bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2057: Protocadherin 10-mediated suppression of tumorigenesis and metastasis in colorectal cancer
Authors: hung yu-lin 
Published: August 2015

Abstract
Colorectal cancer (CRC) is one of the leading types of cancer death worldwide, and over one third of these patients will die of their disease mainly due to distant metastasis. Genomic deletion that occurs at tumor suppressor loci is a common genetic aberration in CRC. By using loss of heterozygosity analysis, we identified Protocadherin 10 (PCDH10) as a novel tumor suppressor gene in CRC. Ectopic expression of PCDH10 reduced cancer cell proliferation, anchorage-independent growth, migration and invasion, as well as increased serum starvation-induced apoptosis in vitro. Subcutaneous injection of PCDH10-expressing CRC cells in SCID mice showed the reduction of tumor growth compared with that observed in mock-inoculated mice. Furthermore, via intrasplenic implantation, the re-expression of PCDH10 in silenced cells restrained liver metastasis and improved survival in SCID mice. The molecular mechanisms of PCDH10-mediated tumor suppression are involved in the up-regulation of p53-p21 pathway and down-regulation of active β-catenin. Taken together, PCDH10 could restrain cell growth and epithelial-to-mesenchymal transition, and thus inhibit the development and progression of CRC.
Keywords:
PCDH10, tumor suppressor gene, colorectal cancer, molecular mechanism
Category : MCB04 Oncogenes and Tumor Suppressor Genes
Citation Format: yu-lin hung. Protocadherin 10-mediated suppression of tumorigenesis and metastasis in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2057. doi:10.1158/1538-7445.AM2015-2057
Abstract 2059: Novel roles for GNA13 and RHOA as tumor suppressor genes
Authors: O'hayre Morgan , Inoue Asuka , Sales Katiuchia , Kufareva Irina , Callejas Valera Juan Luis , Guo Fukun , Mikelis Constantinos , DiPasquale Giovanni , Finkel Kira , Aoki Junken , Zheng Yi , Bugge Thomas H. , Gutkind J. Silvio 
Published: August 2015

Abstract
G-protein coupled receptors (GPCRs) and G-proteins are critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. However, mutations and disruptions in the expression or function of these molecules have been linked to growth, progression and metastasis of various cancers. Recently, major efforts in the area of genome-wide sequencing of tumors have unveiled numerous previously uncharacterized mutations in G-proteins and GPCRs, which could have significant implications to cancer initiation and progression. In particular, mutations in the gene encoding the G-protein G13 (GNA13) and/or its downstream effector, RhoA, have been identified in B cell lymphomas (particularly Burkitt's lymphoma and Diffuse Large B cell Lymphoma), T cell lymphomas, and Head and Neck Squamous Cell Carcinomas (HNSCCs). Our analyses indicate that these mutations are highly statistically significant over background cancer gene mutation rate, and mutations in GNA13 alone occur in ∼10-15% of patients with Burkitt's lymphoma and Diffuse Large B cell Lymphoma. Surprisingly, although G13 and RhoA have previously been linked to cellular transformation and metastatic potential of epithelial cancers, our data suggests that the mutations in GNA13 and/or RHOA in these B cell lymphomas and HNSCC are inhibitory in nature. Furthermore, our results indicate a tumor suppressive function for wild-type GNA13 and RHOA in in vivo cancer models. Overall, our data suggest a novel function tumor suppressive function for the G13/RhoA axis in multiple human malignancies.
Citation Format: Morgan O'hayre, Asuka Inoue, Katiuchia Sales, Irina Kufareva, Juan Luis Callejas Valera, Fukun Guo, Constantinos Mikelis, Giovanni DiPasquale, Kira Finkel, Junken Aoki, Yi Zheng, Thomas H. Bugge, J. Silvio Gutkind. Novel roles for GNA13 and RHOA as tumor suppressor genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2059. doi:10.1158/1538-7445.AM2015-2059
Abstract 2090: GLI3 repressor levels determine Hedgehog pathway activity and predict response to Smoothened antagonist in acute myeloid leukemia
Authors: Chaudhry Parvesh , Singh Mohan , Triche Tim , Jorapur Aparna , Gill Parkash S. , Merchant Akil 
Published: August 2015

Abstract
The Hedgehog (Hh) signaling pathway is activated in most hematological and solid cancers and is a promising target for therapeutic development. Deletions in the receptor Patched (PTCH) or activating mutations in the upstream positive regulator Smoothened (SMO) have been reported in a few cancers such as basal cell carcinoma and medulloblastoma, but are largely absent in most tumor types; therefore, the mechanism of pathway activation in most cancers remains unknown. In normal tissues, Hh pathway activation via PTCH/SMO causes an increase in the downstream activating transcription factor GLI1 and a decrease in the transcriptional repressor GLI3R. We confirm that the Hh pathway is active in acute myeloid leukemia (AML) and is required for cell survival, however, this activity is largely independent of the upstream activator SMO. Using siRNA knock down of GLI1, GLI3 and SMO in AML cell lines, Gli3 conditional knock out mice, and primary AML samples, we are able to show that loss of the GLI3R repressor function is sufficient to activate Hh target gene expression independent of ligand binding, and GLI3R levels correlate inversely with GLI1 levels. Importantly, we show that GLI3R is required for the therapeutic effect of SMO antagonists in AML samples and restoration of GLI3R restores sensitivity to SMO antagonists in AML cell lines. Epigenetic and gene expression analysis of the TCGA AML data set reveals that the GLI3 expression is silenced in most AML patient samples. We demonstrate in vitro and in patients that treatment with hypomethylating agents restores GLI3R levels and sensitivity to SMO antagonists in AML. In a transgenic mouse model of myeloproliferative disease (vav-Jak2V617F, gift of Joe Zhao, OUHSC) effective treatment with SMO antagonists are associated with increases in GLI3R but no changes in GLI1. Finally we show that GLI3R can directly repress expression of AKT and in vivo responses to SMO antagonists are correlated with changes in AKT expression, independent of GLI1 levels. In summary, this study provides the first evidence that GLI3R plays an essential role in SMO independent Hh signaling in AML, and suggests that GLI3R could serve as a potential biomarker for patient selection in SMO antagonist clinical trials. Furthermore, these data provide important mechanistic data to support rational combinations of hypomethylating agents with SMO antagonists in clinical trials.
Citation Format: Parvesh Chaudhry, Mohan Singh, Tim Triche, Aparna Jorapur, Parkash S. Gill, Akil Merchant. GLI3 repressor levels determine Hedgehog pathway activity and predict response to Smoothened antagonist in acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2090. doi:10.1158/1538-7445.AM2015-2090
Abstract 2096: High sensitivity of cutaneous T-cell lymphoma (CTCL) to CABE, a component of propolis
Authors: Jayakumar Arumugam , Venugopal Radjendirane , Zielinski Rafal , Rusin Aleksandra , Fokt Izabela , Skora Stanislaw , Ni Xiao , Duvic Madeleine , Priebe Waldemar 
Published: August 2015

Abstract
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of diseases characterized by clonal expansion of malignant T-cells in the skin. In the course of our quest to screen and identify a potent, selective anti-proliferative drug for CTCL, we discovered that caffeic acid benzyl ester (CABE), a natural component of edible plant species found in high concentrations in propolis, showed increased potency for CTCL (IC50 4 μM) in vitro compared to other tumor types such as melanoma (IC50 25 μM), glioma (IC50 25 μM), multiple myeloma (MM) (IC50 70 μM), head and neck squamous cell carcinoma (HNSCC) (IC50 25 μM), ovarian cancer (OC) (IC50 17 μM), breast carcinoma (IC50 43 μM), and Hodgkin's B-cell lymphoma (IC50 33 μM). Cell death in CTCL MJ and HH cell lines was accompanied by increased caspase-3 and poly (ADP-ribose) (PARP) cleavage and annexin V staining. There is growing evidence that CABE and its analogs exert their anticancer activity by modulating expression level of key transcription factors. Here, we evaluated the effects of CABE on the activity of different transcription factors and the expression of total and phosphorylated proteins in MJ cells by use of the transcription factor activation profiling array (TFAPA) and the reverese-phase protein array profiling (RPPA) assays. The activity of 48 transcription factors (TFs) and expression of 225 unique total and phosphorylated proteins could be monitored simultaneously by using a collection of biotin-labeled DNA probes and 225 unique antibodies. TFAPA analysis revealed that 18 TFs (including STAT1, STAT4, and RXR) were up-regulated and 3 TFs (STAT3, STAT5, and SATB1) were down-regulated to a variable extent in cells treated with 10 μM CABE for 5 h as compared to vehicle-treated control. RPPA analysis revealed 41 differentially expressed proteins between vehicle control and cells treated with 10 μM CABE. These can be functionally categorized into functional groups: DNA repair, cell cycle, apoptosis, phosphoinositide 3-kinase (PI3K)/AKT/mTOR, and receptor kinase pathways. Our results suggest that CABE targets multiple signaling pathways in CTCL in vitro, warranting the development of a pre-clinical animal model for the testing of CABE efficacy in vivo.
Acknowledgement: These studies were supported in part by the grant from Moleculin, LLC
Citation Format: Arumugam Jayakumar, Radjendirane Venugopal, Rafal Zielinski, Aleksandra Rusin, Izabela Fokt, Stanislaw Skora, Xiao Ni, Madeleine Duvic, Waldemar Priebe. High sensitivity of cutaneous T-cell lymphoma (CTCL) to CABE, a component of propolis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2096. doi:10.1158/1538-7445.AM2015-2096
Abstract 2102: TBX2 promotes rhabdomyosarcoma (RMS) tumorigenesis by repression of PTEN expression
Authors: Zhu Bo K. , Davie Judith K. 
Published: August 2015

Abstract
RMS is most common soft tissue sarcoma in children. We previously identified TBX2 as an oncogene and showed that TBX2 is required for tumor formation. Here, we identified the tumor suppressor PTEN as a novel target of TBX2 in RMS and normal muscle. PTEN, which regulates the PI3K-AKT pathway, is repressed in RMS. Our work shows that TBX2 functions to regulate PTEN expression and thus, PI3K-AKT signaling, to enhance the malignancy of RMS tumors.
Both quantitative real time PCR and western blot assays were used to assay PTEN expression at the level of mRNA and protein respectively. Immunofluorescence staining was performed to assay the protein expression in human RMS tumor samples. Muscle tissue slides of proliferating myoblasts were assayed by co-immunofluorescence staining, and the proliferating myoblasts were induced by activating satellite cells with cardiotoxin induced muscle damage. Reporter constructs for luciferase assay were based on PTEN promoter. Chromatin immunoprecipitation (ChIP) assays were used to detect protein binding on gene promoters. Xenograft assays were conducted to assay TBX2 function in tumor malignancy.
We have found that PTEN was up-regulated upon muscle differentiation, but little expression of PTEN was observed in RMS cells. Although TBX2 was expressed in proliferating myoblasts, it was highly down-regulated upon myogenic differentiation. Human RMS tumor samples showed a down-regulation of PTEN and an up-regulation of TBX2 compared with normal tissues. Over-expression of TBX2 repressed PTEN expression in both C2C12 myoblasts and 10T1/2 fibroblasts. Either depletion of TBX2 or a dominant negative TBX2 increased PTEN expression in RMS cells. Luciferase assays confirmed the regulation of PTEN by TBX2 and ChIP assays demonstrated that TBX2 recruited HDAC1 to the PTEN promoter for repression. The role of HDAC1 in repression of PTEN was confirmed by treatment with HDAC inhibitors, which abrogated the repression of PTEN by TBX2.
This work demonstrates that the high expression of TBX2 in RMS is involved in the activation of PI3K-AKT signaling pathway by repressing PTEN, underlying the oncogenic function of TBX2 in tumor cells.
Citation Format: Bo K. Zhu, Judith K. Davie. TBX2 promotes rhabdomyosarcoma (RMS) tumorigenesis by repression of PTEN expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2102. doi:10.1158/1538-7445.AM2015-2102
Abstract 2110: Modulating NRAS mRNA translation by nucleic acid clamp-mediated stabilization of the 5′- UTR G-quadruplex
Authors: Hao Taisen , Brooks Tracy A. 
Published: August 2015

Abstract
NRAS, a proto-oncogene belonging to the RAS oncogene superfamily, is a intracellular signal cascade mediator, with intrinsic GTPase activity, functioning to initiate the MAPK cell signaling pathway. Among the RAS oncogene superfamily that is mutated in approximately 30% of all cancers, the NRAS mutation accounts for about 15% of RAS related human malignancies, particularly myeloid leukemias and cutaneous melanomas. Recently, a stable G-quadruplex (G4) was previously identified in the 5′-untranslated region (UTR) of NRAS mRNA. This G4 functioned as a translational silencer, downregulating NRAS protein and leading to the hypothesis that a small nucleic acid clamp could be optimized to facilitate the formation of specifically this G4, decrease NRAS expression, and facilitate cell death in melanoma cells. In the present study, a set of clamps were designed and examined for their ability to facilitate the formation of a G4 in the 5′-UTR sequence of NRAS. These clamps are comprised of ribonucleotides complementary to the RNA 5′- and 3′-regions flanking the G4-forming sequence held together by a small linker element. Based on binding studies consisting of electromobility shift assays and circular dichroism, an optimal flank length and linker length was chosen for cellular studies. Effects on cellular viability and NRAS expression are being examined in leukemia and melanoma cells, and RNA ChIP-Seq is being used to localize the intracellular activity of the clamps to the 5′-UTR. These nucleic acid clamps offer a high degree of selectivity for G4s over linear RNA facilitated by the small linker region; moreover, the approach of complementary nucleotides, versus small molecule-mediated G4 stabilization, allows for specificity for just one G4 out of all of the intracellular structures. This approach not only provides a solid base for developing the clamp into a non-small molecule cancer therapy, but also opens a new window for modulating oncogenic gene expression at the transcriptional or translational levels. The current study, in particular, offers a novel approach to anti-NRAS-mediated therapies for the treatment of myeloid leukemias and cutaneous melanomas.
Citation Format: Taisen Hao, Tracy A. Brooks. Modulating NRAS mRNA translation by nucleic acid clamp-mediated stabilization of the 5′- UTR G-quadruplex. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2110. doi:10.1158/1538-7445.AM2015-2110
Abstract 215: Tracking transplanted cells with paramagnetic fluorinated nanoemulsions
Authors: Kislukhin Alexander A. , Xu Hongyan , Adams Stephen R. , Narsinh Kazim , Tsien Roger Y. , Ahrens Eric T. 
Published: August 2015

Abstract
Visualization of distinct cell populations in vivo is one of the most formidable challenges in biomedical sciences. Clinical translation of cutting-edge therapies that involve administration of live immunotherapeutic or stem cells can benefit from understanding the fate of injected cells in vivo. Magnetic resonance imaging (MRI) is emerging as a prime method for non-invasive, longitudinal cell tracking. Fluorine-19 MRI (19F MRI) involves the use of non-radioactive 19F label in the form of biologically inert, cytocompatible perfluorocarbons (PFC). Immediately prior to injection, cells of interest are labeled ex vivo with water-based PFC nanoemulsions. 19F MRI yields background-free images of labeled cells in an anatomical context provided by conventional 1H MRI. Both datasets are acquired on the same scanner in one imaging session. This technology has recently been used to detect immunotherapeutic dendritic cells delivered to colorectal adenocarcinoma patients.
We sought to enhance sensitivity and versatility of 19F MRI by using paramagnetic relaxation agents. Covalent modification of clinically relevant PFCs with metal-binding ligands enabled stable and uniform incorporation of gadolinium and iron in the fluorous phase of nanoemulsions. Paramagnetic relaxation enhancement resulted in up to 50-fold reduction in 19F longitudinal relaxation time (T1) compared to state-of-the-art commercial tracers. The ultralow 19F T1 of our paramagnetic tracers enabled in vivo cell tracking with rapid, three-dimensional, zero time-to-echo (ZTE) 19F MRI pulse sequences in mice bearing subcutaneous allografts of 19F-labeled GL261 cells. Moreover, the high local concentration of paramagnetic metals imparted negative contrast in T2*-weighted 1H images.
Combination of the new agents with conventional 19F tracers comprises a previously unavailable toolbox of 19F contrast agents, selectively detectable by appropriate acquisition methods. This enables “multicolor” 19F MRI tracking of multiple cell populations, e.g., for monitoring the interaction of host immune cells with injected therapeutic cells or cancer xenografts. Overall, the design of biocompatible, fast-relaxing 19F tracers addresses the issue of modest sensitivity of 19F MRI and reduces the barriers to widespread adoption of this powerful imaging technique.
Citation Format: Alexander A. Kislukhin, Hongyan Xu, Stephen R. Adams, Kazim Narsinh, Roger Y. Tsien, Eric T. Ahrens. Tracking transplanted cells with paramagnetic fluorinated nanoemulsions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 215. doi:10.1158/1538-7445.AM2015-215
Abstract 2153: Kinome inhibitor screen identifies kinase inhibitors that inhibit selectively the survival of mutant K-Ras-dependent human cancer cells
Authors: Berndt Norbert , Zhang Xiaolei , Jiang Rays H.Y. , Sebti Said M. 
Published: August 2015

Abstract
While mutant (mt) KRas has proven to be difficult to target directly, mt KRas-driven cancer cells may gain dependencies on other signal transduction pathways. Therefore, exploring these dependencies may lead to the discovery of pathways and targets whose inhibition may induce synthetic lethality in cancer cells that depend on mt KRas. We have screened a kinase inhibitor library against 7 human cancer cell lines that harbor mt KRas; 4 mt KRas-dependent (A427 and H358 (lung), SW620 and SK-CO-1 (colon)); and 3 mt KRas-independent (HCT116, DLD-1 and HCT-8 (colon)) to identify kinase inhibitors that selectively inhibit the survival of mt KRas-dependent cancer cells. Our results show that 13 of the kinase inhibitors suppressed potently the survival of all 7 human cancer cell lines, 31 inhibited very weakly and 84 inhibited differentially each cell line, and the remaining compounds showed varied activities across cell lines. Importantly, 7 kinase inhibitors inhibited preferentially (p&lt; 0.01) the viability of mt KRas-dependent over -independent human cancer cell lines. These results suggested that the 7 compounds may target kinases whose inhibition preferentially affects mt KRas-dependent cells. Analysis of the kinases that are targeted by these inhibitors revealed that these compounds target predominantly tyrosine kinases suggesting that at least in these cell lines these compounds may disrupt mt KRas “addiction” by inhibiting tyrosine kinase-dependent signaling.
Citation Format: Norbert Berndt, Xiaolei Zhang, Rays H.Y. Jiang, Said M. Sebti. Kinome inhibitor screen identifies kinase inhibitors that inhibit selectively the survival of mutant K-Ras-dependent human cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2153. doi:10.1158/1538-7445.AM2015-2153
Abstract 216: Pancreatic cancer fluorescence-­guided surgery with a fluorophore­-conjugated antibody to carcinoembryonic antigen (CEA) improves surgical resection and increases disease-free and overall survival in orthotopic mouse models
Authors: Metildi Cristina A. , Kaushal Sharmeela , Luiken George A. , Hoffman Robert M. , Bouvet Michael 
Published: August 2015

Abstract
We established nude­ mouse models of human pancreatic cancer with surgical orthotopic implantation of the human BxPC­3 pancreatic cancer for fluorescence-guided surgery (FGS). After 2 weeks, mice then underwent bright-­light surgery (BLS) or FGS 24 hours after intravenous injection of anti CEA­-Alexa Fluor 488. Completeness of resection was assessed from postoperative imaging. Mice were followed postoperatively until premorbid to determine disease-free survival (DFS) and overall survival (OS). Complete resection was achieved in 92% of mice in the FGS group compared to 45.5% in the BLS group (p = 0.001). FGS resulted in a smaller postoperative tumor burden (p = 0.01). Cure rates with FGS compared to BLS improved from 4.5 to 40%, respectively (p = 0.01), and 1­year postoperative survival rates increased from 0% with BLS to 28% with FGS (p = 0.01). Median DFS increased from 5 weeks with BLS to 11 weeks with FGS (p = 0.0003). Median OS increased from 13.5 weeks with BLS to 22 weeks with FGS (p = 0.001). FGS resulted in greater cure rates and longer DFS and OS using a fluorophore-­conjugated anti ­CEA antibody. The present results demonstrate that FGS has potential to improve the surgical treatment of pancreatic cancer.
Citation Format: Cristina A. Metildi, Sharmeela Kaushal, George A. Luiken, Robert M. Hoffman, Michael Bouvet. Pancreatic cancer fluorescence-­guided surgery with a fluorophore­-conjugated antibody to carcinoembryonic antigen (CEA) improves surgical resection and increases disease-free and overall survival in orthotopic mouse models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 216. doi:10.1158/1538-7445.AM2015-216