bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5647: EGCG suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the VEGF/VEGFR axis
Authors: Kubota Masaya , Shirakami Yohei , Shimizu Masahito , Adachi Seiji , Moriwaki Hisataka 
Published: February 2011

Abstract
The receptor tyrosine kinase (RTK) vascular endothelial growth factor (VEGF) receptor (VEGFR) plays an important role in tumor angiogenesis of hepatocellular carcinoma (HCC). (−)-Epigallocatechin gallate (EGCG), the major biologically active component of green tea, inhibits growth in a variety of human cancer cells by inhibiting the activation of several types of RTKs. In this study, we examined the effects of EGCG on the activity of the VEGF/VEGFR axis in human HCC cells. The levels of total and phosphorylated (i.e. activated) form of VEGFR-2 protein (p-VEGFR-2) were observed to increase in a series of human HCC cell lines in comparison to the Hc normal human hepatocytes. EGCG preferentially inhibited the growth of HuH7 HCC cells, which express the constitutive activation of the VEGF/VEGFR axis, in comparison to Hc cells. Treatment with HuH7 cells with EGCG caused a time- and dose-dependent decrease in the expression of VEGFR-2 and p-VEGFR-2 proteins. The production of VEGF from HuH7 cells was reduced by the treatment with EGCG. Drinking of EGCG significantly inhibited the growth of HuH7 xenografts in nude mice and this was associated with the inhibition of the activation of VEGFR-2 and its related downstream signaling molecules, including ERK and Akt. EGCG drinking also decreased the expression of Bcl-xL protein and VEGF mRNA in the xenografts. These findings suggest that EGCG can exert, at least in part, its growth inhibitive effect on HCC cells by inhibiting the VEGF/VEGFR axis. EGCG might therefore be useful in the treatment of HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5647.
Abstract 5652: Cytoplasmic expression of estrogen receptors in breast cancers
Authors: Choi Young J. 
Published: February 2011

Abstract
Nuclear expression of estrogen receptor(ER)-A has been used as the prognostic and therapeutic marker for breast cancer. However, ER cytoplasmic expression (CyE) has not gained such support for its contribution to estrogenic response and clinical significance. Membrane ER or unliganded cytoplasmic hormone receptors may represent non-genomic actions of ER or subcellular dislocation during malignant transformation due to inappropriate /dysfunctional trafficking of transcription factors and cofactors. Here, we tested CyE of ERs in breast cancer tissues and breast cancer cell lines (BCC) to further define its role.
Design; Tissue microarray sections of 271 cancers, 45 normals, 62 benign proliferative disease (BPD) of breast tissues and 11 BCC (MCF-7, T-47D, ZR-75, MB-361,MB 468, BT 474, MB-453, SK-BR-3,MB-231, Hs578T, BT-549) were tested by immunohistochemistry for the expression of ER-A (ID5, Dako), 5 different clones of ER-B (AR385-5R, Biogenex; PPG5/10, Dako;Ab288/14C8, ABCAM; EMR02, Novacastra; 57/3, AbD Serotec), Her-2 (HercepTest, Dako), Ki-67, AIB-1 (Clone 34, BD), TIF-2 (Clone 29, BD). Non-specific protein and peptide antigen were blocked by using serum block (Dako, CA) and peptides, respectively. Over 5% positive nuclear and cytoplasmic expression in each tissue core was considered positive.
Results: ER-A-CyE was noted in 9.0% (27/271) of breast cancers; 6 were ER-A-/Her-2+, and 3 were ER-A+/Her-2+. One BCC, BT474 with ER-A+/Her-2+ showed ERA-CyE. ER-B-CyE was noted in 29.1 % (81/271) of cancers and 4 of 11 BCC. CyE of 5 ER-B clones were consistent expression in each breast tissue and BCC. The staining of ER-B-CyE in BCC showed diffuse, membranous or dotted appearance. In breast cancer, that of ER-B-CyE was diffuse and was prominent in high grade cancer with desmoplastic reaction and heavy lymphocytic infiltration. ER-B-CyE was noted in 47.0 % (47/100) of stage IV cancer including recurrent and tamoxifen resistant cancers, and 19.2 0% (33/171) stage I to III cancers. ER-B-CyE was associated with over expression of Her-2 in 22.2% (18/81), Ki-67 in 23.4% (19/81), TIF-2 in 46.5% (38/81) and AIB-1 in 21.0% (17/81). Only cytoplasmic ER-A and ER-B in breast cancer was noted in 3.3% (9/271) and in 8.4% (23/271), respectively. CyE levels in normals and BPD tissues were insignificant.
Conclusion:
Our study demonstrates the potential significance of cytoplasmic ER, particularly ER-B. Proteins translated from single and multiple exon deletion variant transcripts which lack nuclear localization signals may remain in the cytoplasm of breast cancer tissues and contribute to estrogen responses. Further study is in progress to test cytoplasmic expression of various ER isoforms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5652.
Abstract 5658: Quercetin induces tumor-selective apoptosis involving downregulation of Mcl-1 and activation of Bax
Authors: Cheng Senping , Chen Gang , Son Young-ok , Luo Jia , Shi Xianglin 
Published: February 2011

Abstract
Quercetin is a promising antitumor agent that induces apoptosis in a variety of tumor cells. However, the underlying mechanisms how this drug works are unclear. Here we report that administration of quercetin in human leukemia cells resulted in marked release of cytochrome c, cleavage of caspase 8, 9, 7 and 3, and apoptosis. Pronounced apoptosis was also noted in diverse primary leukemia cells but not in normal blood peripheral mononuclear cells. These events were accompanied by Mcl-1 down-regulation, most likely through a rapid dephosphorylation of translation initiation factor eIF4E. Following quercetin, Bax protein underwent conformational change and mitochondrial translocation which triggered cytochrome c release. Knockdown Bax by siRNA partially reversed querctin-induced apoptosis. Essentially, knockout of Bax completely abrogated the activation of caspase 9, 7 and 3, PARP cleavage and apoptosis, indicating that Bax is primarily required for quercetin lethality. Ectopic expression of Mcl-1 attenuated quercetin-mediated Bax activation, translocation and cell death. Conversely, interruption of Mcl-1 by siRNA enhanced Bax activation and translocation, as well as lethality induced by quercetin. However, the absence of Bax had no effect on quercetin-mediated Mcl-1 down-regulation. These results suggest that Mcl-1 may operate upstream of Bax. Finally, addition of quercetin increased Bid cleavage. The caspase 8 specific inhibitor prevented Bid cleavage, Bax activation, and subsequent caspase 3 processing. Knockout of Bax had no effect on the processing of caspase 8 and Bid. These observations indicate that Bax activation is also mediated by caspase 8 dependent Bid cleavage upon quercetin treatment. Collectively, these findings demonstrate that quercetin mediates Mcl-1 down-regulation and Bid cleavage which potentiate Bax activation and mitochondrial translocation, events that cooperate to engage the intrinsic and extrinsic apoptotic cascades, and apoptosis.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5658.
Abstract 5663: Docosahexaenoic acid protects against UV-induced oxidative stress through upregulation of heme oxygenase-1 and NAD(P)H: Quinone oxidoreductase in mouse epidermal cells
Authors: Park Hyun Jung , Shin Jun-Wan , Surh Young Joon 
Published: February 2011

Abstract
UV radiation is an important environmental factor in the pathogenesis of skin aging and cancer. Exposure of mammalian skin to UV results in oxidative damage, caused by increased cellular levels of reactive oxygen species (ROS). These include DNA breaks, protein inactivation, altered gene expression, loss of membrane lipid-bound essential polyunsaturated fatty acids and apoptosis. Omega-3 fatty acids, which occur at high levels in some fish oils, are known to have ROS scavenging activity and exert protective effects against photoaging and cancer. Their chemopreventive effects against UV-induced carcinogenesis are thought to be mediated through induction of antioxidant / phase 2 detoxifying enzymes, which are involved in elimination of ROS. In our present study, docosahexaenoic acid (DHA), a representative ω-3 fatty acid, significantly up-regulated the expression of two representative antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase (NQO1) in a time-dependent manner with maximal induction observed at 12 hr and 24 hr, respectively in mouse epidermal JB6 cells. Nuclear factor E2-related factor 2 is a principal transcription factor that plays a pivotal role in the induction of many genes encoding antioxidant and other cytoprotective proteins. DHA (50 μM) treatment enhanced nuclear translocation of Nrf2 and its subsequent binding to antioxidant response element (ARE). DHA treatment increased the activity of mouse HO-1 promoter in JB6 cells as as assessed by the luciferase reporter assay. siRNA knock down of Nrf2 abrogated DHA-induced expression of HO-1 and NQO1. Moreover, DHA pretreatment significantly suppressed intracellular ROS formation in response to UVB. Over expression of HO-1 vector in JB6 cell abolished the ROS generation induced by UVB. These findings, taken together, suggest that DHA exerts protective effects against UVB-induced oxidative stress in mouse epidermal cells through Nrf2-induced expression of HO-1 and NQO1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5663.
Abstract 5667: Identification of chemopreventive agents against dibenzo[a,l]pyrene-induced DNA adducts and potential mechanisms
Authors: Russell Gilandra K. , Vadhanam Manicka V. , Gupta Ramesh C. 
Published: February 2011

Abstract
Intervention with compounds of natural origin with little or no known toxicity is considered an effective means to prevent cancer development. We describe here a microsomal activation system in combination with 32P-postlabeling adduct assay to identify efficacious phytochemicals against the potent lung and breast carcinogen, dibenzo[a,l]pyrene (DBP). Briefly, salmon testes (st)-DNA was incubated with test agents (150 µM), DBP (10 µM), β-naphthoflavone-induced rat liver microsomes, co-factors in Tris. HCl (50 mM, pH 7.4). After incubation for 60 min at 37°C, the reaction was terminated. Analysis of the purified DNA by 32P-postlabeling showed essentially the same spectra of multiple adducts in all samples. However, quantitative differences were observed. Of nine phytochemicals tested, several compounds almost completely abolished the DNA adduct formation, some showed modest inhibition, while others were ineffective: resveratrol (95% reduction), delphinidin (94%), tanshinone I, (84%) tanshinone IIA (78%), diindolylmethane (73%), indole-3-carbinol (49%) and cyanidin (46%) and withaferin A (33%); cucurbitacin B showed insignificant reduction. All adducts were found to be equally inhibited, suggesting that activity of both CYP1A1 and 1B1, the major cytochromes P450s involved in the metabolism of DBP, were similarly affected. Oltipraz included as positive control, as expected, showed over 80-90% inhibition. To determine if the adduct inhibition occurred due to scavenging of electrophilic metabolites of DBP, st-DNA was incubated with the most effective test agents in the presence of anti-dibenzo[a,l]pyrene diolepoxide (anti-DBPDE). Analysis of the resultant adducts showed that only delphinidin, cyanidin and resveratrol showed modest inhibition (30-45%); other compounds were ineffective. Ellagic acid, which is known to scavenge the DBP electrophilic metabolite, almost completely abolished the adduct formation. Together, our data suggest that resveratrol, delphinidin, tanshinones and diindolylmethane are potent inhibitors of microsomal DBP-DNA adduct formation. While, the adduct inhibition for delphinidin and resveratrol may occur, in part, due to scavenging of the electrophilic metabolite of DBP, both these agents, tanshinones and diindolylmethane may also elicit their activity by inhibiting the cytochromes P450 activity. In summary, resveratrol, delphinidin, tanshinones and diindolylmethane, all of which are consumed either in fruits and vegetables or via folklore medicine (tanshinones) may be useful in the prevention of DBP-mediated lung and mammary tumorigenesis (Supported from the USPHS grants CA-118114, ES-011564 and Agnes Brown Duggan Endowment).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5667.
Abstract 567: Inhibition of growth and induction of differentiation by apigenin, baicalein and quercetin in colon cancer cells
Authors: Deutsch Jill K. , Lea Michael A. 
Published: February 2011

Abstract
There is considerable data to support the concept that polyphenolic molecules that occur in fruits and vegetables may have beneficial effects as cancer chemopreventive agents. We have shown previously that these polyphenolic molecules can induce enzyme markers of differentiation either alone, or in combination with histone deacetylase (HDAC) inhibitors. These data raise the question whether the induction of enzyme markers for differentiation are due to the anti- or pro-oxidant properties of polyphenols. We have compared the action of three flavonol molecules, apigenin, baicalein, and quercetin on four cell lines derived from human colon cells (Caco-2, SW1116, HT-29, and NCM460). The three polyphenols caused increases in alkaline phosphatase activity but no increase or decrease in aminopeptidase activity in Caco-2 cells. There was no induction of differentiation in the other cell lines by the three polyphenols. Since production of hydrogen peroxide has been reported when some polyphenolic compounds are incubated with serum-containing medium, we examined this phenomenon with the three polyphenols. Production of hydrogen peroxide was greater with baicalein than with quercetin or apigenin. When Caco-2 cells were incubated with hydrogen peroxide, there was some increase in alkaline phosphatase, but the concentrations required were higher than for the polyphenols and the magnitude of the effect was less. Further studies were performed with baicalein because that molecule had resulted in greater production of hydrogen peroxide. To test the significance of the hydrogen peroxide formation, we added catalase, but this addition did not prevent the increase in alkaline phosphatase or the decrease in protein synthesis in Caco-2 cells after incubation with baicalein. In addition, we wanted to determine the potential of the three polyphenols in combination with butyrate to increase the activity of alkaline phosphatase in Caco-2 cells. Synergistic effects were seen for the increase in alkaline phosphatase activity in Caco-2 cells for baicalein and quercetin, but not with apigenin. In conclusion, Caco-2 human colon cancer cells are notably sensitive to growth inhibitory and differentiating effects of apigenin, baicalein, and quercetin. It was evident that these polyphenols can have pro-oxidant effects, but our data suggested that this action was not the sole determinant of growth inhibitory or differentiating effects on colon cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 567.
Abstract 568: Transcriptional repression of SKP2 is impaired in MYCN-amplified neuroblastoma
Authors: Westermann Frank , Henrich Kai-Oliver , Fischer Matthias , Schwab Manfred 
Published: February 2011

Abstract
The cell cycle regulator, SKP2, is overexpressed in various cancers, and plays a key role in p27 degradation, which is involved in tumor cell dedifferentiation. Little is known about the mechanisms leading to impaired SKP2 transcriptional control in tumor cells. We used neuroblastoma as a model to study SKP2 regulation because SKP2 transcript levels gradually increase with aggressiveness of neuroblastoma subtypes. Highest SKP2 levels are found in neuroblastomas with amplified MYCN. Accordingly, we found 5.5-fold (range 2-9.5) higher SKP2 core promoter activity in MYCN-amplified cells. Higher SKP2 core promoter activity in MYCN-amplified cells is mediated through a defined region at the transcriptional start site (TSSR). This region includes a specific E2F-binding site that makes SKP2 activation largely independent of mitogenic signals integrated through the SP1/ELK-1 site. We demonstrate by chromatin immunoprecipitation that SKP2 activation through the TSSR in MYCN-amplified cells is associated with low abundance of pRB-E2F1 complexes bound to the SKP2 promoter. Transcriptional control of SKP2 via this regulatory mechanism can be re-established in MYCN-amplified cells by restoring pRB activity using selective small compound inhibitors of CDK4. In contrast, doxorubicin or nutlin-3 treatment - both leading to p53-p21 activation - or CDK2 inhibition had no effect on SKP2 regulation in MYCN-amplified cells. Together, this implies that deregulated MYCN protein levels in MYCN-amplified neuroblastoma cells activate SKP2 through CDK4 induction, abrogating repressive pRB-E2F1 complexes bound to the SKP2 promoter.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 568.
Abstract 5698: MicroRNA-31 acts as an oncomir in lung cancer by repressing specific tumor suppressors
Authors: Liu Xi , Sempere Lorenzo F. , Ouyang Haoxu , Memoli Vincent A. , Andrew Angeline S. , Luo Yue , Demidenko Eugene , Korc Murray , Shi Wei , Preis Meir , Dragnev Konstantin H. , Liu Hua , DiRenzo James , Bak Mads , Kauppinen Sakari , Freemantle Sarah J. , Dmitrovsky Ethan 
Published: February 2011

Abstract
MicroRNAs (miRNAs) encode small RNAs that regulate gene expression. The expression profiles of miRNAs have proven useful to improve classification, diagnostic and prognostic information for human cancers. We sought to uncover miRNAs preferentially over-expressed in lung cancers versus adjacent normal lung tissues. We comprehensively interrogated miRNA array expression profiles conducted on lung cancers versus adjacent normal lung tissues isolated from murine transgenic cyclin E models that were engineered. Notably, miR-136, miR-376a and miR-31 were each significantly over-expressed in murine lung cancers as compared to adjacent normal lung tissues. Real-time RT-PCR and in situ hybridization assays independently confirmed these miRNA expression profiles in paired normal-malignant lung tissues from transgenic mice as well as from a well characterized panel of paired human normal-malignant lung tissues. Knock-down of miR-31, but not other highlighted miRNAs, using a synthetic antagonist significantly repressed lung cancer cell growth and in vivo tumorigenicity. Bioinformatically predicted miR-31 target genes were identified and studied. These included two tumor suppressors: large tumor suppressor 2 (LATS2) and PP2A regulatory subunit B alpha isoform (PPP2R2A) that were each substantially increased by miR-31 knock-down and repressed by miR-31 over-expression. Engineered repression of either LATS2 or PPP2R2A significantly antagonized miR-31-mediated growth inhibition. Luciferase binding assays confirmed that miR-31 directly suppressed LATS2 and PPP2R2A through binding to their respective 3′-untranslated regions (UTRs). Interestingly, miR-31 was inversely expressed relative to these identified target genes in both murine and human lung cancers. Clinical relevance was uncovered using miR-31 in situ hybridization and cyclin E immunohistochemistry assays performed on tissue arrays from the population-based New Hampshire Lung Cancer Registry. As expected, cyclin E expression was significantly associated with miR-31 levels. Real-time RT-PCR assays validated LATS2 and PPP2R2A repression in lung cancers versus adjacent normal lung tissues. Thus, these findings implicate miR-31 as an oncogenic miRNA (oncomir) that exerts its effects by repressing specific tumor suppressors. Taken together, miR-31 is proposed as a novel molecular target for lung cancer therapy and chemoprevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5698.
Abstract 5709: Prevention of colitis-induced carcinogenesis with TNF-α antibody, infliximab; top-down strategy for colitic cancer prevention
Authors: Hahm Ki-Baik , Choi Seok Ryeol , Kim Yoon Jae , Hong Kyung Sook , Chung Joon Won 
Published: February 2011

Abstract
Prevention of colitis-induced carcinogenesis with TNF-α antibody, infliximab; top-down strategy for colitic cancer prevention
Since colitis-associated cancers arise in the setting of chronic inflammation, during which “inflammation-dysplasia-carcinoma” sequence prevails, we investigated whether infliximab can prevent the development of inflammation-associated colon cancer in rat models, for which 6 week old C57BL/6J mice were exposed to 15 cycles of dextran sulfate sodium (DSS) with each cycle consisting of 0.7% DSS for 1 week followed by distilled water for 10days. Infliximab, 4mg/kg, was given intravenously on 1st, 3rd, and 7th week or 25th, 27th, and 31th week after commencement of repeated bouts of colitis to compare cancer preventing effect of “step-up” versus “top-down” strategy. Additionally, molecular changes regarding inflammation and carcinogenesis were compared between colitis cancer group and colitis cancer group treated with infliximab in addition to in vitro documentation of molecular changes in cells. Multiple colorectal tumors developed in 75-80% of control mice, whereas only 16.7% of mice treated with infliximab at 1st, 3rd, and 7th weeks developed colon tumors. This significant reduction in tumor development with earlier administration of infliximab was correlated with significant decreases in serum NO levels, serum and tissue levels of TNF-α, iNOS, and COX-2. The expressions and activities of matrix metalloprotease (MMP)-3, MMP-9, and MMP-11 were significantly decreased in mice treated with infliximab in accordance with attenuated expression of β-catenin accumulated crypts in infliximab treated mice group. However, in repeated set of colitis-induced carcinogenesis experiment, where infliximab was administered at later stage of 25th, 27th, and 31th weeks, no reduction in colon tumor was noted compared to control group. In conclusion, potent anti-inflammatory treatment in the early stage of inflammation could reduce colitis-associated cancer, stratifying the rationale that earlier and intensive therapy with infliximab should be considered for either ameliorating clinical course or preventing colitic cancer in high risk patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5709.