bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B2: Effect of a changing microenvironment on the role of ROR receptors in melanoma progression
Authors: O'Connell Michael P. , Camilli Tura , Weeraratna Ashani T. 
Published: June 2012

Abstract
We have previously demonstrated that increases in Wnt5A result in an increase in metastatic capacity of melanoma cells and a decrease in the melanoma differentiation antigens MART1 and gp100. These data have been supported by several other laboratories, giving rise to the phenotype switching model of melanoma progression. This model suggest that less aggressive melanomas express a proliferative gene expression signature governed by the transcription factor MITF, while more aggressive melanomas express an invasive gene expression signature, governed by Wnt5A (Hoek et al, 2010). We hypothesize that this phenotype switch can be influenced by the changing microenvironment and that ROR receptor expression, also influenced by the microenvironment, is a key metastatic biomarker in melanoma.
The orphan tyrosine kinase receptors, ROR1 and ROR2, make up a superfamily of receptors that, until recently, had no known signal pathway association or ligand identification. ROR2 has since been shown to play a role in Wnt signal transduction and studies from our laboratory have demonstrated an important role for ROR2 in increasing the metastatic potential of melanoma cells. Very little remains know about ROR1 in melanoma. Here, we demonstrate that ROR1 expression is inversely correlated to that of ROR2 and decreasing ROR1 expression increases overall metastatic potential. In keeping with these data, reduction of ROR1 by siRNA demonstrates a decrease in MART1 and GP100, and motility, and an increase in the invasive capability of melanoma cells. In addition, siRNA knockdown of ROR1 expression increased ROR2, Wnt5A, and clathrin expression, and treatment with recombinant WNT5A decreased ROR1 expression, implying that downregulation of ROR1 may be an important event in increasing malignancy in melanoma. Further, ROR2 knockdown in cells that have high levels of Wnt5A, but low levels of ROR1, increases ROR1 expression. Based on this data, ROR1/ROR2 receptor expression appears to be involved in melanoma cell phenotype switching. As ROR2 has previously been shown to be induced by HIF1-α, we asked if this ROR phenotype switch was controlled, in part, by hypoxia. Our data suggests that cells can increase their ROR2 levels by exposure to hypoxia. This is concomitant with a decrease in proliferation and an increase in invasion and Wnt5A expression.
Overall these data suggest that changes in the melanoma microenvironment, such as hypoxia, may result in a switch from ROR1 positivity to ROR2 positivity, which ultimately contributes to increases in metastatic potential.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B2.
Abstract B20: GLI1 overexpression contributes to HCC recurrence partly through the induction of SNAI1-induced epithelial-to-mesenchymal transition
Authors: Zheng Xin , Gai Xiaohong , Fernandez-Zapico Martin , Roberts Lewis , Moser Catherine , Hu Chunling , Nakamura Ikuo , Shire Abdirashid , Yang Judong , Elsawa Sherine , Almada Luciana , Thorgeirsson Snorri 
Published: June 2012

Abstract
Background/Aim: Glioma-associated oncogene 1 (GLI1) is one of the most important transcription factors in the hedgehog (Hh) signaling pathway and has been shown to be involved in embryonic development and tumor progression. The epithelial-to-mesenchymal transition (EMT) is an important cellular program which contributes to invasion and metastasis of cancer. We have previously shown that GLI1 may promote HCC metastasis via EMT. Here, we demonstrate that GLI1 upregulates SNAI1 expression, induces EMT, and promotes HCC recurrence in vivo and in vitro.
Methods: Gli1 mRNA was assessed in 139 HCCs by microarray and its correlation with HCC recurrence and SNAI1 mRNA expression was analyzed. In vitro, the mRNA and protein expression of GLI1 was measured in Gli1-negative Huh7 cells transfected with GU1 and GU1-expressing SNU398 cells transfected with antisense oligonucleotides targeting GU1 (GLI1 ASO). GLI1-dependent transcriptional activity was assessed with GU reporter luciferase assay and electrophoretic mobility shift assay (EMSA). The interaction between Gli1, SNAI1 and EMT was assessed by real-time PCR, Western immunoblotting and immunofluorescence. Effects of GLI1 on proliferation, viability, migration, and invasion of tumor cells were also assessed.
Results: GLI1 mRNA was detected in 74 HCC tumors and found to be upregulated in 43 (58.1 %) HCCs. Increased Gli1 mRNA in HCCs was associated with tumor recurrence after resection. There was a positive correlation between GLI1 and SNAI1 mRNA expression. In HCC cells, GLI1 overexpression increased Gli1-dependent transcriptional activity, proliferation, viability, migration, and invasion of tumor cells. GU1 also increased SNAI1 expression and induced the EMT. Opposite effects were observed in GU1-knockdown models.
Conclusion: Together, these findings identify a novel mechanism mediating HCC recurrence that includes GLI1-mediated activation of EMT via upregulation of SNAI1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B20.
Abstract B3: Induction of Smad4 in response to serum starvation promotes cell death through PUMA stabilization
Authors: Lee Sun-Hye , Jung Youn-Sang , Chung Ji-Yun , Oh Ah-Young , Lee Su-Jin , Park Bum-Joon 
Published: June 2012

Abstract
Smad4 is an essential factor in TGF-β signaling and is also known as frequently mutated tumor suppressor gene in human pancreatic and colon cancer. However, considering the fact that TGF-β can contribute to cancer progression through transcriptional target genes such as Snail, MMPs, and EMT-related genes, loss of Smad4 in human cancer would be required for obtaining the TGF-β signaling independent advantage, which should be essential for cancer cell survival. Here we provide the evidence about novel role of Smad4, serum-deprivation-induced apoptosis. Elimination of serum can obviously increase the Smad4 expression and induces the cell death by p53-independent PUMA induction. Instead, Smad4 deficient cells show the resistance to serum starvation. Induced Smad4 suppresses the PAK1, which promotes the PUMA destabilization. We also found that siah-1 and pVHL are involved in PAK1 destabilization and PUMA stabilization. In fact, Smad4-expressed cancer tissues show the elevated expression of PAK1, also supprots our hypothesis that Smad4 induces PUMA-mediated cell death through PAK1 suppression. Our results strongly suggest that loss of Smad4 render the resistance to serum-deprivation-induced cell death, which is the TGF-β independent tumor suppressive role of Smad4.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B3.
Abstract B33: Transcriptional control of genome surveillance and repair by a metabolic switch
Authors: Di Li-Jun , Wong Madeline M. , Wakano Clay T. , Byun Jung , Varticovski Lyuba , Hunter Kent , Olopade Olufunmilayo I. , Gardner Kevin 
Published: June 2012

Abstract
A hallmark of primitive and more aggressive breast cancer is increased genome instability due to deficits in DNA repair. Recently we described a molecular mechanism through which the NADH regulated protein C-terminal binding protein (CtBP) represses the expression of the Breast Cancer One tumor suppressor gene BRCA1. These initial observations provided a molecular mechanism through which specific aspects of genome repair and stability, mediated by BRCA1, could be controlled by cellular metabolic status. By profiling the global interactions of CtBP with the breast cancer genome via chromatin immuno-precipitation combined with deep sequencing (ChlP-seq), we now reveal that CtBP acts both as a co-transcriptional repressor and activator to integrate distinct pathways that control genome stability, epithelial to mesenchymal transition, and stem cell transcriptional programming. Breast cancer cells depleted of CtBP show increased DNA repair as detected by comet and gamma H2AX foci formation assays. Over-expression of CtBP shows loss of the CD24 luminal surface marker while CtBP depletion increases CD24 expression. Kaplan-Meier survival analysis, based on our CtBP targeted gene lists, distinguishes breast cancer patients with worst outcome/survival in several published gene expression studies. Finally, tissue micro-array studies reveal significantly higher staining of CtBP predominantly in patients with poorly differentiated, triple negative and basal-like morphologic and molecular phenotypes. We propose a model in which CtBP acts at multiple levels to enhance dedifferentiation and genomic instability in malignancies of the breast.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B33.
Abstract B37: A DNA polymerase beta gene harboring the colon cancer-associated G231D variant increases the sensitivity of cells to chemotherapeutic agents and induces cellular transformation
Authors: Nemec Antonia A. , Donigan Katherine A. , Murphy Drew L. , Jaeger Joachim , Sweasy Joann B. 
Published: June 2012

Abstract
Rapidly advancing technology has resulted in the generation of the genomic sequences of several human tumors. These studies have revealed that tumors are heterogeneous and contain many mutations, supporting the mutator phenotype hypothesis of human cancer. Drivers of carcinogenesis are thought to be mutated genes that occur at high frequencies in large numbers of human tumors. However, functional characterization of many of the somatic mutations is lacking. We have identified several mutations of the DNA polymerase beta (POLB) gene in human colorectal cancer. Pol beta is the main polymerase involved in the base excision repair (BER) pathway and aberrant expression of Pol beta has been linked to a cancerous phenotype. In this study, we characterized the homozygous G231D mutation that was identified in a Stage 3 colorectal tumor. We have demonstrated that its expression in epithelial cells induced cellular transformation and increased the rate of proliferation. The transformed phenotype persisted in the cells even once the expression of G231D was extinguished. These data indicated that the expression of G231D caused an inheritable change; this change is most likely due to an increase in genomic instability caused by unfilled gaps proceeding through replication. Expression of G231D was insufficient to rescue Pol beta-deficient cells treated with chemotherapeutic agents suggesting that these agents may be effectively used to treat tumors harboring this mutation. Biochemical analysis of G231D revealed that it was 100-fold slower than WT Pol beta as determined by pre-steady state kinetics. The slow rate was a result of the decreased binding affinity of nucleotides by G231D. Residue 231 of Pol beta lies in close proximity to the template strand of the DNA. Molecular modeling showed that the change from a glycine to a negatively charged amino acid caused a repulsion between the template and residue 231 leading to the disruption of the dNTP binding pocket. Together, these data indicate that a person harboring the G231D Pol beta mutation may have an increased risk of cancer. Moreover, the altered sensitivity to chemotherapeutic drugs in cells carrying the G231D variant may have further implications in how to better improve the therapeutic outcome in patients with this mutation and supports the need for personalized cancer therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B37.
Abstract B48: Aurora kinase A plays a central role in the differentiation, survival, and self-renewal of human neuroblastoma SK-N-BE(2)-derived cancer stem cells
Authors: Sparta Antonino Maria , Potrich Valentina , Quattrone Alessandro , Provenzani Alessandro 
Published: June 2012

Abstract
Aurora kinase A is upregulated in numerous types of cancers. Since this protein is involved in mitotic spindle formation and cell cycle progression, its dysregulation leads to aberrant chromosomal segregation and consequent aneuploidy. It has been clarified that Aurora A is a key player in neuroblastoma because of its ability to protect the oncogene product N-myc from degradation, and the over-expression of the two of them represents a negative prognostic factor. Neuroblastoma usually develops in children and, up to the present time, the available pharmacological therapies have proven inadequate to treat the MYCN amplified sub-type of cancer, which is the most aggressive and malignant form of the tumor. Therefore, there is an urgency to develop new strategies that will improve its treatment. A novel approach to contrast cancer development and relapse is to target the subpopulation of the tumor initiating cells (or cancer stem cells), due to their multi-drug resistance and self-renewal abilities.
In this study, we have employed the SK-N-BE(2) cell line as an in vitro human neuroblastoma model, and compared the effects of Aurora A inhibition on the whole population (WP) and on the derived neurospheres (NS) obtained by their continuous growth in selective medium. We tested the effects of both a specific Aurora A inhibitor, ENMD-2076, and a pan-Aurora isoforms blocker, VX-680, for their influence over cellular physiology, morphology and signaling. The specificity of the results was confirmed by the use of a validated Aurora A siRNA.
In SK-N-BE(2) WP and NS, our findings confirmed the ability of Aurora A to protect N-myc from degradation. Moreover, the isolation and characterization by FACS, confocal microscopy and immunoblotting of an aldehyde dehydrogenase-positive side population, confirmed the presence of a fraction of cells with self-renewal capabilities and stem-like properties. The analysis of the signaling network of Aurora A showed functional relationships with the transcription factor STAT3, which is associated with neuronal survival and differentiation, after IL-6 challenge. Furthermore, either Aurora A pharmacological block or silencing induced the phosphorylation of the microtubule associated protein 2 (map2) specifically in the NS, an event that maintains the microtubule in a dynamic state, which is a prerequisite for neurite outgrowth.
Our results suggest that Aurora A represents an amenable target for the treatment of neuroblastoma, and gives new insights into its role in regulating neuronal plasticity and differentiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B48.
Abstract B54: The ability of NK cells to perform missing-self rejection of target cells is quantitatively different between individuals and controlled by MHC class I through a process of education
Authors: Brodin Petter , Kärre Klas , Höglund Petter 
Published: June 2012

Abstract
NK cells have the capacity to efficiently kill tumor cells. NK cells will be triggered to do so upon loss of MHC class I expression on the tumor cells, that is missing-self recognition. However, not all NK cells in an individual are able to perform such missing-self responses. The ability to perform missing-self is acquired through a process of education where only NK cells with an ability to interact with MHC class I are allowed full functionality.
We have recently shown that this NK cell education is not a binary but a quantitative process, yielding NK cells that are more or less efficient killers depending on the strength of interaction with self MHC class I during education (Brodin et al Blood 2009).
Here we describe our latest unpublished results on the MHC class I medicated influence on the NK cell system in the mouse. We show that MHC class I not only controls function but also NK cell population dynamics leading to a repertoire of NK cells that differ between individuals in a MHC class I dependent way. Combined these MHC class I mediated effects control the ability of an individual to perform missing-self responses cells lacking MHC class I in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B54.
Abstract C27: Phosphorylation of the polycomb group protein polyhomeotic (Ph) induces a relaxed chromatin state through depolymerization of the Ph SAM domain
Authors: Nanves David R. , Leal Belinda , Robinson Angela , Di Lijun , Hakala Kevin , Weintraub Susan , Kim Chongwoo A. 
Published: June 2012

Abstract
The transcriptional repressor polyhomeotic (Ph) is part of the polycomb group (PcG). PcG proteins are responsible for repressing Hox genes, a set of transcription factors that determine segmental identification early in development. PcG proteins are highly conserved throughout evolution, and recent studies have identified that the human homologue polyhomeotic-like protein 3 (PHC3) plays a role in tumor suppression in osteosarcomas. In order to understand how PHC3 functions, we utilized a cellular system with Ph. In our study we found that Ph is phosphorylated at a Ser residue several positions before the SAM domain. This region is important for controlling Ph SAM polymerization raising the possibility that phosphorylation alters the polymeric state of Ph. Phosphorylation was detected only in wild-type Ph and a mutant intended to increase polymerization, but not on polymer deficient Ph mutants. Because Ph repressive ability is dependent on SAM polymerization, we hypothesize that phosphorylation could trigger SAM depolymerization and consequently induce a relaxed chromatin state. To this point, mutating the phosphorylated Ser to Ala produced a better transcriptional repressor than wild-type. These results point to a potential way of controlling Ph SAM polymerization where phosphorylation leads to depolymerization and a replication competent chromatin state. Upon completing replication, the original repressive epigenetic state could be inherited by the daughter cell through dephosphorylation and Ph repolymerization.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C27.
Abstract C34: The role of COX-2/PGE2 in gossypol-induced apoptosis of colorectal carcinoma cells
Authors: Chen Yen-Chou , Ko Ching Huai , Shen Shing Chuan , Yang Liang Yo 
Published: June 2012

Abstract
Our previous study has shown that gossypol (GOS) exhibited the potent cytotoxic effect via apoptosis induction against human colorectal carcinoma cells; however, the role of cyclooxygenase 2 (COX-2)/prostaglandin E2 on GOS-induced apoptosis is still unknown. In the present study, 12-O-tetradecanoylphorbol-13-acetate (TPA) addition significantly inhibited GOS-induced apoptosis in human colorectal carcinoma cells COLO205 in according with inducing COX-2 protein/PGE2 production. TPA inhibition of GOS-induced apoptosis was blocked by adding protein kinase C (PKC) inhibitors including ST, GF, and H7, characterized by an occurrence of cleaved caspase 3 proteins and a decrease in COX-2 protein/PGE2 production in COLO205 cells. Addition of COX activity inhibitors including NS398, aspirin (AS), diclofenac (DI), and indomethacin (IN) suppressed TPA protection of GOS-induced apoptosis with decreased PGE2 production in COLO205 cells. Application of PGE2, but not it analogues PGD2, PGJ2, and PGF2, protected COLO205 cells from GOS-induced DNA ladders, and the EP1 receptor agonist 17PT-PGE2 mimicked the protection by PGE2, whereas the selective EP2 receptor agonist butaprostol (BUT), EP3 receptor agonist sulprostol (SUL), and EP4 receptor agonist PGE1 alcohol (PGE1) showed no significant effect on GOS-induced apoptosis in COLO205 cells. PGE2 protection of GOS-induced apoptosis was reversed by adding a selective EP1 receptor antagonist SC-19220. Furthermore, GOS had less apoptotic effect on HT-29 colorectal carcinoma cells which expressed higher level of endogenous COX-2 protein than COLO205 cells, and decreased COX-2 protein level via COX-2 siRNA significantly elevated GOS-induced cell death in HT-29 cells. COLO205-T cells were established through sustained TPA incubation of COLO205 cells, and COLO205-T cells showed a lower sensitivity to GOS-induced cell death with increased COX-2 (not Bcl-2 and Mcl-1) protein than parental COLO-205 cells. A decrease in COX-2 protein expression in COLO205-T cells by COX-2 siRNA transfection enhanced GOS-induced cell death by MTT assay. The notion of COX-2/PGE2 activation against GOS-induced apoptosis in colon carcinoma cells was demonstrated, and combination of GOS and COX-2 inhibitors to treat colon carcinoma reserved clinical potential for further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C34.