater proliferative index and hence an increase in size. Ultimately, we hope to demonstrate that larger and more numerous adipocytes contribute to the development of pancreatic cancer. These data highlight the importance of lipid metabolism in the tumor microenvironment and identify PEDF as a critical negative regulator of both adiposity and tumor invasion in the pancreas, with implications that PEDF's effect on fat stores may induce cellular events leading to invasive disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4117. doi:1538-7445.AM2012-4117
Abstract 4119: High-throughput proteomics reveals that enzymes of the ketogenic pathway are upregulated during prostate cancer progression
Authors: Saraon Punit , Cretu Daniela , Jarvi Keith , Diamandis Eleftherios P. 
Published: August 2012

Abstract
Prostate cancer is the most common malignancy and the second leading cause of cancer related deaths in men. One common treatment is androgen-deprivation therapy, which reduces symptoms in most patients. However, over time, patients develop tumours that are androgen-independent and ultimately fatal. The mechanisms that cause this transition remain largely unknown, and as a result, there are no effective treatments against androgen-independent prostate cancer. As a model platform, we used the LNCaP cell line, and its androgen independent derivative, LNCaP-SF. By using stable isotope labelling with amino acids in cell culture (SILAC) coupled to mass spectrometry, we assessed the differential global protein expression between the two cell lines. Our proteomic analysis resulted in the quantification of 3355 proteins, in total. Bioinformatic prioritization resulted in 42 up-regulated and 46 down-regulated proteins in LNCaP-SF cells, compared to LNCaP cells. Our top candidate was HMGCS2, an enzyme involved in ketogenesis, was found to be 9-fold elevated in LNCaP-SF cells, based on peptide ratios. After analyzing the remaining enzymes of this pathway (ACAT1, BDH1, HMGCL, OXCT1), we observed increased expression of these proteins in the LNCaP-SF cells. This was further verified using western blotting, indicating the importance of this pathway during the progression of prostate cancer to androgen-independence. To determine whether these enzymes are up-regulated in clinical samples, we performed qPCR analysis on human prostate cancer tissues, from which we observed significantly increased transcript levels of HMGCS2 (p&lt;0.05), OXCT1 (P&lt;0.05), ACAT1 (p&lt;0.001), and BDH1 (p&lt;0.001). In addition, the protein expression of all five ketogenic pathway enzymes was elevated in high grade prostate cancer (Gleason Grade &gt;8) based on immunohistochemistry analysis. ACAT1 displayed the most prominent protein expression patterns, as it exhibited very minimal staining in normal samples, moderate levels in low grade cancer, and high expression during high grade disease. Further assessment of ACAT1 expression demonstrated significantly greater ACAT1 expression in bone metastatic lesions (P&lt;0.001). Altogether, our results indicate that enzymes belonging to the ketogenic pathway become up-regulated during high grade prostate cancer, and could serve as potential biomarkers for diagnosis of high grade disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4119. doi:1538-7445.AM2012-4119
Abstract 4120: UDP-Glucuronosyltransferase 1 (UGT1A1) down-regulation correlates to menopausal status and stage of disease in human breast cancer tissues
Authors: Starlard-Davenport Athena , Word Beverly R. , Lyn-Cook Beverly D. 
Published: August 2012

Abstract
Estrogen metabolism, catalyzed by UGTs, is a major drug-metabolic pathway that results in the complete inactivation of estrogens and their hydroxylated metabolites. Alterations in UGTs, resulting in decreased UGT expression and glucuronidation activity towards estrogens and their metabolites, has been suggested to play a potential role in breast cancer risk. The purpose of this study was to: 1) compare the mRNA expression levels of UGTs responsible for conjugating estrogens in human breast cancers and normal breast tissues from women; 2) compare UGT1A1 mRNA expression to tumor stage, ER status, ethnicity, and menopausal status in a group of human breast tumors and normal breast tissues, and 3) investigate the association between variations in the number of TA repeats in the promoter region of UGT1A1 to gene expression. Quantification of UGT mRNA in breast tissues revealed that UGT1A4, UGT1A9, UGT1A10, and UGT2B7 mRNA levels were decreased in breast cancers as compared to normal breast tissues. UGT1A1 mRNA levels were also significantly decreased in breast cancers (N = 17) as compared to normal breast tissues (N = 30) (p = 0.02). UGT1A1 down-regulation strongly correlated with menopausal status (premenopausal vs. postmenopausal; p = 0.04) and stage of breast disease (p = 0.01). This may account for variations in response to chemotherapy used for the treatment of more aggressive breast cancers. UGT1A1 mRNA was also decreased in breast tumors as compared to normal breast tissues from both African American and European American women. We postulated that the decreased levels of UGT1A1 mRNA in breast cancers may be due to a genetic variant in the promoter of UGT1A1. In all UGT1A1 genotypes observed in our study, the mean UGT1A1 mRNA expression levels was significantly decreased among breast cancer cases as compared to controls (p = 0.04). Our research findings suggest that further investigations are necessary to determine the role of UGT1A1 in breast carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4120. doi:1538-7445.AM2012-4120
Abstract 4141: The role of microRNA in gastric cancer
Authors: Li Jianfang , Yu Beiqin , Feng runhua , Su liping , Zhu zhenggang , Liu bingya 
Published: August 2012

Abstract
Objectives: To expore miRNA expression pattern in gastric cancer and investigate the role of miRNAs in the tumorigenesis of gastric cancer. Methods: We globally analyzed the miRNA expression profile in 9 gastric cancer cell lines and 6 normal gastric mucosa and the tumor tissues and its corespending adjacent normal tisuues of 30 patients through miRNA microarray. The differential expression of miRNAs from miRNA microarray were confirmed by qRT-PCR. Then, we extended our assay to sixty paired gastric cancer tissues and the relationship between miR-126 expression level and clinicopatholoic variables was explored. The specific miR-126 precursor or miR-126 expression vector were transfected into gastric cancer cell line SGC-7901 to up-regulate miR-126 expression and its biological effects on SGC-7901 cells were investigated. Finally, the target gene of miR-126 was predicted by bioimformatic method and validated by luciferase reportor system. Results: found that 17 miRNAs were up-regulated in gastric cancer cell lines and 146 miRNAs were down-regulated compared with normal gastric mucosa. Then we performed quantitative real-time PCR of 15 up-regulated miRNAs and 26 logRatio &lt; –5.0 down-regulated miRNAs in gastric cancer cell lines and gastric cancer tissues for further analysis. The coincidence of microarray data and qPCR results was in an acceptable range and 15 miRNAs were finally selected. These candidate miRNAs were associated with gastric cancer clinicopathology in different degree. Meanwhile, high expression of hsa-miR-93 and hsa-miR-409-3p were found to predict poor survival (median, 16 months vs 40 months, LogRank p &lt; 0.05). we show that miR-126 is significantly down-regulated in gastric cancer tissues and associated with clinicopathological features such as tumor size, lymph node metastasis, local invasion and TNM stage. Ectopic expression of miR-126 in SGC-7901 gastic cancer cells potently inhibits cell growth by inducing cell cycle arrest at G1 phase, migration and invasion in vitro and tumorigenicity in vivo. Mechanistically, we identify adaptor protein Crk as a target of miR-126. Taken together, our findings demonstrate miR-126 may function as a tumor suppressor in gastric cancer through regulation of genes such as Crk. Conclusions: These findings may suggest vital roles of miRNAs in huamn gastric cancer, and provide clues for understanding the molecular basis of miRNAs in various biological processes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4141. doi:1538-7445.AM2012-4141
Abstract 4143: microRNA-874 as a tumor suppressor in maxillary sinus squamous cell carcinoma based on microRNA expression signature
Authors: Hanazawa Toyoyuki , Nohata Nijiro , Kinoshita Takashi , Kikkawa Naoko , Fuse Miki , Chiyomaru Takeshi , Yoshino Hirofumi , Enokida Hideki , Nakagawa Masayuki , Okamoto Yoshitaka , Seki Naohiko 
Published: August 2012

Abstract
(BACKGROUND) Maxillary sinus squamous cell carcinoma (MSSCC) comprises 2-3% of all cancers of head and neck tumor and the annual incidence rate is 0.5-1.0 per 100,000 populations. After introduction of multimodality treatment comprising radiation therapy along with concomitant intra-arterial chemotherapy, rates of local control was improved. However the prognosis of advanced MSSCC is still worse. The 5-years survival rate of T4 tumors is 50% around. Local recurrence is the most common cause of treatment failure and death. Greater understanding of the molecular oncogenic network in MSSCC could help improve diagnosis, therapy, and prevention of the disease. No studies have been carried out for the purpose of identifying specific microRNA (miRNA) alterations in MSSCC. In this study, we focused on the functional siginificance of the most downregulated miRNA in MSSCC on the basis of miRNA expression signature. (METHODS) We used PCR-based methods to investigate the downregulated miRNAs in clinical specimens of MSSCC. Genome-wide gene expression analysis was performed to identify the molecular networks of microRNA-874 (miR-874) by microarray technique. Cell proliferation and invasion assays were performed to investigate the functional significance of miR-874 and its target genes in MSSCC cell lines. (RESULTS) Our miRNA signature identified that 23 miRNAs were significantly reduced in cancer cells. We focused on miR-874 as the most downregulated novel miRNA in our analysis. Ectopic miR-874 overexpression showed potential tumour suppressive functions such as inhibition of cancer cell proliferation and invasion. A molecular target search of miR-874 revealed that protein phosphatase 1, catalytic subunit, alpha isozyme (PPP1CA), proteasomal ATPase-associated factor 1 (PAAF1) and trans-golgi network protein 2 (TGOLN2) were regulated by miR-874. Overexpression of these genes was observed in MSSCC clinical specimens and each gene expression was inversely correlated with miR-874 expression. Moreover, silencing of the PPP1CA gene significantly inhibited cancer cell proliferation and invasion. (CONCLUSION) The downregulation of miR-874 was a frequent event in MSSCC, which suggests that miR-874 functions as a tumour suppressive miRNA, directly regulating PPP1CA that has a potential role of an oncogene. The identification of novel miR-874-regulated cancer network could provide new insights into potential molecular mechanisms of MSSCC oncogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4143. doi:1538-7445.AM2012-4143
Abstract 4193: TNF-α dynamically modulates genome-wide cross-regulation of cRel, ΔNp63 and TAp73 promoter binding and gene expression in head and neck cancer: TP53 and NFκB ChIP-Seq in HNSCC
Authors: Si Han , Lu Hai , Yang Xinping , Jang Minyoung , Burnett Jeffery , Davis Sean , Sun Hong-wei , Xiao Wenming , Wei Lai , Meltzer Paul , Waes Carter Van , Chen Zhong 
Published: August 2012

Abstract
We previously showed that cRel, ΔNp63, and TAp73, members of NF-kappaB and TP53 transcription factor (TF) families, together regulate broad biological processes critical for inflammation and cancer survival. However, the underlying molecular mechanisms explaining the global cross-regulation of transcriptome and interactive signal network have not been revealed. Here, we demonstrate that inflammatory cytokine TNF-α induces a dynamic, genome-wide increase in cRel and ΔNp63 chromatin occupancy after replacing TAp73 binding activity, using Illumina Next Generation ChIP-sequencing and fitting the data into a dynamic Poisson distribution model integrated in MACS. Globally, significant binding peaks (p&lt;10-5) were highly enriched in promoter regions (∼10%). These binding peaks further showed significant enrichment around transcription starting sites (±2000bp), and co-localized peaks for any of the two TFs were prevalent within a distance of ∼200 bp. De novo motif search using Gibbs Sampler indicated that cRel and ΔNp63 bound to p53 motifs while TAp73 binding switched from p53 to AP1 motifs when treated with TNF-α. Motifs from these TFs also co-localized within ∼200 bp. Binding activities of individual transcription factors were validated by ChIP-PCR and oliogo-ELISA based binding assays. In addition, TNF-α modulated 1050 differentially expressed genes detected by microarray, of which one-third exhibited binding activity for at least one TF, and 73 genes were identified with co-binding activities for the three TFs simultaneously. Ingenuity Systems Pathway Analysis (IPA) and Gene Ontology revealed that these genes are enriched in cancer-related transcription factors and signaling pathways. Our data suggest a novel mechanism of genome-wide replacement of TAp73 by cRel and ΔNp63, supporting cross-regulation and interactive network between NF-kappaB and TP53 families.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4193. doi:1538-7445.AM2012-4193
Abstract 4198: Transcriptional regulation of breast cancer microRNAs by GATA3 and TFAP2A
Authors: Huang Simo , Yee Kathy , Bockhorn Jessica , Kim Sun , Huo Dezheng , Olopade Olufunmilayo , Liu Huiping , Greene Geoffrey 
Published: August 2012

Abstract
Metastasis remains a major obstacle in the successful treatment of breast cancer because it is responsible for an estimated ninety percent of breast cancer related deaths. An emerging field in the understanding of breast cancer metastasis is the study of microRNAs (miRNAs) which are short nucleotide sequences shown to be involved in the regulation of cell self-renewal, epithelial-to-mesenchymal transition (EMT) and cancer progression [1]. Our previous data suggested that miR-200 and other miRNAs regulate EMT and breast cancer metastasis [2]. Given the significant roles of miRNAs and their modulated levels in cancer, it is important to understand their regulatory mechanisms. We hypothesize that miRNAs are transcriptionally regulated in breast cancer. Our preliminary data with clinical breast cancer specimens suggests correlative relationships between transcription factors TFAP2A and GATA3 with mir-200a and other miRNAs. The goal of this project is to determine whether TFAP2A and GATA3 regulate these miRNA levels in breast cancer cells. Using quantitative real-time PCR, the miRNA levels were measured in MDA-MB 231 breast cancer cells with modulated expression of GATA3 or TFAP2A. The results show that overexpression of GATA3 in MDA-MB 231 cancer cells significantly increased the expression of miRNAs aberrantly downregulated in ER- breast tumors, such as miR-138. Chromatin-immunoprecipitation and reporter luciferase assays will be used to determine whether the regulation of miRNAs by GATA3 and TFAP2A is a direct transcriptional regulation. 1. Mani, S.A. et al., 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 70415. 2. Park, S.M. et al., 2008. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22, 894-907.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4198. doi:1538-7445.AM2012-4198
Abstract 4200: Translation initiation factor eIF3b expression and its role in cancer cell growth and metastases
Authors: Wang Hong , Wang Xuejiao , Ru Yuanbin , Conaway Mark R. , Kieft Jeffery S. , Theodorescu Dan 
Published: August 2012

Abstract
The initiation of translation in eukaryotes is promoted by multi-protein eukaryotic initiation factor complexes (eIFs). While several eIF subunits are overexpressed in cancer, very few have been conclusively implicated as drivers of human cancer phenotypes. Through a transcriptomic analysis of human bladder cancer our studies suggested that eIF3b, considered to be the major scaffolding subunit within the eIF3 complex, is elevated compared to normal urothelium. We went on to functionally evaluate eIF3b in human bladder cancer by siRNA depletion in UMUC3 and lul2 human bladder cancer lines. This reveled that expression of eIF3b was important for anchorage dependent and independent cell growth and G1 to S cell cycle transition. Depletion of eIF3b also inhibited cell migration in vitro and this was associated with disruption of actin cytoskeleton organization and focal adhesion formation through integrin [[Unsupported Character - Symbol Font &#61537;]]5, which in turn decreased FAK phosphorylation and downstream Akt phosphorylation. We also observed the similar results from PC3 prostate cancer cells. In vivo, UMUC3 and lul2 cells depleted of eIF3b formed smaller tumors that grew more slowly following subcutaneous inoculation and these cells formed fewer lung metastases following intravenous inoculation. This data provides the first demonstration of a causal role of eIF3b in human cancer cell phenotypes in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4200. doi:1538-7445.AM2012-4200
Abstract 4214: Identifying cell surface receptor VAP targets to sensitize melanoma to chemotherapy
Authors: Sun Xiaowen , DeMali Kris A. 
Published: August 2012

Abstract
Melanoma accounts for 79% of all skin cancer deaths. The incidence rate has doubled throughout the past three decades, while the survival rate remains consistently low. Melanoma is unusually lethal as it metastasizes early and is highly resistance to all available chemotherapeutics. The newest treatment utilizes a small inhibitor targeting the BRAF pathway, considering the BRAF V600E mutation occurs in 65% of clinical melanoma cases. Unfortunately, it is clear that there is both primary and acquired resistance to the drug. Recent studies demonstrate that engaging defective cell surface adhesion receptors known as integrins increases the sensitivity of melanoma to traditional DNA damaging agents. Our laboratory has identified a novel peptide denoted vinculin activating peptide (VAP) that increases integrin engagement from within the cell by targeting the integrin cytoplasmic binding partner, vinculin. Furthermore, VAP sensitizes melanoma to DNA damaging agents in vitro and in vivo. The goal of this project is to identify the cell surface target of VAP. Both α1and β3 integrins are highly over-expressed in melanoma, suggesting that VAP targets one or both of these defective integrins. To test this possibility, melanoma cells lacking β1 or β3 integrins were generated. In the absence of β1 integrins, VAP did not induce elevations in p53 levels or increase apoptosis in melanoma cell lines treated with cytotoxic agents. In addition, its ability to sensitize melanoma cells to therapeutics in biological assays was ablated. Furthermore, the β1 integrin-dependency of VAP's effect was confirmed by examining melanoma cells lacking β3 integrins. Ongoing experiments are testing the requirement for β1 integrin in mouse models of melanoma. Taken together, these findings suggest that β1 integrins are required for VAP to sensitize melanomas to chemotherapy agents. The successful completion of these studies will provide the mechanistic underpinning for a new class of therapeutics that sensitize melanomas to chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4214. doi:1538-7445.AM2012-4214