bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5556: Role of the aberrant intracellular iron metabolism in rat liver carcinogenesis
Authors: Shpyleva Svitlana I. , Muskhelishvili Levan , Tryndyak Volodymyr , Beland Frederick A. , Pogribny Igor 
Published: June 2012

Abstract
Intracellular iron homeostasis in normal cells is tightly regulated by the coordination of several proteins that are responsible for the uptake, intracellular storage, and removal of iron from cells. Cancer cells, including liver cancer cells, are characterized by profound abberations in intracellular iron metabolism. Dysregulated iron homeostasis has been found not only in rodent and human hepatocellular carcinomas, but also in several preneoplastic pathological states associated with liver cancer development; however, the precise mechanistic role of iron metabolic disturbances in the initiation and early progression of liver carcinogenesis has remained unexplored. In the present study, using an in vivo model of rat hepatocarcinogenesis induced by 2-acetylaminofluorene, we found extensive alterations in cellular iron metabolism at preneoplastic stages of liver carcinogenesis characterized by a substantial decrease in the levels of cytoplasmic non-heme iron in initiated hepatocytes and altered expression of the major genes responsible for the proper maintenance of accurate intracellular homeostasis. Specifically, analysis of the gene expression patterns revealed prominent up-regulation of the ferroportin (Fpn) gene and down-regulation of the hepcidin (Hamp) gene in the preneoplastic livers. This indicates that the decreased intracellular levels of non-heme iron in preneoplastic foci may be attributed to increased iron export from the cells driven by the loss of an inhibitory effect of hepcidin on Fpn. This suggestion is supported by a substantial up-regulation of Fpn (3-fold) compared to transferrin receptor (Tfrc) gene, (1.6 fold), the latter of which is responsible for the iron intake into cell. These data indicate that in preneoplastic livers there is a disruption in the balance of regulatory networks controlling cellular iron uptake and export. Interestingly, we detected similar gene expression changes in initiated preneoplastic liver cells that were transformed by culturing of non-tumorigenic TRL-1215 rat liver cells in the presence of iron. In conclusion, our results demonstrate the significance of altered intracellular iron metabolism in the progression of liver carcinogenesis and suggest that correction of these alterations may affect liver cancer development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5556. doi:10.1158/1538-7445.AM2011-5556
Abstract 5565: Differential changes of proteome profiles in the dorsal-lateral vs. ventral prostate of during TRAMP carcinogenesis
Authors: Zhang Jinhui , Wang Lei , Zhang Yong , Lu Junxuan 
Published: June 2012

Abstract
The transgenic adenocarcinoma of mouse prostate (TRAMP) model is being widely used in the field of prostate cancer chemoprevention. As is understood today, the TRAMP represents at least two models of prostate carcinogenesis in the dorsal-lateral prostate (DLP, epithelial) and ventral prostate (VP, neuroendocrine). However, the molecular basis for the two lobe-specific lineages of carcinogenesis is poorly defined. To this end, we profiled concurrently the proteomes of DLP and VP lobes from the prostate of both TRAMP and wild type littermate C57BL/6 mice at the age of 17-18 weeks by 2D LC-MALDI-TOF/TOF with iTRAQ labeling. Totally 748 proteins were identified. In wild-type mice, 84 proteins were found to have different expression levels (cut-off 20%) between DLP and VP, including experimental autoimmune prostatitis antigen 2 (EAPA2), beta-tropomyosin, heat shock protein 5 (GRP78) and clusterin. In TRAMP mice, 118 proteins were found to be significantly changed in DLP and/or VP during TRAMP carcinogenesis. Among these 118 proteins, 55 and 36 proteins were uniquely changed in DLP or VP lobe, respectively, and 27 proteins in both DLP and LP lobe. 24 of the 27 proteins shared the same trend, albeit the extent of change was not exactly the same. Those shared changes such as up-regulation of HMGB 1&2 and down-regulation of calponin-1 indicated possible common molecular events associated with TRAMP carcinogenesis. The other three proteins, clusterin, polymeric immunoglobulin receptor and aldose reductase went in opposing directions in DLP versus VP during carcinogenesis. Those three proteins, as well as other proteins changed only in DLP or VP (e.g. EAPA2 in DLP and alpha-2-macroglobulin in VP), are more likely related to lobe-specific mechanisms of carcinogenesis. The lobe-specific and TRAMP-related expression patterns of GRP78 and clusterin were further validated by western blot. Ingenuity Pathway Analysis identified 14-3-3 zeta/delta (up-regulated only in DLP), epidermal growth factor (EGF, up-regulated only in DLP) and NF-κB as distinct inferred network nodes in TRAMP carcinogenesis in DLP lobe, whereas ERK1/2 and FGF2 were recognized as network nodes in VP lobe during carcinogenesis. Additional experiments confirmed lobe-specific expression patterns of NF-κB p65 and FGF2 in both wild type and TRAMP mice. Overall our data-sets highlight different mechanisms were likely involved in modifying carcinogenesis in DLP and VP.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5565. doi:10.1158/1538-7445.AM2011-5565
Abstract 5584: Green tea polyphenols inhibit histone deacetylases and modulate p53 transcriptional activities in human prostate cancer cells
Authors: Gupta Karishma , Thakur Vijay S. , Bhaskaran Natarajan , Gupta Sanjay 
Published: June 2012

Abstract
Inhibitors of histone deacetylases (HDACs) are emerging as a promising class of anticancer drugs. HDAC inhibitors have been demonstrated to induce cellular activities similar to p53-mediated responses such as induction of cell cycle arrest and apoptosis in various malignant cells. Green tea polyphenols (GTP) have shown protective effects against development and progression of various human cancers. GTP-mediated cellular responses include p53 activation, cell cycle arrest and induction of apoptosis in cancer cells. In the present study, we sought to determine whether GTP-mediated cellular responses are similar to that elicited by HDAC inhibitors. For these studies, we used human prostate cancer LNCaP cells, possessing wild-type p53, infected with short hairpin (sh) RNA vector and sh-p53 RNA vector to generate isogenic cell lines. Knockdown of p53 in LNCaP cells caused an increase in the activity of class I HDACs with specific increase in the protein expression of HDAC viz. 1 and 8, respectively. Treatment of both cell lines with 20, 40 and 80 mcg/mL doses of GTP for 24 h resulted in dose-dependent decrease in the total HDAC activity and protein expression of HDAC 2, 3 and 8 and HDAC 1, albeit at highest GTP dose. Similar dose-dependent responses were achieved by trichostatin A (TSA), a well known pharmacological inhibitor of class I and II HDACs in these cells. Interestingly, chemosensitization by GTP was more pronounced in the cells expressing p53 than the isogenic cell lines lacking p53 as observed by cell cycle analysis and annexin V flow cytometric analysis. Furthermore, GTP treatment resulted in marked increase in acetylation of p53 at its C-terminal amino acid positions K373 and K382, other than K305 along with increase in the acetylated forms of histone H3 and H4 which correlated with increased p53 expression, cell cycle arrest and apoptosis. Taken together, these results suggest that interaction of HDACs with p53 probably results in p53 deacetylation, thereby reducing the transcriptional activity; whereas GTP has the ability to cause deacetylation of p53 by reducing the levels of class I HDACs. This seems likely to be, in part, the mechanism for GTP-mediated p53 activation, a similar response elicited by HDAC inhibitors, which are developed as a promising class of drugs for the treatment of various human malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5584. doi:10.1158/1538-7445.AM2011-5584
Abstract 5593: Are variants in the syndecan-1 gene associated with breast cancer risk in older women
Authors: Madeleine Margaret M. , Resler Alexa J. , Johnson Lisa G. , Malkki Mari , Petersdorf Effie W. , McKnight Barbara , Malone Kathleen E. 
Published: June 2012

Abstract
Syndecans are transmembrane proteins on the cell surface that act as receptors for ligands from a number of protein families. These proteoglycans are involved in a large number of important normal cell functions, including signaling, proliferation, and cell-matrix adhesion; they are also involved in aberrant cell functions such as inflammation, angiogenesis, and carcinogenesis. In a recent pathway directed re-analysis of GWAS data (Menashe, Cancer Research, 2010), variants in the syndecan-1 (SDC1) gene on chromosome 2p were found to be associated with excess risk of breast cancer. We sought to extend this finding by investigating the association between tagging SNPs in the SDC1 gene and risk of breast cancer in our case-control study (The PACE study) in older women. This population-based study includes 845 women who were 65-79 years old at diagnosis of incident breast cancer and 807 age-matched unaffected controls from the Seattle area. The analysis was restricted to Caucasian women. A total of 11 SNPs were chosen to represent 10 bins using Snagger, with double coverage of one large bin. Five SNPs failed genotyping, leaving six SNPs for analysis. At the gene level, a P-min permutation test was not significant for SDC1 (p=0.10). Three SNPs, rs10495704, rs2002090, and rs3771240, were in high linkage disequilibrium in our controls (r2 0.81-0.87) and all three were separately associated with marginally increased risks of breast cancer (OR 1.2, 95% CI 1.0-1.4). One of these SNPs, rs10495704, is in the 5’UTR and thus could be associated with protein processing. No excess risk of breast cancer was associated with the other three SDC1 variants: rs4432408, rs2348478, or rs2015110. A similar pattern of marginally increased risk for the three polymorphisms in high LD (rs10495704, rs2002090, and rs3771240) was found in two subsequent analyses restricted to women with ductal histology and luminal type tumors. We are currently assessing other genes related to inflammation that may be related to breast cancer risk in this study population. The data for SDC1 in the PACE study cannot rule out a modest association with breast cancer risk.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5593. doi:10.1158/1538-7445.AM2011-5593
Abstract 5599: Screening for large genomic rearrangements in the FANCA and FANCJ genes reveals extensive genomic FANCA deletion in a Finnish breast cancer family
Authors: Solyom Szilvia , Winqvist Robert , Nikkilä Jenni , Pylkäs Katri 
Published: June 2012

Abstract
A portion of familial breast cancer is accounted for by mutations in the same genes that are inactivated in Fanconi anemia (FA). In the current study we set out to evaluate the role of large genomic rearrangements in the FANCA and FANCJ/BRIP1 genes in Finnish breast cancer families. Mutations in the upstream FANCA gene account for the majority of FA patients, and about one-third of all FANCA mutations are large intragenic deletions. Based on the gene's hypermutable nature, the protein's interaction with BRCA1 and its involvement in genomic integrity maintenance, we considered FANCA as a candidate for breast cancer susceptibility. In FANCJ, which is a downstream FA and known breast cancer susceptibility gene, early truncating mutations have been reported, but no large deletions have been recognized so far.
For the present study, blood DNA from affected index persons of 100 Northern Finnish breast cancer families were assessed for possible constitutional exonic deletions or amplifications in FANCA and FANCJ by using the multiplex ligation-dependent probe amplification (MLPA) method.
We identified a novel large heterozygous FANCA deletion in one of the studied breast cancer families, removing the promoter region and the first 12 exons of the gene. The defective allele was absent from all of the tested 124 controls as well as 540 unselected breast cancer cases, but was present in the father of the index patient having pancreatic cancer. No large deletions in FANCJ were uncovered.
We conclude that large FANCA deletions might contribute to breast cancer susceptibility, therefore more extensive studies on their involvement in the disease are needed. To our knowledge, this is the first report on the existence of a large-size genomic deletion in an upstream FA gene in association with familial breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5599. doi:10.1158/1538-7445.AM2011-5599
Abstract 5614: Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: Findings from the Breast Cancer Association Consortium
Authors: Figueroa Jonine D. , Garcia-Closas Montserrat ,   Studies from the Breast Cancer Association Consortium (BCAC), Easton Douglas , Spurdle Amanda 
Published: June 2012

Abstract
A recent genome-wide association study identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as markers of susceptibility for breast cancer. Using case-control studies from the Breast Cancer Association Consortium (BCAC), we sought to estimate more precisely the breast cancer risk associated with these loci, and investigate if these risks differ by breast tumor characteristics. Analyses included genotyping data from rs11249433 (1p.11.2) and two highly correlated SNPs at 14q24.1 (RAD51L1) (rs999737or rs10483813, r2=0.98) on up to 46,748 breast cancer cases and 47,048 controls from 39 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity by tumor characteristics was assessed using polytomous logistic regression models for multiple level outcomes, and tested using case-only analyses with tumor characteristics as the outcome. Tumor characteristics evaluated were estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and histopathological type. We confirmed that both rs11249433 (per allele OR and 95%CI 1.10, 1.08-1.12 P=3.2×10−22) and 14q24.1 SNPs rs999737/ rs10483813 (per allele OR and 95%CI 0.92, 0.90-0.94, P=9.21×10−14) are associated with invasive breast cancer risk. SNP rs11249433 was associated with ER-positive but not ER-negative breast cancer (P-heterogeneity =0.00008) and PR-positive but not PR-negative breast cancer (P-heterogeneity=0.007). SNP rs11249433 showed stronger associations with ER-positive tumors of lower grade (P-heterogeneity =6.67 x103) and lobular compared to ductal tumors (P-heterogeneity =0.01). In contrast, there was no evidence that the OR for rs999737/ rs10483813 differed by ER, PR, HER2, grade, node status, tumor size, or histopathological type, and in particular was associated with both ER-positive and ER-negative disease. Further studies aimed at identifying the causal variants in these regions and the biological mechanisms underlying these associations are warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5614. doi:10.1158/1538-7445.AM2011-5614
Abstract 57: Integrating transcriptome profiling and in silico pathway analysis toward reduction of therapeutic dimensionality in nasopharyngeal carcinoma
Authors: Bao Ying-Na , Dai Yilin , Yan Yongpan , Lu Wen-Hua , Peng Li-Xia , Zheng Fang-Jing , Li Xin-Jian , Kang Tie-Bang , Zeng Yi-Xin , Trent Jeffrey M. , Qian Chao-Nan 
Published: June 2012

Abstract
Nasopharyngeal carcinoma (NPC) has its highest incidence in southern China and Southeast Asia. In order to obtain deeper insights into the molecular mechanism of NPC tumorigenesis, we performed genome expression profiling combined with computerized pathway analyses on 18 NPC tissues and 18 age-matched tissues of non-cancerous nasopharyngeal mucosa from individuals in the endemic area, Guangdong province, China, between Dec 2007 and Oct 2010. Gene expression profiling was performed using an Agilent gene expression kit and Agilent 4×44K microarray gene chips. One-way analysis of variance was used to identify the genes differentially expressed between cancer and non-cancerous tissues. Genes with a false discovery rate of less than 0.001 and a fold-change larger than 2 or less than 0.5 were selected for in silico network mapping combined with pathway analysis using GeneGo software. Pathways were prioritized based on the gene enrichment analysis. The genes’ connectivity was also integrated to identify the regulatory hotspots in the key pathways. Genes within or surrounding these hotspots constitute potential therapeutic targets. Genes previously known to be up-regulated in NPC that were detected in our study included CCND1, CDKN1A, STAT1, BCL2A1, SGK1, RAI14, FOXM1, EPHB2, PMAIP1, COL1A1, GADD45A, ICAM1, FANC1, ZWINT, LAMB3, CKAP4, ISG15, and MMP3; known down-regulated genes included ATM and INPP5D. However, what was of interest was the identification of a series of previously unrecognized genes: those up-regulated more than 10-fold included MMP1, HOXC8, KREMEN2, and HOXA1, and those down-regulated more than 10-fold included LTF, C7, SHISA3, SKLC26A7, and C16orf89. Although the deregulated pathways in NPC encompass many cytological functions, pathway analysis has been helpful in ranking a series of the most significant deregulated pathways, which include ECM remodeling pathways; alternative complement pathway; plasmin signaling pathway; the TGF, WNT, and cytoskeletal remodeling pathways; leukocyte chemotaxis pathway; and the BAFF and PLAU signaling pathways. Results will be presented on key genetic changes within these pathways that have been verified by biologically. In conclusion, we are beginning to recognize key genes and pathways, prioritized by pathway analysis, that appear likely to identify possible novel mechanisms of NPC tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 57. doi:10.1158/1538-7445.AM2011-57
Abstract 572: Suppression of urokinase plasminogen activator receptor blocks recruitment of endothelial cells by inhibiting irradiation-induced monocyte chemo-attractant protein-1 in meningioma
Authors: Nalla Arun Kumar , Gogineni Venkateswara Rao , Gupta Reshu , Rao Jasti S. 
Published: June 2012

Abstract
Chemokines, a common outcome of inflammatory reaction, play a vital role in recruiting various cell types during tissue repair. Radiation, a major therapeutic modality in cancer treatment, has been described to induce inflammatory response, which might lead to the expression of several chemokines. In the present study, we investigated the mechanisms underlying radiation-induced monocyte chemo-attractant protein (MCP-1) in meningioma cell lines and the paracrine effect on human microvascular endothelial cells (HMEC). Upon radiation, meningioma cell lines (IOMM Lee and SF 3061) showed an increased expression of MCP-1. In addition, irradiated meningioma cancer cell culture conditioned medium (CM) demonstrated an increased ability to attract HMEC and stimulated MCP1-induced protein (MCPIP), VEGF and angiogenin expression in HMEC as compared to HMEC grown in non-irradiated cancer cell CM. This chemotactic activity and angiogenic stimulator effect in HMEC was nearly abrogated by depleting MCP-1 from the irradiated cancer cell CM using a neutralizing anti-MCP-1 monoclonal antibody. Inhibition of ERK activation and NF-κB nuclear translocation hindered irradiation-induced MCP-1 expression in both meningioma cell lines. Considering that radiation induces uPA/uPAR expression and stimulates the ERK signaling pathway, we correlated the role of irradiation-induced uPA/uPAR in MCP-1 regulation. Supplementing cancer cells with exogenous ATF-uPA (with and without radiation) activated ERK phosphorylation, nuclear translocation of the NF-κB p65 sub-unit (Rel-A), and MCP-1 expression. Downregulation of uPA and uPAR by transfecting the cancer cells with a siRNA-expressing plasmid (pU) inhibited irradiation-induced ERK activation, nuclear translocation of Rel-A, NF-κB DNA binding activity, and MCP-1 expression. Further, pU-transfected cancer cells (with or with radiation) reduced the potential to attract and stimulate angiogenic signaling in HMEC under in vitro conditions. Under in vivo conditions, we observed that pU transfected cancer cells (with and without irradiation) showed a significant reduction in number of CD31+ endothelial cells and CD14+ monocytes present in the tumor regions compared to tumor formed from irradiated cancer cells. In conclusion, we demonstrated that blockade of uPA/uPAR expression inhibits irradiation-induced MCP-1, thereby inhibiting the chemo-attractant ability of cancer cells to recruit other cells during the inflammatory process induced by radiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 572. doi:10.1158/1538-7445.AM2011-572