bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5119: Overexpression of EIF5A2 enhances cell motility and promotes HCC metastasis through Rho and Rac signaling pathways
Authors: Dong Sui-Sui , Tang Dong-Jiang , Ma Ning-Fang , Fu Li , Chen Leilei , Guan Xin-Yuan 
Published: February 2011

Abstract
Hepatocellular carcinoma is characterized by its high incidence of tumor recurrence and metastasis; however, the underlying molecular mechanisms are largely unknown. In the present study, a novel metastasis-related gene, EIF5A2, was characterized for its role in HCC metastasis and underlying molecular mechanism. Overexpression of EIF5A2 mRNA was detected in 50/81(61.7%) of HCCs, which was significantly higher than those in nontumorous liver tissues. Compared with matched primary HCC, higher expression of EIF5A2 protein was observed in 25/47 (53.2%) metastatic tumors. In vitro assays showed that ectopic expression of EIF5A2 could enhance cancer cell migration and invasion, and experimental mouse model demonstrated that over expression of EIF5A2 promoted tumor metastasis in vivo. Moreover, inhibition of EIF5A2 by siRNA or deoxyhypusine synthase (DHPS) inhibitor GC7, which inhibits EIF5A2 maturation, could effectively decrease cell motility. Further study found that EIF5A2 could activate RhoA/Rac1 to stimulate the formation of stress fiber and lamellipodia. The rearrangement of cytoskeleton further induced epithelial-mesenchymal transition (EMT), a key event in tumor invasion and metastasis, characterized by downregulation of epithelial markers (E-cadherin and β-catenin) and upregulation of mesenchymal markers (fibronectin, N-cadherin, α-SMA and vimentin). Moreover, the activation of Rho GPases by overexpression of EIF5A2 also influenced cell cycle progression. Conclusions: EIF5A2 promotes HCC invasion and metastasis by stimulating cytoskeleton rearrangement through activation of RhoA and Rac1.
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 5119.
Abstract 5123: 1,25D3 regulates cell-matrix and cell-cell adhesion and reduces experimental metastasis in a squamous cell carcinoma model system
Authors: Ma Yingyu , Su Bing , Yu Wei-Dong , Seshadri Mukund , Turowski Steven G. , Kong Rui-Xian , Gillard Bryan M. , Trump Donald L. , Johnson Candace S. 
Published: February 2011

Abstract
1,25D3, the most active vitamin D metabolite, has broad spectrum anti-tumor activity. We demonstrated that 1,25D3 affects squamous cell carcinoma (SCC) cell adhesion to extracellular matrix and inhibits cell motility, markers of metastasis. In this study, we extended these observations. In situ zymography assay revealed that 1,25D3 strongly suppressed the ability of SCC cells to degrade gelatin. 1,25D3 reduced the adhesion of SCC cells to laminin, and by flow cytometry, the expression of the laminin receptors integrin α6 and β4. 1,25D3 promoted the activation of focal adhesion kinase (FAK) and the formation of focal adhesion as shown by immunofluorescence. To study the effects of 1,25D3 on cell-cell adhesion, the expression level of cadherins were examined by flow cytometry. 1,25D3 enhanced the expression of E-cadherin and R-cadherin, but did not alter that of N-cadherin. Of note, a 1,25D3-resistant variant of SCC (SCC-DR) was developed and these findings were not observed in SCC-DR cells. To investigate the in vivo effect of 1,25D3, C3H/HeJ mice were injected i.v. into tail vein with 104 SCC cells, and then half of the mice received 0.625 μg of 1,25D3 i.p. daily for 3 days while the other half received saline. Treatment with 1,25D3 dramatically inhibited the development of pulmonary tumor formation, as assessed by MRI analysis and colony counts. Our study suggests that 1,25D3 suppresses SCC metastasis, possibly through the promotion of E-cadherin-mediated cell-cell adhesion and the inhibition of cell motility and invasion.
This study was supported by NIH/NCI grants CA067267, CA095045 and CA085142.
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 5123.
Abstract 5135: Breast cancer antiestrogen resistance-3 influences breast cancer cell migration by regulating Rac and Rho GTPase signaling
Authors: Schrecengost Randy S. , Wilson Ashley L. , Guerrero Michael S. , Bouton Amy H. 
Published: February 2011

Abstract
Breast Cancer Antiestrogen Resistance-3 (BCAR3) was initially identified as a gene whose expression confers resistance to endocrine therapy, such as the antiestrogen tamoxifen. However, work from our group as well as others implicate BCAR3 as a prominent regulator of cell migration and invasion. This is of interest because expression of BCAR3 is elevated in more aggressive breast cancer cell lines. In this study, we have taken both a gain-of-function and loss-of-function approach to determine the mechanism by which BCAR3 regulates cell migration and invasion. We found that overexpression of BCAR3 in less aggressive breast cancer cells resulted in enhanced cell migration and increased protrusive activity. Additionally, BCAR3 was co-localized at the cell membrane with an established scaffold protein, p130Cas (also known as BCAR1 or Cas). Conversely, siRNA-mediated depletion of BCAR3 in more aggressive breast cancer cells inhibited cell migration and decreased membrane protrusiveness, coincident with a significant reduction in Rac GTPase activity. This was accompanied by mislocalization of Cas and a decrease in Cas tyrosine phosphorylation. Loss of BCAR3 was also associated with stabilization of stress fibers, reduced adhesion turnover, and increased ROCK-dependent phosphorylation of myosin light chain, a major downstream target of Rho GTPase. Inhibition of ROCK in BCAR3-depleted cells disrupted stress fibers and restored membrane protrusions, confirming and indicating that the effect of BCAR3 depletion on stress fiber dynamics was dependent on ROCK. Furthermore, Cas localization to the cell periphery was restored and partial rescue of Cas tyrosine phosphorylation was observed. Taken together, these results suggest a model whereby BCAR3 expression influences cell migration and invasion by promoting Cas phosphorylation and Cas-mediated Rac activation, while negatively regulating Rho-mediated contractility. While the major mechanisms of BCAR3 as a critical regulator of breast cancer cell migration are addressed here, future studies will determine whether elevated BCAR3 expression promotes metastasis in animal models and is associated with clinical outcome in 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 5135.
Abstract 5140: Rsu1 and the IPP adhesion complex can regulate adhesion and migration in glioma cell lines
Authors: Buckingham John , Gonzalez-Nieves Reyda , Cutler Mary L. 
Published: February 2011

Abstract
One hallmark of high grade glioblastoma is invasive growth that is dependent on ability of the tumor cells to migrate from the tumor into surrounding brain tissue thus preventing complete surgical resection. Rsu1, a member of the Integrin Linked Kinase-PINCH1-Parvin (IPP) cell adhesion complex, is encoded by a gene on human chromosome 10p13 in a region frequently deleted in high grade gliomas. Previous studies from our lab demonstrated that ectopic expression of Rsu1 in a human glioma cell line inhibited the tumorigenicity of the cells. The current study addresses the effect of Rsu1 on adhesion and migration in human glioma cell lines. The results with stable Rsu1 transfectants in the U87 glioma cell line indicate that Rsu1 expression results in enlarged cells with increased filapodial extensions and an increase in the number of focal adhesions. This phenotype correlates with increased cell adhesion and 30-50% decreased cell migration in Boyden chamber assays using PDGF, TPA or HGF as inducers of migration. siRNA-mediated depletion of Rsu1 concomitantly reduces the level of other IPP proteins, particularly the Rsu1 binding protein PINCH1. This loss of cell adhesion proteins reduces adhesion and enhances in vitro migration of highly oncogenic tumor cells. Infection of U87 and U251 glioma cell lines or immortalized human astrocytes and their Ras-transformed counterparts with adenovirus encoding Rsu1 decreased or eliminated phosphorylation of Akt on serine 473 compared to control vector. This finding and previous work demonstrating that signaling through the JNK pathway can be influenced by Rsu1 and PINCH11,2,3 suggest that both JNK and PI-3-kinase pathways are regulated by Rsu1 to limit cell migration. These studies identify deletion of Rsu1 as a mechanism that inhibits the IPP complex -induced adhesion as a potential mediator of the migratory behavior of high grade gliomas exhibiting chromosome 10 loss or 10p13 deletion.
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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 5140.
Abstract 5146: Reprogramming metastatic melanoma with the embryonic chick neural crest microenvironment
Authors: Kasemeier-Kulesa Jennifer C. , Romine Morgan , Seftor Elisabeth A. , Seftor Richard EB , Hendrix Mary JC , Kulesa Paul M. 
Published: February 2011

Abstract
Our previous work demonstrated that metastatic melanoma cells transplanted into the chick embryonic neural crest microenvironment invade into the host tissue, migrate along host neural crest cell migratory pathways without forming tumors, and assume a neural crest cell-like phenotype (Kulesa et al., 2006; Hendrix et al., 2007; Kasemeier-Kulesa et al., 2008). Here, we aim to elucidate the tissues and signals within the ancestral embryonic neural crest microenvironment capable of reprogramming metastatic melanoma cells. We find that in vitro co-culture of C8161 melanoma cells with various chick tissues, including head, branchial arches, and trunk, reveal that embryonic day 4 trunk tissue induces an overall 6% re-expression of MART-1, a marker of a melanocyte like phenotype. This MART-1 re-expression is highest in cells in close proximity to the co-cultured tissue. We also tested known differentiation factors present in embryonic day 4 trunk tissue, and found NGF to have a 5-fold increase of MART-1 re-expression on C8161 cells. Further work will help establish whether the neural crest embryonic microenvironment initiates a more stable, long-lived reprogramming of the aggressive, metastatic melanoma cells to a more benign neural crest cell phenotype.
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 5146.
Abstract 5148: A neural stem cells marker fatty acid binding protein 7 (FABP7) is involved in proliferation and invasion of glioblastoma cells
Authors: Rosa Antonella De , Rossi Marco , Pellegatta Serena , Tunici Patrizia , Malusa Federico , Magnoni Letizia , Raggiaschi Roberto , Bakker Annette 
Published: February 2011

Abstract
Malignant brain tumours are among the most deadly cancers. Current treatment strategies, such as surgery, chemotherapy and radiotherapy only modestly improve patient survival. The limited success of these strategies is largely due to a high incidence of tumor recurrence after the treatment. Recent evidences suggested that a rare population of stem-like cells (or tumour initiating cells) present in brain tumours might be responsible for the aggressiveness and recurrence of these tumours. These cells, named brain tumor stem-like cells (BTSC), share many properties of normal neural stem cells, including self renewal, extended proliferation, formation of neurospheres (when cultured in vitro in the presence of growth factors) and potential to differentiate into neurons and glial cells. Further investigations have suggested that studying this BTSC population in glioblastoma (GBM) is a more relevant system for exploring glioma biology than the adherently growing glioma cell lines.
In the current study we identified target genes and proteins that are differently expressed between adherent glioma cell lines and sphere growing BTSC, using microarray and differential proteomics, respectively.
Fatty acid-binding protein 7 (FABP7) was identified as overexpressed in BTSC compared to glioma adherent cell lines both at the gene as well as at the protein level.
FABP proteins are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. FABPs are thought to play important roles in fatty acid uptake, transport, and metabolism. Functionally, FABPS were described to play a role in gene regulation, cell signaling, cell growth and differentiation. The functional role of FABP7 in glioblastoma was investigated by assessing the effect of silencing FABP7 on migration and cell proliferation of glioblastoma cells. We observed that down-regulating FABP7 expression significantly reduced in vitro cell proliferation and even more the migration of BTSC.
Since increased tumour infiltration was reported as a consequence of radiotherapy, the potential involvement of FABP7 in this process was evaluated. Irradiated BTSCs displayed significantly higher FABP7 protein levels and therefore we suggest that FABP7 may contribute to the radiotherapy-induced aggressive phenotype of BTSCs.
Moreover, further mechanistic investigations indicated that directly or indirectly reducing the expression of FABP7 significantly impacts on the behaviour of glioblastoma derived BTSC.
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 5148.
Abstract 5150: Differential epigenetic regulation of sonic hedgehog GLI1 on downstream target genes in medulloblastoma and astrocytomas
Authors: Shahi Mehdi H. , Fan Xing , Sinha Subrata , Afzal Mohammad , Eberhart Charles , Castresana Javier S. 
Published: February 2011

Abstract
Sonic hedgehog (Shh) signaling in astrocytic tumorigenesis has not been as thoroughly investigated as in medulloblastoma. We have attempted to understand the regulatory status of GLI1, the immediate activator of Shh signaling pathway on its downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6. We attempted to correlate the expression pattern of GLI1 and its regulated genes in 14 cell lines (8 of astrocytoma and 6 of medulloblastoma) and 41 primary samples (27 astrocytomas and 14 medulloblastomas). We also determined the promoter methylation of Cyclin D2 and PTCH1 in the 14 cell lines and in a total of 58 primary samples (44 astrocytomas and 14 medulloblastomas).
The dependence of the GLI1 modulated genes on expression of GLI1 was confirmed by knockdown experiments with the help of GLI1-siRNA. We also found that Shh-GLI1 signaling shows different patterns of regulation of downstream target genes in medulloblastomas and astrocytomas: Cyclin D2 and Plakoglobin were upregulated in medulloblastoma but downregulated in astrocytoma; however, PAX6 and NKX2.2 showed over all a low expression pattern of expression in both tumors. However, in several cell lines (A172, SW1783, T98G, CCF-STTG-1 and GOS-3), exposure to both 5-Aza-2′deoxycytidine and Trichostatin A increased the expression of the GLI1 downstream target gene Cyclin D2 (p=0.0014). These results were verified by promoter methylation studies in the 14 cell lines and the 58 primary samples. Our promoter methylation studies revealed a significant number of astrocytoma cell lines (63%) and primary astrocytomas (32%) showing that methylation of Cyclin D2 related to its own level of expression; something that did not occur in medulloblastoma. Compared to Cyclin D2, PTCH1 promoter methylation did not influence on PTCH1 expression in the cell lines and tumor samples.
Our results demonstrate that Shh-GLI1 signaling acts differentially for the regulation of target genes in medulloblastoma and astrocytoma. Secondly, PTCH1 and Cyclin D2 are under epigenetic regulation besides the transcriptional regulation exerted by GLI1. This finding may open new ways for treating patients by demethylating agents.
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 5150.
Abstract 5155: BMP-2 inhibits the tumorigenicity of human osteosarcoma tumor-initiating cells
Authors: Wang Lin , Park Paul , Zhang Huina , Marca Frank La , Lin Chia-Ying 
Published: February 2011

Abstract
Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)-β superfamily, were originally identified as molecules that induce bone and cartilage formation and are now considered as multifunctional cytokines. More recently, there have been a number of studies showing the inhibitory effects of BMP-2 on tumorigenesis in many cancers. However, very little has been investigated to date about the role of BMP-2 in human osteosarcoma. In the present study we show that BMP-2 inhibits the tumorigenicity of an aggressive human osteosarcoma cell line, OS99-1. Based on the stem cell theory of cancer, a subpopulation of cells showing characteristics of stem cells was identified using high aldehyde dehydrogenase (ALDH) activity (ALDHbr cells) from xenografts. These stem-like cells were found to be highly tumorigenic and were classified as tumor initiating cells. In vitro, the growth of the sorted tumorigenic ALDHbr cells was significantly inhibited by the addition of 300 ng/ml of BMP-2 in the presence of 0.5% fetal bovine serum (FBS) for 48h, as evaluated by cell proliferation assay. In addition, using RT-PCR analysis, we found BMP-2 down-regulated the expressions of embryonic stem cell markers Oct3/4, Nanog, and Sox-2. Conversely there was an increase in the transcription of osteogenic markers Runx-2 and Collagen Type I in the sorted tumorigenic ALDHbr cells treated with the same BMP-2 solution for 48h compared with the same volume of vehicle. In vivo, tumor formation in animals was compared to a control receiving ALDHbr cells maintained under identical conditions without BMP-2. All animals receiving untreated ALDHbr cells developed large tumor masses that showed characteristic osteosarcoma features, including nuclear atypia, extensive neovascularization, and high mitotic activity. Conversely, ALDHbr cells treated with 30μg/animal of BMP-2 did not form significant tumors. Further immunostaining confirmed most Ki-67 positive cells were shown in the tumor sections from mice injected with ALDHbr cells without BMP-2, whereas few Ki-67 positive cells were present in the sections of tumor from ALDHbr cells treated with BMP-2. Based on these results, it appears that BMP-2 may suppress tumor growth by inducing the differentiation of tumor -initiating cells. BMP-2 or BMP-2-mimetic drugs, if properly delivered to tumor and combined with traditional therapies, may therefore provide a new therapeutic option.
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 5155.
Abstract 5156: Wnt5A enhances the malignant phenotype of lung cancer cells via non-canonical signaling
Authors: Ripley Robert T. , Rao Mahadev , Kemp Clinton D. , Mathur Aarti , Hussain Mustafa , Hong Julie A. , Zhang Mary , Schrump David S. 
Published: February 2011

Abstract
Objective: Previously, we reported that cigarette smoke condensate dramatically increases tumorigenicity of lung cancer cells via epigenetic silencing of Dickkopf-1(Dkk-1), which encodes an inhibitor of Wnt stem cell signaling. Furthermore, we demonstrated that knock-down of Dkk-1 up-regulates Wnt5A in lung cancer cells. Expression of this non-canonical Wnt ligand correlates with adverse outcome in lung cancer patients. The present study was undertaken to ascertain if Wnt5A directly modulates the malignant phenotype of lung cancer cells. Methods: Calu-6, H358, A549, and H841 lung cancer lines were transduced with lentiviral vectors expressing Wnt5A or control sequences. Cell count, scratch, and matrigel assays were used to evaluate in-vitro proliferation, migration, and invasion of transduced cells. Similar experiments were performed with exogenous recombinant Wnt5A (rWnt5A). Nude mouse xenograft experiments were used to assess tumorigenicity of lung cancer cells transduced with Wnt5A or vector controls. Canonical and non-canonical Wnt signal pathways were evaluated using western blot, promoter-reporter, and focused quantitative RT-PCR array techniques. Results: Wnt5A transduced lung cancer cells exhibited significantly increased proliferation, migration, and invasion relative to vector controls (p&lt;0.05; 2-tailed t-test); this phenomenon was pronounced under low serum conditions, and was observed following exposure of parental cells to rWnt5A. Relative to vector controls, Calu-6 and H358 cells constitutively expressing Wnt5A exhibited increased tumor take (p&lt;0.05) and size of subcutaneous xenografts (p&lt;0.05). Whereas microarray and Wnt Super Array experiments demonstrated upregulation of genes implicated in canonical as well as non-canonical Wnt signaling, western blot and promoter-reporter assays revealed that Wnt5A predominantly mediated activation of non-canonical signaling. Calu-6 and H358 cells constitutively expressing Wnt5A exhibited upregulation of the nuclear orphan receptor, ROR2, as well as activation of c-jun terminal N-kinase (Jnk) and c-jun kinase, which mediate non-canonical Wnt signaling. Consistent with these findings, rWnt5A abrogated rWnt3A-mediated activation of β-catenin signaling in lung cancer cells. Conclusion: Wnt5A enhances proliferation, migration, invasion, and tumorigenicity of cultured lung cancer cells via non-canonical pathways. Collectively, these findings warrant evaluation of inhibitors of Wnt5A-mediated signaling for lung cancer therapy.
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 5156.