bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1508: SLPI enhances the expression of PLSCR1 in the HEY-A8 ovarian cancer cell line
Authors: Altwerger Gary H. , Han Jasmine J. , Kohn Elise C. , Yu Minshu 
Published: June 2012

Abstract
Secretory leukocyte protease inhibitor (SLPI) is a secreted protease inhibitor that governs inflammation and whose importance has been demonstrated in both pathologic and non-pathologic states. We have defined SLPI as an influential component of the tumor microenvironment promoting growth, survival, and tumor aggressiveness in ovarian cancer. Extracellular SLPI interacts with progranulin, an ovarian cancer growth factor and parental molecule of the pro-inflammatory granulins. Recently, intracellular SLPI has been shown to bind to the cytosolic domain of phospholipid scramblase 1 (PLSCR1) in CD4 T-cells. PLSCR1 is a ubiquitous transmembrane proinflammatory protein with oncogenic properties. PLSCR1 overexpression has been identified in malignant colorectal cancer and xenograft tumor models with increased metastatic and invasive potential. We hypothesized that SLPI remains cytosolic or reenters the cytosol from the tumor microenvironment where SLPI can influence its intracellular receptor, PLSCR1. Preliminary western blot data demonstrated PLSCR1 protein expression in both OVCAR8 and HEY-A8 human ovarian cancer cells with OVCAR8 expressing far less PLSCR1. OVCAR8 is also known, from previous studies, to express less SLPI than Hey-A8 cells. These data led us to investigate SLPI and PLSCR1 interactions using confocal microscopy where we stained HEY-A8 cells and found colocalization of SLPI and PLSCR1. Using HEYA8 with constitutively forced expression of SLPI and protease inhibitor null mutant Leu71PheSLPI, we examined the effect of SLPI on PLSCR1. The increased secretion of SLPI in these stably transfected cells is associated with increased PLSCR1 expression regardless of protease inhibitor activity; additional mutants are currently under examination. These data suggest a positive feedback mechanism between SLPI and its intracellular receptor, PLSCR1 in human ovarian cancer cells. Inhibition of SLPI, already credentialed as a molecular target in ovarian cancer, may be enhanced by interruption of its effects on PLSCR1.
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 1508. doi:10.1158/1538-7445.AM2011-1508
Abstract 1512: Hypoxic activation of FVII gene in cancer cells mediated by interaction among HIF2α, Sp1, and HDAC4
Authors: Koizume Shiro , Miyagi Etsuko , Hirahara Fumiki , Nakamura Yoshiyasu , Takano Yasuo , Ruf Wolfram , Miyagi Yohei 
Published: June 2012

Abstract
Blood coagulation factor VII (fVII) is a key enzyme of the extrinsic coagulation cascade that is produced predominantly by hepatocytes. Tissue factor/fVIIa complex formation on the cell surface initiates key pathogenic mechanisms in cancer, including cell motility, invasion, cell survival, and angiogenesis. We have shown that various cancer cells ectopically synthesize fVII, resulting in activation of cell motility and invasion [1]. We have also shown that fVII expression is ectopically induced in ovarian cancer cells under hypoxia, potentially leading to a major complication of cancer patients, thromboembolism via secretion of fVII-positive microparticles [2].
Hypoxia inducible factors HIF1α and HIF2α are known to form a heterodimeric complex with a constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-ARNT complex binds to hypoxia response elements (HREs) within gene regulatory regions, resulting in transcriptional activation. We previously found that fVII gene (FVII) is inducible under hypoxia by HIF2α dependent mechanism. Unexpectedly, chromatin immunoprecipitation (ChIP) analysis revealed that HIF2α but not HIF1α was found to bind to FVII promoter without HRE [1].
In this study, we further investigated this characteristic transcriptional activation mechanism. Reporter gene, ChIP, and RNA interference (RNAi) experiments revealed that interaction between Sp1 and HIF2α in the promoter region is essential for FVII induction. Histone acetylation is known as a major mechanism for transcriptional activation. Thus, we additionally investigated effect of histone acetylation within the promoter region on HIF2α-Sp1 mediated transcriptional activation. We unexpectedly found that unlike typical transcriptional activation mechanisms, acetylation of histones negatively regulates FVII gene induction. ChIP and RNAi, followed by real-time PCR analysis revealed that a class II histone deacetylase HDAC4 is recruited to FVII promoter under hypoxia and is a coactivator responsible for this transcriptional induction. Furthermore, immunohistochemical experiments with an ovarian cancer xenograft model revealed that fVII presents in tissues strongly expressing HIF2α. These results suggest that hypoxic activation of FVII gene in cancer cells involves novel deacetylation dependent mechanism mediated by HIF2α-Sp1 interaction.
References
[1] Koizume, S. et al. Cancer Res. 66: 9453-9460, 2006.
[2] Yokota, N. et al. Br. J. Cancer, 101: 2023-2029, 2009.
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 1512. doi:10.1158/1538-7445.AM2011-1512
Abstract 152: MicroRNAs in head and neck squamous cell carcinoma
Authors: Uemura Mamoru , Mydlarz Wojciech , Chang Steven , Hennessey Patrick , Sun Wenyue , Shao Chunbo , Ha Patric , Sidransky David , Califano Joseph 
Published: June 2012

Abstract
Background: The accumulating evidence indicates that microRNAs play a key role in tumor development and progression. The aim of this study is to assess the role and function of microRNAs in head and neck squamous cell carcinoma.
Method and Results: We investigated expression profiles of microRNA in head and neck squamous cell carcinoma by using a miRNA microarray platform. Profiles from tumor samples (n=10) and nontumor tissues (n=10) were compared. We identified 24 differentially expressed miRNAs, of which 1 was significantly downregulated, while the other 23 were upregulated in tumor tissues. Mir-21 was most notably upregulated in tumor tissues (P=0.0002), and mir-375 was a potential tumor suppressive microRNA that was significantly downregulated in tumors (P=0.0002). Expression profiles of these two microRNAs were validated by qRT-PCR with separate clinical samples (16 tumors and 15 normal tissues). In vitro assays confirmed that mir-21 stimulated cell growth and mir-375 had a tumor suppressive role. Next, to assess downstream target genes, cells were subjected to microarray analysis after transient transfection with each microRNA or its negative control. We also conducted a bioinformatics search (TargetScan, PicTar, miRanda). By combining these data, we identified potential target genes including YWHAZ (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide) for mir-375 and BNC2 (Basonuclin 2) for mir-21. These potential target genes were downregulated after forced expression of mir-375 or mir-21. The activities of a luciferase reporter containing these microRNA's binding sequences at the 3’ untranslated region (UTR) of some potential target mRNAs were repressed by the ectopic expression of miR-375 or miR-21, suggesting that some of these candidates are specific targets of these microRNAs.
Conclusions: Mir-21 is a potential oncogenic microRNA, and miR-375 is a potential tumor-suppressive microRNA in head and neck squamous carcinoma. Further investigation including pathway analysis of these microRNAs may lead to the detection of therapeutic targets of head and neck 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 152. doi:10.1158/1538-7445.AM2011-152
Abstract 1520: Beta-endorphin neuron transplants suppress mammary tumor growth and progression via neuroimmune activation
Authors: Sarkar Dipak K. , Zhang Changqing , Dokur Madhavi , Boyadjieva Nadka I. , Ortigüela Maria , Rafferty Nicole , Mojtehedzadeh Sepideh , Reuhl Kenneth , Sengottuvelan Murugan 
Published: June 2012

Abstract
A review of studies that evaluated psychological factors and outcome in cancer patients suggested an association between certain psychological factors and the growth and progression of cancer. It has been suggested that the effect of stress on the immune system may in turn affect the growth of some tumors. We have previously shown that a set of hormone secreting nerve cells in the hypothalamus, called beta-endorphin (BEP) neurons, plays a role in regulating stress response and immune function. Hence, we tested whether activation of BEP neurons reduces stress hormone levels and prevents the N-nitroso-N-methylurea (NMU)-induced mammary tumor burden and malignancy rate. To test this we differentiated rat neural stem cells from the hypothalamus into BEP neurons in culture, which were later transplanted into the paraventricular nuclei (PVN) of the hypothalamus of 90 day old Sprague-Dawley female rats, which were injected with MNU 4 weeks prior to cells transplantation. Control rats were transplanted with cortical cells or not operated. Animals were palpated every week to check for tumor growth for additional 12 weeks. Tumor length and width were measured with a calibrator. Sixteen weeks after MNU injection, animals were sacrificed, tumors were collected, and slices of tumors were put in formalin and processed for histological staining for pathology. Additionally, the impact of cell transplants on plasma levels of stress hormone corticosterone and cytokines interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α) in plasma and the levels of natural killer (NK) cell and macrophage cytotoxic activities in peripheral blood and spleen were evaluated. When the BEP neurons were transplanted into the PVN of an adult rat, they integrated well with the surrounding cells and produced BEP and it precursor gene proopiomelanocortin. We found that BEP implanted animals have significantly lower tumor incidence, tumor volume, tumor number and malignancy rate. Rats with BEP neuron transplants also showed reduced plasma corticosterone levels, increased NK cell and macrophage activities in the spleens and peripheral blood mononuclear cells, elevated plasma levels of anti-inflammatory cytokine INF-γ and decreased levels of inflammatory cytokine TNF-α. These results identify a protective role of BEP neurons against MNU-induced mammary tumor (animal model for breast cancer) growth and progression via increasing the innate immune function and reducing the inflammatory milieu. (Supported by NIH Grant AA015718).
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 1520. doi:10.1158/1538-7445.AM2011-1520
Abstract 1531: HtrA1 sensitizes ovarian cancer cells to cisplatin-induced cytotoxicity by targeting XIAP for degradation
Authors: He Xiaoping , Khurana Ashwani , Maguire Jacie L , Chien Jeremy , Shridhar Viji 
Published: June 2012

Abstract
We have previously identified serine protease HtrA1 as a down-regulated gene in ovarian cancer and loss of HtrA1 may contribute to cell resistance to cisplatin treatment. However, the exact mechanism by which HtrA1 regulates chemosensitivity in ovarian cancer is currently unknown. Here, we used mixture-based oriented peptide library approach and identified XIAP, an important member of the inhibitor of apoptosis (IAP) protein family, as one possible substrate of HtrA1. Recombinant wild type (WT) HtrA1 but not protease-inactive SA mutant HtrA1 can cleave XIAP protein in vitro. Over-expression of HtrA1 led to decreased level of XIAP in OV167 and OV202 ovarian cancer cells, while down-regulation of HtrA1 resulted in increased level of XIAP in SKOV3 ovarian cancer cells. CDDP treatment enhanced the cleavage of XIAP by HtrA1. Immuno-precipitation assay revealed that HtrA1 binds to XIAP directly both in vitro and in vivo. Increased cell resistance to cisplatin treatment was observed in SKOV3 and TOV-21G cells after stable knockdown of HtrA1 with shRNA. In contrast, over-expression of HtrA1 in OV202 cells promotes cell sensitivity to cisplatin treatment which can be reversed by increased expression of XIAP. In conclusion, our experiments reveal XIAP as a novel substrate of HtrA1 and the mechanism by which HtrA1 confers cell sensitivity to cisplatin treatment may be partially through its degradation of XIAP.
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 1531. doi:10.1158/1538-7445.AM2011-1531
Abstract 1536: UVB-irradiation regulates VLA-4-mediated melanoma cell adhesion to endothelial VCAM-1 under flow conditions
Authors: Liu Wei , Wang Lei , Shirure Venktesh S. , Burdick Monica M. , Wu Shiyong 
Published: June 2012

Abstract
The major aspect contributing to the mortality of melanoma is its ability to spread, or metastasize. Ultraviolet B light (UVB) is considered an indirect cause of melanoma formation. However, little is known about the potential effects of UVB to melanoma metastasis. Integrins, a large family of cell adhesion molecules expressed on the melanoma cell surface, are important for cell signaling, growth, and migration during metastasis. Most critically, tumor cell tissue invasion is dependent on the initial interaction of tumor cells with vascular endothelium at the target organ, and there is increasing evidence for a prominent role of melanoma very late antigen-4 integrin (VLA-4, α4β1 integrin) binding to its endothelial ligand vascular cell adhesion molecule-1 (VCAM-1) in this process. This research focuses on the quantitative modulation of VLA-4 integrin expression and function on melanoma cells after UVB irradiation. The present data show that at 3, 12, and 18 hours post-UVB irradiation, VLA-4 expression was unchanged relative to untreated cells, but adhesion to VCAM-1 decreased significantly. Immunofluorescence studies implied that the spatial organization of α4 integrin on the melanoma cell surface contributed to the changes in avidity for VCAM-1 upon UVB irradiation. Further analysis suggested that the surface level of α4 integrin was maintained by Akt activity after UVB irradiation. The level of cell surface α4 integrin was significantly increased after UVB-irradiation when Akt was inhibited. Inhibition of Akt also reversed the reduction of avidity of cells after the irradiation. Our data also show that UVB reduces the level of Akt. The inhibition of Akt activity correlated with a reduced amount of coupled cNOS and reduced amount of iNOS after UVB-irradiation. However the effect of NOSs on melanoma cell adhesion appears due to their roles in regulation of apoptosis after UVB-irradiation.
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 1536. doi:10.1158/1538-7445.AM2011-1536
Abstract 154: miRNAs in plasma of pancreatic cancer patients
Authors: Ali Shadan , Almhanna Khaldoun , Chen Wei , Philip Philip A. , Sarkar Fazlul H. 
Published: June 2012

Abstract
Pancreatic cancer (PC) has the poorest overall survival rate among all human cancers, which is in part could be due to the lack of early diagnosis; however, there are no reliable tools for early detection of PC, emphasizing the need for the discovery of novel biomarkers. In the current study, we investigated the expression profile of microRNAs (miRNAs) in the plasma of 50 PC patients and compared with 10 normal volunteers. The data was further validated by quantitative real-time PCR and cell-based assays. Moreover, we have tested the biological significance of our findings from plasma miRNAs experimentally by assessing differential expression of miRNAs in two parental and four chemo-resistant human PC cell lines by miRNA profiling and quantitative RT-PCR. We found 37 miRNAs that were down-regulated and 54 were up-regulated in the plasma from patients diagnosed with PC. The expression of miR-21 was significantly higher, and the expression of let-7 family (especially let-7d) and miR-146a was significantly lower in PC. The higher expression of miR-21 predicted worse survival, and although the overall expression of let-7d was lower in PC, the lowest expression predicted better survival compared to PC patients with relatively higher expression of let-7. Interestingly, we also found that miR-21 family was markedly over-expressed in chemo-resistant PC cell lines, which was consistent with the plasma data from PC patients. Our previous studies showed increased expression of miR-21 with concomitant loss of PTEN expression, which is consistent with current findings showing the loss of three additional targets of miR-21 (PDCD4, Maspin and TPM1). These results suggest that identifying and validating the expression of miRNAs in newly diagnosed patients could serve as a potential biomarker for tumor aggressiveness. Based on our findings, we conclude that miR-21 expression may serve as a novel plasma biomarker for early detection of PC. Hence such miRNAs could be useful for the screening of high-risk patients, which may further lead to the development of novel strategies by which miR-21 could be targeted for future drug 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 154. doi:10.1158/1538-7445.AM2011-154
Abstract 1541: Secondary mutations in ALK and resistance to ALK kinase inhibitors
Authors: Sasaki Takaaki , Okuda Katsuhiro , Zheng Wei , Butrynski James , Capelletti Marzia , Wang Liping , Gray Nathanael , Wilner Keith D. , Christensen James G. , Demetri George D. , Shapiro Geoffrey I. , Rodig Scott J. , Eck Michael J. , Jänne Pasi A. 
Published: June 2012

Abstract
Background: The anaplastic lymphoma kinase (ALK) inhibitor crizotinib is clinically effective in cancer patients whose tumors harbor ALK translocations. However, drug resistance will ultimately develop in most if not all patients. We studied drug resistance mechanisms using both in vitro models and analyses from tumors of patients that had developed crizotinib resistance.
Methods and Results: We identified a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harbouring a RANBP2-ALK translocation who progressed while crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. We also evaluated the impact of mutations in the ALK gatekeeper residue (L1196) and engineered all possible gatekeeper mutations resulting from a single nucleotide change into the background of EML4-ALK. Three of the mutations (L1196M, L1196Q and L1196V) in the background of EML4-ALK led to IL-3 independent growth. Furthermore the EML4-ALK L1196M mutant resulted in a greater baseline ALK phosphorylation, cell growth and downstream signaling compared to EML4-ALK alone. A chemically distinct ALK inhibitor, TAE684, or the HSP90 inhibitor 17-AAG are both effective in models harbouring the F1174L or the L1196M ALK mutations.
Conclusions: We identify secondary mutations in ALK that confer crizotinib resistance. In addition, we identify therapeutic strategies, alternative ALK inhibitors or HSP90 inhibitors that may be clinically effective in patients that have developed crizotinib resistance. Understanding the mechanistic basis of drug resistance is necessary in order to develop effective clinical treatments for patients with ALK-translocated cancers.
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 1541. doi:10.1158/1538-7445.AM2011-1541
Abstract 1550: The effect of snail on cellular adhesion in prostate cancer cells
Authors: Neal Corey L. , Mckeithen Danielle , Odero-Marah Valerie 
Published: June 2012

Abstract
PURPOSE: The purpose of the study is to determine the role of Snail transcription factor on cellular adhesion to fibronectin and collagen, in human prostate cancer cells. Adhesion of cells to one another or the extracellular matrix (ECM) is responsible for normal and abnormal cellular activity, such as cell migration, invasion, metastasis of tumor cells, and angiogenesis. Snail transcription factor induces epithelial-mesenchymal transition (EMT) in which epithelial cells loose expression of specific genes and acquire traits of mesenchymal genes. We hypothesized that Snail will lead to decreased cellular adhesion to fibronectin and collagen matrix, concomitant with increased cell migration. DESIGN METHODS: We stably overexpressed Snail in LNCaP (LNCaP-Snail) and ARCaP (ARCaP-Snail) prostate cancer cells, or stably knocked down Snail in C4-2 and ARCaP-Snail cells using shRNA. We performed cell adhesion and migration assays on fibronectin and collagen I matrices using these cell models. Flow cytometry was also used for integrin expression analysis. RESULTS: We found that ARCaP prostate cancer cells transfected with Snail displayed decreased adhesion to fibronectin and collagen I, which was reversed by Snail knockdown. Additionally we have seen a decrease in the expression of the α5 and α2 integrin among ARCaP cell lines over expressing Snail, concomitant with an increased migration in cell lines overexpressing Snail. CONCLUSION: We have shown that Snail decreases cell adhesion to fibronectin and collagen, and inversely increases cell migration. These studies define a new role for Snail transcription factor that may be crucial for cell detachment and subsequent metastasis. Supported by grants P20MD002285-01 & G12RR003062-22
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 1550. doi:10.1158/1538-7445.AM2011-1550