bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4118: Hypoxia affects the metabolic activation and detoxification of the environmental mutagen benzo(a)pyrene
Authors: Schooten Frederik-Jan Van , Schults Marten , Sanen Kathleen , Godschalk Roger , Theys Jan , Chiu Roland 
Published: August 2012

Abstract
Hypoxia is characteristic for a number of pathologies and promotes genetic instability, as exposure to low oxygen levels results in an elevated mutation frequency. We have previously shown that activation of the hypoxia responsive transcription factor HIF-1α, in the presence of sufficient oxygen, enhanced mutation frequencies induced by the environmental mutagen benzo[a]pyrene (BaP). Since proper carcinogen metabolism depends on oxygen we examined how varying oxygen levels influenced BaP metabolism by studying its activation and deactivation. The human lung carcinoma cell line A549 was treated with BaP under different oxygen concentrations (20%, 5%, and 0.2%) for 18 hours and alterations in BaP-metabolism were determined. First, we analyzed the BaP induced expression of key metabolic enzymes; expression levels of CYP1A1 and CYP1B1 was higher under hypoxia, while expression of the detoxifying enzymes UGT1A6 and UGT2B7 were significantly reduced by hypoxia. Then, several BaP metabolites in supernatants were determined by HPLC-fluorescence detection. In general, low oxygen levels lead to slower metabolism of BaP leaving more of the parent molecule intact. At the same time, BaP-7,8-dihydrodiol, the pre-cursor metabolite of the reactive metabolite BaP-7,8-dihydroxy-9,10-epoxide (BPDE), was formed in higher concentrations under hypoxia. Finally, under hypoxia DNA adducts accumulated over a period of 168 hours, whereas DNA adducts were efficiently removed under 20% oxygen, eventually leading to 1.6 times higher adduct levels under hypoxic conditions. These data indicate that the metabolism has shifted towards increased activation of BaP instead of detoxification under hypoxic conditions. These data support the idea that modulation of carcinogen metabolism may be an important additional mechanism for the observed HIF1 mediated genetic instability.
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 4118. doi:1538-7445.AM2012-4118
Abstract 4121: Glycine N-methyltransferase deficiency affects hepatic cholesterol homeostasis and steatosis-associated inflammation
Authors: Fang Cheng-Chieh , Liao Yi-Jen , Chen Yi-Ming 
Published: August 2012

Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder with excess accumulation of lipid within hepatocyte. Severe NAFLD is associated with inflammation and contributes to the development of hepatocellular carcinoma (HCC). Previously, we reported that glycine N-methyltransferase knockout (Gnmt-/-) mice develop chronic hepatitis and HCC. The aim of this study was to understand the role of GNMT and its interactive proteins play in the pathogenesis of NAFLD. Firstly, we found that Gnmt-/- mice had hyperlipidemia and steatohepatitis and GNMT was down-regulated in the liver tissues from patients with NAFLD as well as from mice fed with high fat diet, high cholesterol diet or methionine/choline deficient diet. Besides, Q-PCR showed that the liver tissues of Gnmt-/- mice had higher levels of TNF-α, IL-6, IL-12p40 and IL-1α than the wild-type mice. Single photon emission computed tomography images demonstrated that Gnmt-/- mice had slower hepatic cholesterol uptake and excretion rates than the wild-type mice. Yeast two-hybrid screenings and co-immunoprecipitation assays elucidated that the Niemann-Pick type C2 protein (NPC2) interacts with GNMT. Confocal microscopy demonstrated that NPC2 was released from lysosomes and interacts with GNMT in the cytosol when cells were treated with low density lipoprotein. Over-expression of GNMT prolonged the half-lives of both NPC2 isoforms and reduced cholesterol accumulation in cells. In conclusion, we demonstrated that GNMT regulates the homeostasis of cholesterol metabolism and steatosis-associated inflammation. This study provides novel targets for the prevention and treatment of steatohepatitis and HCC.
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 4121. doi:1538-7445.AM2012-4121
Abstract 4122: Induction of steroid sulfatase expression by bacterial lipopolysaccharides in human prostate cancer cells: Possible role of STS in tumor cell migration
Authors: Im Hee-Jung , Park Nahee , Chun Young-Jin 
Published: August 2012

Abstract
Steroid sulfatase (STS) is responsible for the conversion of estrone sulfate to estrone that can stimulate growth in endocrine-dependent tumors such as breast and prostate cancer. Although STS is considered as a therapeutic target for the estrogen-dependent diseases, cellular function of STS are still not clear. Previously, we found that tumor necrosis factor (TNF)-α significantly enhances steroid sulfatase expression in PC-3 human prostate cancer cells through PI3K/Akt-dependent pathways. Here, we studied whether bacterial lipopolysaccharides (LPS) which are known to induce TNF-α may increase STS expression. Treatment with LPS in PC-3 cells induces STS mRNA and protein in concentration- and time-dependent manners. Because LPS-induced STS mRNA expression was strongly suppressed by NF-κB inhibitors such as Bay 11-7082 and bortezomib, the involvement of NF-κB pathways on STS expression was suggested. To determine whether IkBα is involved in NF-κB-dependent STS expression, the effect of IKKα siRNA was elucidated. IKKα siRNA significantly suppressed STS mRNA and protein expression. Interestingly, overexpression of STS by transfecting expression vector induced wound healing effect whereas knockdown of STS by siRNA significantly decreased wound healing effect in PC-3 cells. Moreover, treatment with LPS in STS knockdowned cells recovered wound healing effect. Taken together, these results strongly suggest that STS may contribute tumor cell migration.
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 4122. doi:1538-7445.AM2012-4122
Abstract 4123: Cholesterol and breast cancer
Authors: Danilo Christiane , Mainieri Maria Antonietta , Lisanti Michael P. , Frank Philippe G. 
Published: August 2012

Abstract
Breast cancer is the most commonly diagnosed type of cancer among women with an incidence rate five times greater in the Western world than elsewhere. Relocation studies have ruled out genetics as the sole factor in this discrepancy, since immigrant populations develop breast cancer at rates similar to indigenous Western populations, thus indicating an environmental effect on breast cancer incidence. Amongst possible environmental factors, diet and obesity have long been considered likely risk factors for cancer development. Despite this probability, a specific role of cholesterol in breast cancer has not yet been specifically examined. Cholesterol is an integral component of the plasma membrane and is the precursor to biomolecules such as steroid hormones and vitamins. Epidemiologic evidence indicates that cancer patients display abnormal levels of the cholesterol carrying lipoproteins, high density lipoprotein (HDL) and low density lipoprotein (LDL), thus suggesting a role for cholesterol in breast cancer. Recent research in our laboratory shows that when fed a high fat, high cholesterol diet, PyMT Tg mice, a model of breast cancer, develop larger, more advanced tumor lesions. These mice also develop a significant increase in HDL-cholesterol levels and an increase in the expression of the HDL-C receptor, SR-BI compared to PyMT Tg mice fed a control chow diet. In the present study, we aim to elucidate the role of SR-BI in breast cancer. To do so we manipulate cellular levels of SR-BI in human breast cancer cell lines. In vitro, we show that ablation of SR-BI in human breast cancer cells leads to a decrease in cellular proliferation, migration, and invasion. Xenograft mouse models indicate that SR-BI depletion confers protection against tumor growth in vivo with concomitant dysregulation of key mitogenic signaling pathways. These results suggest a role for SR-BI in breast cancer.
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 4123. doi:1538-7445.AM2012-4123
Abstract 4125: Suppression of the mevalonate pathway and oncogenic signaling may underlie the tumor-suppressing effects of KLK5 in breast cancer
Authors: Pampalakis Georgios , Obasuyi Osahon , Papadodima Olga , Chatziioannou Aristotelis , Zoumpourlis Vassileios , Sotiropoulou Georgia 
Published: August 2012

Abstract
Kallikrein-related peptidase 5 (KLK5) has been implicated in different types of cancer based on its aberrant expression in tumor cell lines and tissue specimens and in vitro data, however, functional association is missing. Here, we confirmed that KLK5 is very frequently down-regulated or inactivated in breast cancers of different subtypes. Reconstitution of KLK5 expression by stable transfection in KLK5-negative MDA-MB-231 cells remarkably reversed their malignant phenotype both in vitro (wound scratch and soft agar assay) and in vivo (orthotopic xenograft growth in SCID mice). We found that in KLK5 transfectants Snail1 and the mesenchymal marker vimentin were highly downregulated, pointing to a potential involvement of KLK5 in mesenchymal-to-epithelial transdifferentiation, however, re-expression of E-cadherin could not be demonstrated. Importantly, it appears that KLK5 may severely affect the overall output of the proteolytic web as it minimized the proteolytic activities of MMP9 and MMP3. Unexpectedly, transcriptomic profiling revealed that reconstitution of KLK5 expression suppresses the mevalonate pathway of cholesterol biosynthesis by highly up-regulating INSIG1 (insulin induced gene 1), a major negative regulator of HMGCR (3-hydroxy-3-methylgluratyl-CoA reductase), while KLK5 may also affect cholesterol uptake, as the LDLR (LDL receptor) and PCSK9 (proprotein convertase subtilisin-like/kexin type 9), the main regulator of LDLR, were both found significantly upregulated in KLK5 transfectants. A functional role of KLK5 in the regulation of the mevalonate pathway and protein-prenylation circuitries was demonstrated by reduced cellular cholesterol and prenylation levels, end products of this pathway. Reduced prenylation was shown by the remarkable reduction in the levels of activated RhoA, which must be subjected to isoprenylation (mainly geranyl-geranylation) for activation. To our knowledge, this is the first demonstration of a protease involved in the crosstalk between metabolic pathways and oncogenic signaling. Moreover, among the genes found up or down-regulated upon KLK5 re-expression (i.e. the “KLK5 signature”) were several genes known to be involved in atherosclerosis and other lipid-related metabolic disorders. Overall, KLK5 may represent a nodal interconnection of proteolytic and signaling pathways in cancer but may also participate in pathways associated with metabolic diseases, in support of the emerging concept of common genetic networks governing both cancer and lipid-associated disorders.
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 4125. doi:1538-7445.AM2012-4125
Abstract 4126: Synergism of polyamine synthesis inhibition and AMP kinase activation on human melanoma proliferation and migration
Authors: Hsueh Eddy C. , Zhang Yanping , Guangyong Peng 
Published: August 2012

Abstract
Introduction: Metformin has been shown to inhibit human cancer cell growth via activation of MAP kinase with resultant inhibition of mTOR signaling pathway. We have reported the over-expression of ornithine decarboxylase (ODC) in human melanoma cell lines. ODC is a key enzyme in polyamine biosynthesis. We determined the effect of metformin in combination with DMFO, an ODC inhibitor, on tumor proliferation and migration, and the possible mechanisms, using human melanoma cells. Methods: Human melanoma cells were treated with Metformin, DFMO, or combination. Cell proliferation assay was performed using Cell Titer Blue proliferation assay. Cell migration assay was performed by seeding melanoma cells in 24-well plate. After overnight incubation, an artificial homogenous wound was created onto the monolayer with a plastic micropipette tip. After wounding, the migration of cells into the wound was observed at 0- and 48-hour time points. Quantitative RT-PCR for ODC1 detection was performed using Assay-on-Demand Hs00159739-ml. GAPDH served as housekeeping control. Western blotting was performed to determine the expression of AMP kinase, mTOR, p70S6K and 4E-BP1, Raf-1 and Raf-B. Data were presented as means ± SD for the three separate experiments. For comparison between groups, the student's t test was used and p&lt; 0.05 was considered to be statically significant. Results: There was dose-dependent inhibition of melanoma cell proliferation and migration with either metformin or DFMO. Synergistic inhibition was observed with the combination treatment on both cell migration and proliferation. There was synergistic inhibition of ODC expression with the combined treatment compared with DFMO alone (p&lt;0.01). The combination treatment also lead to significant enhancement of AMPK activation and increased phosphorylation of AMPKΨ at Thr-172 compared with metformin alone (p&lt;0.01). The combination treatment resulted in inhibition of mTOR signaling with decreased phosphorylation of mTOR, p70S6K and 4E-BP1, Raf-1 and Raf-B in treated cancer cells, when compared with individual drug treatments. Conclusion: We have observed a synergistic effect of AMP kinase activation and polyamine synthesis inhibition on suppressing human melanoma proliferation and migration. The synergism is due to enhanced inhibition of both polyamine synthesis and mTOR signaling pathways.
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 4126. doi:1538-7445.AM2012-4126
Abstract 4127: MiR-183/96/182 cluster confers cell motile advantages in hepatocellular carcinoma
Authors: Leung Wilson , He Mian , Law Priscilla , Ching Arthur , Chan Anthony , Wong Nathalie 
Published: August 2012

Abstract
Profilings of microRNA expressions in hepatocellular carcinoma (HCC) have highlighted common upregulations of the miR-183/96/182 cluster. We showed in this study concordant over-expression of miR-183, miR-96 and miR-182 can be frequently detected in primary HCC tumors (59%; n=47/80). In addition, miR-183/96/182 up-regulation correlated with metastatic features including presence of microvascular invasion (P&lt;0.05) and advanced tumor differentiation (P&lt;0.01), and poorer disease-free survival of patients (P&lt;0.05). Univariate and multivariate analyses further establish miR-183/96/182 over-expression as an independent prognostic factor (Relative Risk: 2.0471; P=0.0289). Functional knockdown of individual miR-183, miR-96 and miR-182 in two invasive HCC cells indicated significant inhibition on cell migration and invasion (P&lt;0.01), although an effect on cell viability was not apparent. In silico TargetScan analysis showed putative target seed sequences of miR-183, miR-96 and miR-182 on the FOXO1 3′UTR. To verify the possible interaction between miR-183/96/182 and FOXO1 in HCC, we conducted Western blot analysis which showed knockdown of miR-183, miR-96 and miR-182 concomitantly enhanced FOXO1 protein expression. Subsequent reporter assay indicated knockdown of miR-183/96/182 could significantly augmented the luciferase signal of wild-type FOXO1 3′UTR but not mutant (P&lt;0.01). Our finding highlighted over-expression of miR-183/96/182 as an independent prognostic predictor for HCC patients, and the oncogenic role of this miRNA cluster in promoting HCC cell motility, possibly via FOXO1 repression.
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 4127. doi:1538-7445.AM2012-4127
Abstract 413: Genome-wide microarray expression and array-CGH analysis in neuroblastoma stem-like cells by use of the neurosphere-formation assay
Authors: Gallo Gabriel , Legarra Sheila , Fan Xing , Pata-Merci Noemie , Guegan Justine , Danglot Gisele , Bernheim Alain , Castresana Javier S. 
Published: August 2012

Abstract
In this work, we aimed at analyzing genome-wide gene expression and DNA gains and losses in neuroblastoma cell lines and in neurospheres containing stem-like cells. SKNDZ and SIMA neuroblastoma cell lines were grown in DMEM cell culture medium, and in DMEM-F12 selective serum free medium (with EGF, bFGF and B27; to induce the neurosphere-forming phenotype). After RNA and genomic DNA extractions from the 4 cell lines (2 standard, 2 neurosphere-forming cell lines), expression microarrays and array-CGH analyses were performed (Aligent Technologies). Array-CGH did not show any significant differences between standard and neurosphere-forming cell lines, both in SKNDZ and in SIMA. Microarray expression analysis demonstrated a total of 425 upregulated and 170 downregulated genes in neurosphere-forming cell lines. The differentially expressed genes were classified using the PANTHER classification system (www.pantherdb.org). As a result, apoptosis, cell adhesion, cell communication, cell cycle, and immune system processes appeared upregulated and downregulated in neurospheres. Some of those genes participate in pathways related with cancer (Table 1). In conclusion, the stem-like phenotype does not seem to be linked to anatomic changes at the level of deletions/gains of DNA, but to changes in expression of genes, like those of the TGF-beta, Notch and Sonic Hedgehog pathways. Those pathways, specially TGF-beta, widely described as an important therapeutic target against cancer, should be further studied to determine their real implication in the neurosphere-formation process in neuroblastoma, and therefore, as candidate targets for the treatment of neuroblastoma stem-like cells.

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 413. doi:1538-7445.AM2012-413
Abstract 4130: Bariatric surgery profoundly changes circulating MicroRNA profile in the rat
Authors: Wu Qianxin , Li Jia V. , Seyfried Florian , Ashrafian Hutan , Gooderham Nigel John 
Published: August 2012

Abstract
Obesity is a worldwide public health issue which can lead to cardiovascular disease, type 2 diabetes, and cancers. Bariatric surgery can provide sustained weight loss and a significant reduction of cancer risk. MicroRNAs are approximately 22 nucleotide long post transcription regulators. MicroRNAs are suggested to play important roles in obesity and metabolic syndrome related biological processes, but also are involved in different types of cancer. Recently microRNAs have been shown to be present in blood, and it is proposed that circulating microRNAs may be biomarker of tissue biochemistry and pathology. The aim of this study is to investigate if the circulation microRNA profile is changed by bariatric surgery and whether the altered microRNA expression could contribute to the long term reduced predisposition cancer risk associated with such surgery. Total plasma RNA from 53 days post bariatric surgery and sham operated rats were isolated and then examined using Taqman Rodent MicroRNA A+B Cards which have the capacity to evaluate expression levels of 373 rat microRNAs. Four different normalization methods (Global, cel-miR-39 spiked in, U6 endogenous and five endogenous microRNAs normalization) were tested. Five endogenous microRNAs normalization was found to be optimal and selected for all downstream analysis. Our preliminary data showed that 113 microRNAs were expressed in the plasma of bariatric surgical rats and 92 in sham operated rats. Furthermore, an OPLS-DA model clearly showed that bariatric surgery changed the circulating microRNA expression profile. Among nineteen of the most significantly changed microRNAs, nine of them are relevant to cancer. In summary, our data suggest that bariatric surgery fundamentally changed circulating microRNA expression. Understanding the significance of these changes in circulating microRNA may give clues to the mechanisms whereby bariatric surgery affords health benefits to individual undergoing such surgery, including a reduced predisposition to disease such as cancer.
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 4130. doi:1538-7445.AM2012-4130