bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4075: Tolfenamic Acid Inhibits Prostate Cancer Cells Growth and Tumor Development in Orthotopic Mice
Authors: Mahammad Riyaz B. , Madero-Visbal Rafael , Baker Cheryl H. , Colon Jimmie , Safe Stephen , Abudayyeh Ala , Abdelrahim Maen 
Published: February 2011

Abstract
Introduction: Transcription factors, Specificity proteins (Sp) play a critical role in growth and metastasis of cancer and there is clear evidence that Sp1 expression is a negative prognostic factor for survival in some cancer patients. Sp proteins regulate the expression of several genes, including PSA gene and c-Met which are associated with prostate cancer. Nonsteroidal anti-inflammatory drug, tolfenamic acid (TA) induces the degradation of specific Sp proteins (Sp1, Sp3 and Sp4) which play critical role in tumor growth and metastasis. Sp proteins also regulate the expression of survivin, a member of inhibitor of apoptosis gene family which is associated with resistance to chemotherapy and radiotherapy in several cancers. We have evaluated the anti-cancer activity of TA in prostate cancer.
Methods and Results: Human prostate cancer cells (PC-3, DU-145 and LNcaP) were grown in the presence of DMSO (vehicle) or various concentrations (25, 50 and 100 µM) of TA and cell number and viability were measured at 24, 48, and 72 h post-treatment. Cell viability was measured using Cell Titr Glo kit (Promega) and the experiments were performed in triplicate. Cell lysates were prepared from the cells exposed to DMSO or 50 µM TA for 48 h and evaluated the expression of Sp proteins (Sp1, Sp3 and Sp4), and c-Met through Western blot analysis. For in vivo studies nude mice were injected with PC-3 Luc cells into the right prostate. Treatment (vehicle or 50 mg/kg TA/2 days) was initiated after one week and tumor growth was continuously monitored through Kodak imaging system. 4 weeks after the treatment tumors were isolated, measured and processed for immunohistochemistry to analyze the expression of Sp proteins and c-Met. In vitro studies show a significant decrease in the cell proliferation and viability and these results are dose and time dependent in all the cell lines. Furthermore, TA treatment for 48 h significantly decreased the expression of Sp1, Sp3 and c-Met in PC-3 cells. In vivo studies revealed that TA significantly decreased the tumor weight and volume which was associated with a low expression of Sp1, Sp3 and c-Met in tumor sections as evaluated by immunohistochemistry.
Conclusion: Targeting key transcription factors such as Sp proteins using a small molecule compound, TA is a new strategy for the treatment of prostate cancer and our results are very crucial in the development of a safe, cost effective drug for the treatment of this devastating disease. Studies to test the effect of TA on critical genes associated with prostate cancer and TA's impact on developing higher response to radiation therapy are underway.
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 4075.
Abstract 4078: Over-expression of FOXM1 is associated with cell migration/invasion in ovarian cancer
Authors: Lok Gabriel Tm , Chan David W. , Liu Vincent Ws , Ngan Hextan Ys 
Published: February 2011

Abstract
FOXM1 is a typical transcription factor regulating the S- and M-phase progression in cell cycle. It is frequently over-expressed and is associated with tumor stages in numerous human cancers. The influence of FOXM1 expression on cell proliferation has been well studied, yet its impact on other tumor characteristics in ovarian cancer, like cell migration/invasion remains unclear. In the present study, we demonstrated that FOXM1 was significantly up-regulated in ovarian cancer cell lines at both RNA and protein level by semi-quantitative RT- PCR and Western blot analyses. Immunohistochemical analysis showed that FOXM1 was highly correlated with the high-grade ovarian cancer. To examine the effect of FOXM1 on ovarian cancer cell motility, the FOXM1 specific inhibitor, thiostrepton, was used to reduce FOXM1 expression in OVCA433 cells. The FOXM1 reduced OVCA433 cells, as a result, showed a significant decrease in cell migration using wound healing assay. By using MEK specific inhibitor, U0126, we demonstrated that the inhibition of ERK activity caused a reduction of FOXM1 level in a time dependent manner and significant reduction of cell migration rate in the wound healing assay in OVCA433. In sum, FOXM1 is over-expressed and regulated by constitutive activated ERK activity in ovarian cancer cells. Our data also suggested that the ERK /FOXM1 signaling axis is crucial in regulating migration/invasion of ovarian cancer cells. Further studies on the molecular mechanism of FOXM1 in the regulation of ovarian cancer cell migration/invasion are warranted.
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 4078.
Abstract 4091: Epigenetic silencing of microRNA in the pathobiology of CLL
Authors: Sampath Deepa , Liu Chaomei , Wierda William G. , Keating Michael J. 
Published: February 2011

Abstract
MicroRNAs (miRs, miRNA) are a class of non-coding RNA that control gene expression at a post-transcriptional level. Specific and aberrant miRNA signatures distinguish indolent and relapsed forms of chronic lymphocytic leukemia (CLL). In this study, we focused on the expression and cellular targets of a set of microRNA (miR15a, miR-16, miR-29b and miR-101) that are differentially expressed in indolent and refractory disease. The tumor suppressor microRNAs, miR-15a and miR-16, are downregulated in 68% of all CLL and associated with an indolent course. These miRNA are located on an intron of the dleu2 gene within a genomic locus (chr13q) that is frequently deleted in leukemia. However, deletions in 13q usually involve only one allele and do not adequately account for the low expression levels of miR-15a and miR-16. We hypothesized that aberrant recruitment of the histone deacetylases could be a novel mechanism that drives the silencing of miR-15a and miR-16 in CLL. Correspondingly, exposure to a variety of small molecule histone deacetylase inhibitors led to the re-expression of miR-15a and miR-16 in 30% of samples that undergo silencing. We then evaluated the cellular targets of miR-15a and miR-16 in CLL. Ectopic expression of miR-15 and miR-16 in primary leukemia cells led to a loss of Bcl-2 and Mcl-1. However, pharmacological re-expression of these miRNA led to decreases in Mcl-1 protein, with no loss in Bcl-2. Losses in the levels of Mcl-1 were associated with induction of cell death in these leukemia cells. In contrast to miR-15a and miR-16, the microRNAs miR-29b and miR-101 are well expressed in indolent disease but become silenced in relapsed/refractory disease by unknown mechanisms. We identified that exposure to a variety of histone deacetylase inhibitors induced the re-expression of miR-29b and miR-101 in 30-50% of the downregulated samples. Chromatin immunoprecipitation experiments demonstrated that deacetylase inhibition led to an increase in permissive chromatin marks at the gene promoters for these miRNA. miR-29b is known to target Mcl-1, Tcl-1 as well as the DNA methyltransferases 3a and 3b. Ectopic expression of miR-29b in CLL cells led to the decrease of Mcl-1 protein. In parallel, expression of miR-101 led to the inhibition of EZH2 expression. Correspondingly, pharmacological re-expression of miR-29b and miR-101 was associated with losses in Mcl-1 and EZH2 in CLL cells and apoptotic death of these leukemia cells. These results identify a role for epigenetic mechanisms in the pathological silencing of miRNA in both indolent and relapsed CLL. They also offer a novel therapeutic strategy by which to reverse epigenetic silencing of miRNA for therapeutic benefit.
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 4091.
Abstract 4095: Aberrant expression of epigenetically regulated microRNAs in liver cancer
Authors: Wong Chun-Ming , Wong Carmen Chak-Lui , Tam Aegean Hoy Kam , Ng Irene Oi-Lin 
Published: February 2011

Abstract
Liver cancer (hepatocellular carcinoma, HCC) is a major malignancy worldwide. Despite definite improvements in the outcome of patients with HCC, the overall prognosis of this cancer is still unsatisfactory because of late presentation and frequent tumor recurrence after surgical resection. New diagnostic and adjuvant treatment modalities are much awaited. MicroRNAs (miRNAs) are a class of small (∼22 nt) single-stranded noncoding RNAs widely expressed in eukaryotic cells. miRNAs play an important role in modulating gene expression by promoting mRNA degradation or translational repression. There is mounting evidence that miRNAs are implicated in almost all major physiological processes, including cell proliferation, differentiation, apoptosis, and human carcinogenesis. Epigenetic alterations including aberrant DNA methylation and histone modification are important in regulating chromatin structure and gene expression. In this study, we investigated the role of epigenetic alterations in miRNA deregulation in human HCC. miRNA expression changes of HCC cell lines upon treatment with DNA demethylating agent (5-Aza-dC) and histone deacetylase inhibitor (Trichostatin A, TSA) were compared with stem-loop RT-qPCR based TaqMan low density array. In total, 98 miRNAs were remarkably up-regulated upon 5-Aza-dC/TSA treatment. Among these, 35 miRNA were commonly upregulated by treatment with the epigenetic inhibitors in both cell lines. The majority of these miRNAs was either associated with promoter CpG islands or located on imprinted regions. Expression analysis revealed that these epigenetically regulated miRNAs were frequently deregulated in human HCCs, and their expression pattern was able to distinguish primary HCCs from their corresponding non-tumorous livers. Interestingly, CpG island-associated miRNAs tended to be down-regulated in human HCCs, whereas, miRNAs located on imprinted regions were frequently overexpressed in human HCC samples. Our findings suggest that aberrant epigenetic silencing and loss of imprinting may contribute to miRNA deregulation in human 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 4095.
Abstract 4103: Sphingosine kinase-1 mediates LPA-induced gastric cancer cell proliferation
Authors: Ramachandran Subramaniam , Shida Dai , Nagahashi Masayuki , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki 
Published: February 2011

Abstract
The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine-1 phosphate (S1P) are important mediators of a variety of biological processes important for maintenance and progression of cancer. Autotaxin and sphingosine kinase 1 (SphK1), the enzymes responsible for synthesis of LPA and S1P, respectively, are elevated in many cancer types. We previously reported that LPA markedly enhanced SphK1 and S1P3 receptor mRNA levels, transactivated EGFR, and caused migration in MKN-1 gastric cancer cells [Shida et al., Cancer Res. 68:6569, 2008]. We have now shown that LPA potently stimulates proliferation of MKN-1 cells and downregulation of SphK1 or treatment with the isozyme-specific SphK1 inhibitor, SK1-I, markedly reduced LPA-mediated proliferation. The signaling pathways responsible for LPA-induced SphK1 upregulation were also investigated. U0126, a MEK1/2 inhibitor, completely abrogated LPA-induced elevation of SphK1 mRNA, while inhibitors of PI3K, protein kinase C, p38, JNK or NF-κB did not have an effect. Additionally, siRNA mediated downregulation of ERK2, but not AKT 1 or Akt2, blocked LPA-mediated SphK1 mRNA increase. These results were further confirmed by adenoviral expression of dominant negative MEK1, which inhibited LPA-induced SphK1 upregulation, while constitutively active MEK1 increased basal SphK1 mRNA levels. Furthermore, adenoviral expression of dominant negative or constitutively active AKT1 also did not change SphK1 mRNA levels. Our data implicate ERK2 as an important mediator of LPA signaling and upregulation of SphK1 and additionally, point to SphK1 and S1P production as potential therapeutic targets in gastric cancer. This work was supported by NCI grant R01CA61774 to SS and NIH grant 5K12HD055881 and Susan G. Komen for the Cure Research Foundation Career Catalyst Research Grant KG090510 to KT.
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 4103.
Abstract 4107: Human guanylate-binding protein-1 (GBP-1) in colorectal carcinoma
Authors: Britzen-Laurent Nathalie , Lipnik Karoline , Naschberger Elisabeth , Kuhn Elisabeth , Hohenadl Christine , Stürzl Michael 
Published: February 2011

Abstract
The human guanylate binding protein 1 (hGBP-1) is a large GTPase which mediates the anti-proliferative and anti-angiogenic effects of pro-inflammatory cytokines (IC), such as IFNγ, TNFα and IL1α/β, on endothelial cells in vitro. The expression of GBP-1 has been investigated in human colorectal carcinoma (CRC). We could show that GBP-1 is expressed in stromal endothelial cells of 32% of the CRC. This expression was correlated with a better outcome for patients with GBP-1 expression in the tumour stroma. A transcriptome analysis revealed that in the tumours, IFN-γ-induced genes including the major antiangiogenic chemokines CXCL9, CXCL10 and CXCL11 were coexpressed with GBP-1, indicating the presence of an active Th-1-like angiostatic immune reaction. However, the presence of GBP-1 was only detected in the stroma, suggesting that in tumour cells the expression of GBP-1 may be suppressed. In order to investigate the effects of GBP-1 on tumour cells, we reintroduced the protein in the DLD-1 colorectal carcinoma cell line, which does not produce GBP-1 in absence or in presence of IFN-γ. The proliferation rate was lower in GBP-1 expressing DLD-1 cells as compared to control cells. In order to better characterize the in vivo anti-tumourigenic effects of GBP-1, we developed a tumour mouse model using the DLD-1 cell line stably expressing GBP-1. Stable DLD-1 clones, which expressed GBP-1, and respective control cells (transfected with the empty vector plasmid) were xenotransplanted into immunodeficient mice. After 36 days, tumour volumes in the GBP-1 group were significantly smaller than in the control group (p&lt;0.001). This experiment was repeated with identical outcome in two different mouse strains. Immunohistochemistry stainings and Western blot analyses of the tumours confirmed that GBP-1 was highly expressed in the GBP-1 group and absent in control tumours. These results show that GBP-1 expression can inhibit tumour growth in an animal mouse model, indicating that tumour cells may have developed mechanisms to inhibit GBP-1 expression in an IFN-γ dominated microenvironment. The responsible mechanisms are investigated in ongoing studies.
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 4107.
Abstract 4109: EphrinA2 promotes tumorigenicity through Rac1/Akt/NF-kappa B signaling pathway in liver cancer
Authors: Feng Yu-xiong , Zhao Jiang-Sha , Cheng Shu-Qun , Yuan Yunfei , Wang Xiao-fan , Xie Dong 
Published: February 2011

Abstract
Eph/Ephrin family, one of the largest receptor tyrosine kinase families, has been extensively studied in morphogenesis and neural development. Recently, growing attentions have been attracted on its role in initiation and progression of various cancers. However, the role of Eph/Ephrins in hepatocellular carcinoma (HCC) has been rarely investigated. In this study, we found that the expression of EphrinA2 was significantly upregulated in both established cell lines and clinical tissue samples of HCC, and the most significant increase was observed in the tumors invading into the portal veins. Forced expression of EphrinA2 in HCC cells significantly promoted in vivo tumorigenicity, while knockdown of this gene inhibited this oncogenic effect. We further found that suppression of apoptosis, rather than accelerating proliferation, was responsible for EphrinA2-enhanced tumorigenicity. In addition, EphrinA2 endowed cancer cells with resistance to TNF-alpha-induced apoptosis, thus facilitating their survival. Furthermore, we disclosed a novel EphrinA2/Rac1/Akt/NF-kB pathway contributing to the inhibitory effect on apoptosis in HCC cells. In a conclusion, our study revealed that EphrinA2 played an important role in the development and progression of HCC by promoting the survival of cancer cells, indicating its role as a potential therapeutic target in HCC
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 4109.
Abstract 4110: Attenuation of colon cancer cell adaptation to hypoxia by cGMP-dependent protein kinase
Authors: Kwon In-Kiu , Wang Rui , Prakash Nikhil , Browning Darren D. 
Published: February 2011

Abstract
There is growing evidence for the antitumor effects of cGMP-dependent protein kinase (PKG) in colon cancer cells. We reported recently that ectopically expressed PKG resulted in defective angiogenesis in xenografts, and was associated with reduced levels of vascular-endothelial growth factor (VEGF). In order to better understand the therapeutic potential of this enzyme, the present work has examined the mechanism of VEGF regulation by PKG. In contrast to the SW620 xenografts, PKG had no effect on VEGF expression in SW620 cells grown under standard tissue culture conditions in vitro. However, the increase in VEGF expression observed when the cells were subjected to hypoxic stress was significantly attenuated by PKG at both the mRNA and protein levels. Using luciferase reporter assays, PKG was shown to inhibit hypoxia inducible factor (HIF) transcriptional activity in several colon cancer cell lines, including SW620, HCT116, and HT29. The attenuation of HIF by PKG reflected a more fundamental inhibition of the hypoxic response, which was supported by the ability of PKG expression to block the hypoxia-induced activation of glycolytic genes including enolase and hexokinase 2. The reduced levels of glycolytic enzymes in PKG-expressing cells relative to control cells was associated with reduced glycolysis, mitochondrial activity, and cellular ATP levels under hypoxic conditions. While the inhibition of SW620 cell proliferation occurred independently of PKG expression in a 1% O2 environment, PKG reduced cell viability and increased necrosis under these conditions. These findings demonstrate for the first time that PKG can block the adaptation of colon cancer cells to hypoxia, and highlights this enzyme for further evaluation as a potential target for colon cancer treatment.
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 4110.
Abstract 4113: Role of GP88 (Progranulin) in the proliferation and survival of non small cell lung carcinoma
Authors: Xia Guanjun , Kamimura Sayuri , Yue Binbin , Dong Jianping , Serrero Ginette 
Published: February 2011

Abstract
In 2009, 219,000 patients were diagnosed with lung cancer in the US and 159,000 died of the disease. It has been widely reported that results of standard treatment in lung cancer are poor except for the most localized cancers, thereby emphasizing the need to discover novel targets of lung cancer for the development of novel therapies and diagnosis. In the present study, we investigated the role of the autocrine growth and survival factor GP88.
GP88 (also known as Progranulin) is an 88kDa glycoprotein that has been shown to play a critical role in the proliferation and survival of breast cancer. Pathological studies with breast cancer cases in correlation with clinical outcome data have also shown that GP88 expression was associated in invasive ductal carcinoma with increased risk of recurrence. In the present study, we examined the role of GP88 in non small cell lung carcinoma (NSCLC). Examination of GP88 protein expression by immunohistochemistry using Oncostain 88 kit was carried out with formalin fixed paraffin embedded sections of lung cancer cases. Results showed that non small cell lung carcinoma, adenocarcinoma and squamous carcinoma stained positive for GP88 whereas small cell carcinoma sections were mostly negative. In addition, normal lung tissues did not express GP88. Based on this observation, expression and action of GP88 in NSCLC was examined using representative cell lines. We show here that GP88 stimulated proliferation and survival of A549 and H1299 cell lines. GP88 expression was upregulated in cells that were made resistant to cytotoxic drugs such as taxol and velcade. Inhibition of GP88 expression by SiRNA or GP88 action by treating the cells with AG1, an anti-GP88 monoclonal antibody resulted in an inhibition of cell migration and proliferation of these drug resistant cells and increased response to cytotoxic drugs.
Based on these results, studies were carried out to examine the effect of AG1 antibody on migration and tumor formation of A549 and H1299 cells in vitro and in vivo. Our data that will be presented here point out that GP88 is a novel therapeutic target for NSCLC.
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 4113.