bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4015: The role of IL-6/STAT3 axis in the transformation of Epstein-Barr Virus (EBV) infected-immortalized nasopharyngeal epithelial cells
Authors: ZHANG GUITAO 
Published: February 2011

Abstract
The role of IL-6/STAT3 axis in the transformation of Epstein-Barr Virus (EBV) infected-immortalized nasopharyngeal epithelial cells.
Zhang Guitao, Tsang Chi Man, Chen Honglin, Tsao Sai Wah.
Nasopharyngeal carcinoma (NPC) is rare throughout most parts of the world but common in certain geographic area, such as Southern China including Hong Kong. The etiology is based on intricate interactions among environmental factors, genetic susceptibility and Epstein-Barr virus (EBV) infection. Elevated antibody titers to EBV antigens are regularly observed in NPC patients. However, little information is available concerning the role of EBV in the early stage of NPC carcinogenesis. Our laboratory has established and characterized immortalized nasopharyngeal epithelial cells lines as premalignant nasopharyngeal cell models to examine for the transformation property of EBV infection in early stage of NPC development. Our results show that EBV infection activates STAT3 in immortalized nasopharyngeal epithelial cells. We had previously reported that the EBV-encoded LMP1 could upregulate IL-6 secretion to activate STAT3 signaling. Interestingly, we observed that activation of STAT3 in EBV-infected immortalized nasopharyngeal epithelial cells is highly susceptible to the induction by inflammatory cytokines, notably IL-6. Using quantitative real-time PCR, up-regulation of LMP1 was observed after IL-6 treatment on a time course dependent manner. An analysis of IL-6 receptor (IL-6R) indicated that EBV-infected nasopharyngeal epithelial cells have elevated level of IL-6R expression compared with uninfected cells. Activation of STAT3 signaling in immortalized nasopharyngeal epithelial cells by expressing a flag-tagged constitutively active STAT3-C confers transformed properties to cells. Our results support a model that EBV infection may predispose the aberrant STAT3 signaling for inflammatory cytokines involving the activation of LMP1/IL-6/STAT3 axis in premalignant nasopharyngeal epithelial cells. Enhanced STAT3 activation in EBV-infected epithelial cells by stromal inflammatory cytokines could result in irregular-gene expressions and cell signaling essential for malignant transformation, which may represent a crucial function of EBV infection in the development of nasopharyngeal carcinoma.
(This project is supported by The Research Grant Council (Hong Kong) and Area of Excellence on Nasopharyngeal Carcinoma Research Center (Hong Kong)).
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 4015.
Abstract 4017: Identifying Protein-Protein Interactions in Single Protein Complex level by Microchannel Device
Authors: Chou Chao-Kai , Jing Nan , Yamaguchi Hirohito , Tsou Pei-Hsiang , Kameoka Jun , Hung Mien-Chie 
Published: February 2011

Abstract
Cancer is the most threaten disease in this country and deregulations of signal pathways are often responsible for the cancer progression. Many mysteries of cancer related signal pathways have been revealed by current molecular biology research and the detection of protein-protein interactions is one of the critical techniques. The general techniques for protein-protein interactions detection include immuno-precipitation, immuno-fluorescence staining, and fluorescence resonant energy transfer. These techniques can detect specific protein in cultured cell and in tissue and have been applied in most biomedical research. However, all of them have various limitations. For instance, only two molecules could be examined in one experiment and the detection usually require long processing time with complicated procedures and large sample amount. Moreover, the detection of signals currently is still relied on X-ray film exposure or eye-direct observation that may limit the sensitivity and accuracy. We are developing a microchannel detection system in order to avoid these defects and to provide rapid and accurate detection in breast cancer signal transduction research. The principle is that nanochannel fluidics could only allow a single protein complex to pass through the detection point of fluorescence spectroscopy during examination and the result from the single protein complex could provide us most direct information of protein-protein interaction. Since the detection level is down to the single protein complex, it could highly increase the detection sensitivity. Currently, we have successful fabricated different size of microchannels and we recognized that top-down fabrication approach on transparent silicon based wafers could provide the best quality nanochannels. The channel was than integrated to the fluorescence spectroscopy for single fluorescence detection. To test the performance of the device, fluorescence antibodies were loaded into the channel and we successfully detected a single fluorescence signal during the experiment. Subsequently, we detect demonstrated that epidermal growth factor receptor (EGFR) interact with its downstream proteins Src and STAT3 in a single complex after epidermal growth factor (EGF) stimulation. However, only 1.8% of EGFR interact with both Src and STAT3 at the same time which suggests that EGFR/Src/STAT3 is a transition product in the dynamic of EGFR signal transduction. Thus, our system provides the interaction information from a single protein complex with the ratio of interactive proteins to dissect the signal transduction in dynamic aspect and will offer an effective technology.
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 4017.
Abstract 4018: Crosstalk between the pleiotrophin-anaplastic lymphoma kinase axis and the protein tyrosine phosphatase ζ signaling pathways
Authors: Kodack David P. , LaConti Joseph , Noda Masaharu , Wellstein Anton 
Published: February 2011

Abstract
Pleiotrophin (PTN) is a heparin-binding growth factor that can support tumor growth, invasion, angiogenesis, and metastasis. The mechanism of action (receptor signaling pathway) responsible for mediating PTN's biological effects, however, is still controversial. Here we show that an antibody targeting the ligand-binding domain of anaplastic lymphoma kinase (ALK) is capable of blocking the signaling effects of PTN in a glioblastoma cell line that expresses high levels of ALK. This corroborates recent findings by Stylianou, et al. (2009), who showed disruption of PTN activity with a single chain variable IgG fragment that binds to the ALK ligand-binding domain. Furthermore, expression of protein tyrosine phosphatase receptor ζ (Ptprz) in cells resulted in crosstalk with the PTN-ALK signaling axis at the level of p38 MAPK. While PTN increased p38 MAPK phosphorylation, the presence of Ptprz decreased its phosphorylation, both at its basal as well as PTN-enhanced levels. Enhancement of p38 MAPK phosphorylation by PTN is possibly mediated through activation of MKK4, as it was phosphorylated in the presence of PTN. On the other hand, the mechanism for Ptprz-mediated suppression of p38 MAPK is not yet clear, as there was no change in phosphorylation of MKK3, MKK4, or MKK6 after its over-expression. These findings suggest that ALK is playing a direct role in PTN activity, and that the Ptprz signaling pathway may act in a separate but inter-connecting fashion. Parallel targeting of both the ALK and Ptprz signaling pathway may be necessary for the treatment of tumors (glioblastoma) expressing both membrane proteins.
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 4018.
Abstract 402: Role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in chemotherapy induced myeloid leukemia
Authors: Potla Ratnakar , Jaiswal Anil K. 
Published: February 2011

Abstract
Individuals with NQO1P187S mutation have no detectable NQO1 protein levels. These individuals have been extensively predicted to be at high risk for developing chemotherapy-induced leukemia. We have studied the effect of Etoposide, a DNA Topoisomerase II inhibitor used in many chemotherapeutic regimens, on NQO1 gene deleted (NQO1-/-) mice. NQO1-/- mice are born with a myelodysplastic bone marrow. Flow cytometric analysis of blood, bone marrow and spleen showed an increase in megakaryocytic and myeloid cell lineages in NQO1-/- mice. A spectrum of responses ranging from leukopenia to myeloid leukemia were observed with increasing drug concentration by Flow cytometry and confirmed by histochemistry in NQO1-/- mice. C/EBPalpha plays a key role in the myeloid lineage commitment of hematopoietic progenitor cells. NQO1 protects C/EBPalpha from 20S proteasomal degradation in in vitro assays. Altered C/EBPalpha levels are responsible for the preferential increase in myeloid cell lineage in NQO1-/- mice.
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 402.
Abstract 4023: Novel role of neurofibromin in transport of RNA granules
Authors: Arun Vedant , Wiley Joseph , Karim Zia , Guha Abhijit 
Published: February 2011

Abstract
Neurofibromatosis 1 (NF1) is the most common tumor predisposing syndrome in humans, with an incidence of 1:3500 live births. Neurofibromin, encoded by Nf1, acts as a p21-Ras-GAP to directly interact with and inactivate p21-Ras, through its’ GAP Related Domain (GRD). Evidence suggests that non-Ras-GAP functions mediated through interactions with domains outside of the GRD are of importance. By making a number of NF1-GST domain constructs coupled with differential Mass Spec analysis, we identified LRPPRC and Dynein as previously unreported NF1-TBD interacting proteins. LRPPRC was of interest as it is mutated in the Leigh Syndrome French Canadian (LSFC) variant, a cytochrome-oxidase deficiency syndrome, characterized by neurodegeneration, developmental- mental- and growth-retardation, thereby having some similarities with non-tumor manifestations of NF1. We have established that LRPPRC and neurofibromin interact in vitro by immunoprecipitation and reverse bait immunoprecipitation. Use of a novel Proximity Ligation Assay (PLA) was used to further confirm the interaction in situ in cell lines and clinical tissue cryosections. Towards elucidating the functional relevance of the interaction, we have established that the two proteins complex with microtubules and motor proteins, which indicates a role in microtubule-dependant intracellular transport. Since LRPPRC binds with mRNA and is involved in its nucleocytosolic shuttling, we hypothesize that the cargo transported by this complex could be RNA granules. Mass Spec analysis of NF1 immunoprecipitates revealed a number of proteins that are a part of the RNA granule complex which include RNA binding proteins and proteins involved in mRNA translation. By performing RNA Immunoprecipitation (RIP) with NF1 and LRPPRC antibodies, we have demonstrated that the two proteins do complex with 18S and 28S rRNA which is indicative of the presence of intact mRNA. Towards identifying the specific messages transported by the NF1-LRPPRC RNA granule complex we are performing RIP - microarray gene expression profiling (CHIP). The resultant candidate mRNAs will be further investigated to understand the importance of this novel interaction and novel mechanism towards some of the overlap of neurological and developmental manifestations between LSFC and NF1.
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 4023.
Abstract 4029: Sox9 functions downstream of Hedgehog-Gli1 in epithelial transformation
Authors: Deng Wentao , Ruppert J. Michael 
Published: February 2011

Abstract
The Sonic Hedgehog (Shh) signaling pathway plays critical roles in cell fate specification during embryonic and fetal development and in adult tissues. The extracellular morphogen, Shh, signals through Gli family zinc finger transcription factors to regulate the expression of downstream target genes. Constitutive Shh-Gli signaling is implicated in the pathogenesis of several human cancers, including cutaneous basal cell carcinoma (BCC), prostate cancer and medulloblastoma. How Gli can signal through downstream genes to induce malignant transformation remains poorly understood.
In this work, we performed microarray analysis to reveal the gene expression profile after tetracycline-regulated induction of Gli1 for 3 or 6 hours in cultured epithelial cells, identifying multiple known Shh target genes. Among the most rapidly induced genes was Sox9, a member of SRY family of transcription factors. Sox9 is essential for male sex determination and is a master regulator of chondrogenesis. Sox9 is also well established as a Shh-Gli target gene, but how it functions in Shh-Gli signaling is not well understood. We found that Sox9 mRNA and protein levels are greatly increased after short-term or long-term Gli1 expression in a rat culture model of epithelial cells, termed RK3E, and in mouse skin. As shown by reporter assays, Sox9 transcriptional activity was increased by approximately 18-fold in RK3E cells transformed by Gli1. To enable knockdown studies in rat cells, we defined the full-length rat Sox9 coding sequence. Subsequently, suppression of rat Sox9 by siRNA indicated an essential role for this Gli-regulated gene in malignant transformation of RK3E in vitro. Specifically, shRNA plasmids that suppress Sox9 could dramatically reduced the transforming activity of Gli1. In contrast, there was little effect on other transforming oncoproteins including H-Ras and ErbB2. These results establish Sox9 induction as an early response to Gli1, and demonstrate that induction of Sox9 is essential for transformation by Gli1. Further characterization of the Sox9 knockdown phenotype is in progress and will be presented.
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 4029.
Abstract 403: Deletion of HBZ alters lymphomagenesis in HTLV-1 infected humanized SCID mice
Authors: Crawford Lindsey , Banerjee Prabal , Lairmore Michael , Green Patrick , Feuer Gerold 
Published: February 2011

Abstract
Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of Adult T-cell Leukemia (ATL), an aggressive, mature CD4+/CD25+ T-cell malignancy. The early molecular events induced by HTLV-1 infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+ HPCs). Humanized NOD/SCID (HU-SCID) mice generated by injection with HTLV-1-infected CD34+ HPCs demonstrate persistent infection and reproducibly develop CD4+ T-cell lymphomas (∼80%) with clinical characteristics associated with ATL. The HTLV-1 bZIP protein (HBZ) is consistently expressed in all ATL cells and has been implicated in the maintenance of leukemogenesis. HBZ has previously been demonstrated to modulate Tax activity and to interact with the cellular factors CREB, Jun and p53. Transduction of HBZ into CD34+ HP/HSCs using a lentivirus vector suppresses clonogenic colony formation in vitro. Moreover, infection of CD34+ HP/HSCs with an infectious proviral clone lacking functional HBZ (HTLV-1ΔHBZ) results in elevated clonogenic colony formation in vitro, suggesting that HBZ suppresses hematopoiesis. To establish the role of HBZ in HTLV-1 replication and leukemogenesis in vivo, HU-SCID mice were infected with an infectious proviral clone lacking functional HBZ (HTLV-1ΔHBZ). HTLV-1ΔHBZ-infected HU-SCID mice developed lymphoproliferations that were phenotypically characterized as a mixture of immature lymphoid progenitors (CD90+) and mature B-cells (CD19+) starting at ∼10 weeks post-reconstitution, in contrast to wild-type HTLV-1 infection. Lymphoproliferations induced by HTLV-1ΔHBZ successfully engraft and expand in naïve NOD/SCID mice when injected into the peritoneal cavity and leukemic cells and lymphoma cells express HTLV-1 gp46env and p19gag. FACS-purified CD90+CD19− HTLV-1ΔHBZ infected cells also successfully engraft in naïve NOD/SCID mice and mature into CD19+ cells suggesting that these cells may be leukemic progenitors with the capability of maturing in vivo. In addition, a majority of HTLV-1ΔHBZ-infected HU-SCID mice also develop a progressive, flaccid hind limb paralysis with features similar to the neurological disorder, HAM/TSP. These results suggest that HBZ is dispensable for HTLV-1 replication and modulates lymphomagenesis in the HU-SCID model. The humanized SCID mouse provides a novel in vivo platform for analysis of the role of HTLV-1 genes in viral replication and pathogenesis.
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 403.
Abstract 4033: MiR-21 upregulation in breast cancer cells leads to PTEN loss and Herceptin resistance
Authors: Rehman Sumaiyah K. , Huang Wen-Chien , Yu Dihua 
Published: February 2011

Abstract
MicroRNAs (miRNA) are a class of small 22-nucleotides endogenous non-coding RNAs which serve as regulators of gene expression by targeting specific messenger RNAs (mRNA). Aberrant expression of certain microRNAs can lead to therapeutic drug resistance, such as Cisplatin resistance by miR-214 targeting PTEN. Our lab previously found that PTEN loss confers Herceptin resistance in ErbB2-overexpressing breast cancers. Other studies in hepatocellular carcinoma have shown that miR-21 targets the 3′UTR of PTEN mRNA leading to downregulation of PTEN protein levels. Based on these findings, we hypothesized that overexpression of miR-21 may confer Herceptin resistance in breast cancer patients by downregulation of PTEN.
To test this hypothesis, mir-21 and/or control miRNA were transiently transfected and expressed in ErbB2-overexpressing AU565 and SKBr3 breast cancer cell lines, followed by Herceptin treatment. We found that cells with increased miR-21 had reduced PTEN expression and were significantly more resistant to Herceptin treatment versus control miRNA transfected cells. Conversely, when we knocked down miR-21 in high ErbB2 expressing BT474 cells, the cells showed increased PTEN expression and became more sensitive to Herceptin treatment versus control miRNA transfected cells. To determine the clinical relevance of our findings, we detected miR-21 level in patients’ breast cancers with ErbB2 expression that were treated with Herceptin and we found that high miR-21 level significantly correlated with patients’ poor response to Herceptin treatment and disease progression. We are currently identifying other targets of miR-21 to better understand the mechanisms of miR-21 mediated-Herceptin resistance, which may provide new insight on how to overcome Herceptin resistance.
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 4033.
Abstract 4036: The microRNA profile of prostate carcinoma obtained by deep sequencing reveals potential miRNA targets such as myosin VI
Authors: Szczyrba Jaroslaw , Löprich Elke , Wach Sven , Jung Volker , Unteregger Gerhard , Barth Stephanie , Grobholz Rainer , Wieland Wolf , Stöhr Robert , Hartmann Arndt , Wullich Bernd , Grässer Friedrich 
Published: February 2011

Abstract
Background: Prostate cancer is a leading cause of tumor mortality. In order to identify and characterize the underlying molecular mechanisms, we performed microRNA (miRNA) profiling of primary prostate cancers and non-cancer prostate tissue. Furthermore, using database analysis, we sought to identify regulatory targets of aberrantly expressed miRNAs.
Material and Methods: We performed comparative miRNA expression profiling in ten prostate cancer specimens and ten non-cancer prostate tissue samples using deep sequencing of cDNA libraries. The deregulation of selected miRNAs was validated in established prostate cancer cell lines by Northern blotting as well as in 26 paired samples of prostate cancer tissue and adjacent normal tissue by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The regulative capabilities of selected miRNAs on potential target genes were analyzed in vitro using reporter gene constructs and transfection of miRNA expression vectors
Results: Using deep sequencing we found that 16 miRNAs were up-regulated more than 1.5-fold and 17 miRNAs were down regulated more than 1.5-fold. The most pronounced deregulation was noted for miRNAs miR-375 and miR-200c which showed an up-regulation of more than 4.5-fold and miR-143 and miR-145 which were down regulated 4-fold each. The differential expression of these miRNAs could be confirmed by Northern blot analysis of established prostate cancer cell lines. By analyzing 26 primary prostate cancer samples by qRT-PCR we could detect a significant deregulation of the miRNAs miR-375, miR-143 and miR-145 (p&lt;0.05, paired students T-test). Independent target prediction databases (TargetScan, PicTar) indicate, that the 3′ untranslated region (3′UTR) of the Myosin VI gene is a regulative target for both miR-143 and miR-145. This prediction could be confirmed using a luciferase reporter gene vector containing the Myosin VI 3′UTR. Furthermore, transient expression of miR-143 and miR-145 reduced the amount of Myosin VI protein by 20% and 48% respectively.
Conclusion: Our findings indicate that specific miRNAs are reproducibly found to be deregulated in different cohorts of prostate cancer specimens using independent experimental methods. This is the first report to show that miRNAs miR-143 and miR-145 are capable of negatively regulating the protein expression of Myosin VI.
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 4036.