bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1074: Keratinocyte growth factor suppresses malignant phenotype of cutaneous squamous carcinoma cells
Authors: Toriseva Mervi , Ala-aho Risto , Peltonen Juha , Peltonen Sirkku , Grenman Reidar , Kahari Veli-Matti 
Published: August 2012

Abstract
Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. Here, we have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n=6) than in normal skin samples (n=5). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal epidermal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but it suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal epidermal keratinocytes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1074. doi:1538-7445.AM2012-1074
Abstract 1079: Identification of autocrine motility factor (AMF) receptor, HER2 (ErbB2) in breast cancer cells
Authors: Kho Dhonghyo 
Published: August 2012

Abstract
Overexpression of HER2 (ErbB2) oncoprotein is associated with approximately 25% of aggressive breast carcinoma. Although a humanized monoclonal antibody (Trastuzumab) against HER2 is currently considered one of the most effective treatments, a significant number of patients are initially or eventually become resistant to Trastuzumab based therapy. Here, we demonstrate that secreted phosphoglucose isomerase (PGI)/ autocrine motility factor (AMF), an orphan -CXXC- cytokine directly binds to HER2 and activates PI3K and MAPK through HER2 autophosphorylation, and also induces immediately HER2 cleavage in metalloprotease dependent fashion. We therefore speculate that AMF/HER2 signaling pathways play a physiological role in HER2 overexpressing breast cancer cells and contribute to Trastuzumab resistance and propose that AMF can be a novel therapeutic target in Trastuzumab resistant breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1079. doi:1538-7445.AM2012-1079
Abstract 108: Functional characterization of WAC, a candidate tumor suppressor gene in colorectal cancer
Authors: Conboy Caitlin B. , Hatler Julia M. , Scott Pat M. , Sarver Aaron L. , Silverstein Kevin A. , Seshagiri Somasekar , Adams Matthew , Lillemoe Jenna , Dorr Casey R. , Cormier Robert T. , Starr Tim K. , Largaespada David A. 
Published: August 2012

Abstract
Broadening our understanding of the genetic basis of cancer will facilitate construction of relevant pre-clinical models and provide novel targets for drug development. To identify genes that contribute to the initiation or progression of colorectal cancer (CRC) when mutated or dysregulated, we recently conducted a set of forward genetic screens using transposon insertional mutagenesis to drive intestinal tumor formation in mice. These studies were designed to identify novel cancer genes that function in a wildtype genetic context or cooperate with known predisposing alleles (ApcMin/+ or Trp53R270H/+). Over 150 genes were identified, including several known to be important in human CRC (eg. APC, PTEN, and FBXW7) and many novel candidate cancer genes. WW domain containing adaptor with coiled-coil (WAC), is a gene not previously associated with cancer that was identified in all three screens. While the function of WAC is incompletely understood, previous reports indicate that the WAC protein participates in multiple cellular processes, including golgi biogenesis, modulation of gene expression, and induction of p21CIP1 expression and cell cycle arrest in response to DNA damage. In this study, we evaluated the role of WAC in cellular transformation by depleting WAC in mouse colonic epithelial cells conditionally immortalized by expression of a temperature sensitive SV40 large T antigen. In this model, loss of WAC expression increased anchorage-independent growth of colonic epithelial cells in cooperation with mutant APC. In human CRC samples, resequencing the WAC gene identified non-silent mutations in 2 of 74 samples. Further, CRC-associated WAC mutants were found to be functionally deficient in induction of p21CIP1 in a zebrafish embryo model. These data are consistent with the model that WAC functions as a tumor suppressor in the colonic epithelium.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 108. doi:1538-7445.AM2012-108
Abstract 1193: A single phosphorylation site mutant of the Retinoblastoma protein blocks apoptosis induced by UV
Authors: Lentine Brandon , Hunce Raymond A. , Antonucci Lisa , Krucher Nancy A. 
Published: August 2012

Abstract
The Retinoblastoma protein (Rb) is important in the control of cell proliferation and apoptosis. Its activity is controlled by reversible phosphorylation on several serine and threonine residues. When Rb is hypophosphorylated, it inhibits proliferation by preventing passage through the G1- S phase transition. Hyperphosphorylated Rb promotes cell cycle progression. The role of Rb phosphorylation in the control of apoptosis is largely unknown, although several apoptotic stimuli result in dephosphorylation of Rb. It may be the case that dephosphorylation of specific amino acids may signal apoptosis versus cell cycle arrest. Using glutamic acid mutagenesis, we have generated 15 single phosphorylation site mutants from serine/threonine to glutamic acid, to mimic the phosphorylated state. By calcium phosphate transfection mutant plasmids were introduced into C33A Rb-null cells and apoptosis was induced using UV. Apoptosis was measured by ELISA detection of degraded DNA and by immunoblotting to assess proteolytic cleavage of PARP. We found that only threonine-821 when mutated to glutamic acid blocked apoptosis by 50% whereas other sites tested had little effect. In addition, endogenous Rb is dephosphorylated on threonine-821 when cells are undergoing apoptosis. Experiments to determine the effect of this mutation in response to additional apoptotic stimuli are underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1193. doi:1538-7445.AM2012-1193
Abstract 1201: Hypoxia promotes not CXCR7 but CXCR4 expression and its biological activity in gastric cancer cell through activation of hypoxia-inducible factor-1β
Authors: Lee Hyo Jin , Oh Yun Sook , Kim Ha Yon , Yoon Hwan Jung , Jo Deog Yeon , Kim Samyong 
Published: August 2012

Abstract
Background: The chemokine receptor, CXCR4 and CXCR7, which bind with high affinity same chemokine CXCL12/SDF-1, are associated with the biological behavior in several kinds of cancer, but few studies have addressed the expression and regulation of CXCR4 and CXCR7 in gastric cancer. Methods: Gastric cancer cell line KATO III was subjected to hypoxia or normoxia. The expression of CXCR4 and CXCR7 were investigated using RT-PCR, Westerning blotting, and flow cytometry before and after hypoxic conditioning. The regulation of CXCR4 and CXCR7, and their biological effects by hypoxia were evaluated using gastric cancer cells transfected with hypoxia-inducible factor (HIF)-1α shRNA. Result: mRNA and proteins of both CXCR4 and CXCR7 were detectable by RT-PCR and Western blot analysis, respectively, in KATO III cells. A small population of KATO III cells expressed membrane CXCR4 and CXCR7 as determined by flow cytometry. Hypoxia up-regulated CXCR4 proteins and enhanced membrane expression of CXCR4 in human gastric cancer KATO III cells, which constitutively expressed membrane CXCR7 and CXCR4 in a steady state, as revealed by Western blotting and flow cytometry, respectively. In contrast, CXCR7 proteins remained unchanged under hypoxia, and promotion of CXCR7 surface expression on KATO III cells could not be demonstrated by flow cytometry. Hypoxia-induced expression of CXCR4 was mediated through activation of HIF-1α with phosphorylation of AKT and ERK, as revealed by HIF-1α knockdown using shRNA. The chemical inducer of HIF-1α, cobalt chloride, induced upregulation of CXCR4 in KATO III cells under normoxic conditions. In addition, KATO III cells exposed to hypoxic condition showed enhanced wound healing, transwell migration, and invasion in response to stromal cell-derived factor (SDF)-1α, a specific ligand for CXCR4. Conclusions: These findings provide evidences for differential regulation and different role of chemokine receptor, CXCR7 and CXCR4, in gastric cancer cell in vitro.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1201. doi:1538-7445.AM2012-1201
Abstract 121: Novel epigenetic mechanisms of resveratrol regulation of PTEN/Akt pathway in prostate cancer
Authors: Dhar Swati , Li Kun , Dias Steven J. , Levenson Anait S. 
Published: August 2012

Abstract
Resveratrol (Res) (3,5,4′-trihydroxy-trans-stilbene), a natural compound found in grapes and berries, is one of the most promising diet-derived chemopreventive agent with potential chemotherapeutic capabilities. Chemopreventive and anticancer effects of Res may be exerted in part by modulating various components of the epigenetic machinery. We recently demonstrated that Res represses nucleosome remodeling and deacetylation (NuRD) co-repressor complex by inhibiting metastasis associated protein 1/ histone deacetylase 1 (MTA1/HDAC1) subunit, which plays an essential role in governing deacetylation of histone and non-histone proteins. Since Res-induced upregulation of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is concomitant with MTA1-downregulation, we hypothesized that in the absence of Res MTA1 works in cooperation with PI3K/Akt survival pathways. We further hypothesized that Res-induced restoration of PTEN expression and function may occur by dual mechanism through MTA1/HDAC inhibition and regulation of miRNA network. Our data indicate that shRNA-mediated MTA1 knockdown in Du145 cells (wt PTEN) enhances acetylation of PTEN, and that HDAC inhibitor trichostatin (TSA) further potentiates PTEN acetylation. We also showed that Res treatment simultaneously decreases MTA1 and pAkt levels in LNCaP cells, the effect which is enhanced in combination with PI3K inhibitors, LY294002 and BEZ235. To further understand Res-induced MTA1-mediated epigenetic alterations, we analyzed MTA1-associated and Res-induced microRNA (miRNA, miR) changes in LNCaP cells expressing and silenced for MTA1 (shMTA1). Interestingly, Res downregulated miRs (oncomiRs) included members of miR17-92 cluster (miRs-17, 20a, 20b) and miRs 106a and 106b which target PTEN. These findings were further confirmed by real time PCR analysis which showed that Res specifically down-regulated these miRNAs in PCa cells (LNCaP and Du145) but not in normal prostate cell line RWPE-1. Direct interaction of miR-17, miR-20a and miR-106b with PTEN 3′UTR were analyzed in the presence and absence of Res using pmiRGLO luciferase reporter. In summary, we propose novel epigenetic mechanisms of Res regulation of PTEN/ Akt signaling through inhibition of MTA1/NuRD co-repressor complex and MTA1-associated miRNAs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 121. doi:1538-7445.AM2012-121
Abstract 1215: Orexin and their 7-membrane spanning receptors OX1R: a new colon cancer therapeutic target
Authors: Voisin Thierry , Firar Aadil El , couvineau alain , laburthe marc 
Published: August 2012

Abstract
Orexins are hypothalamic peptides involved in sleep/wake control. Unexpectedly, we have shown that orexins promote robust apoptosis in various colorectal cancer cells1. The cell death is mediated by the orexin 1 receptor (OX1R) through an original mechanism. OX1R, a G protein-coupled receptor class I (GPCR), is aberrantly expressed in primary colorectal tumors and liver metastases2. We next investigated the molecular mechanism of OX1Rmediated cell death. OX1R makes use of “tyrosine-based motifs” ITIM (Immunoreceptor Tyrosine-based Inhibitory Motif)3 and ITSM (Immunoreceptor Tyrosine-based Switch Motif)4 to drive apoptosis. These “tyrosine-based motifs” are mandatory for recruitment and activation of the tyrosine phosphatase SHP-2, leading to apoptosis. Orexins promote cell death through Mitogen-/Stress-activated Protein Kinase (MAPK/SAPK) p38 activation in a SHP-2 dependent manner. The present work is original for two reasons: 1) OX1R is the first example of the involvement of both ITSM and ITIM in GPCR signal transduction. ITIM and ITSM sequences are more frequent than initially thought in GPCRs. This emphasizes the need to explore this mechanism of signal transduction in various GPCRs for regulating cellular processes including at least cell apoptosis and proliferation; 2) we provide evidence that OX1R is aberrantly expressed in all primary colorectal tumors and liver metastases and that its activation by exogenous orexins result in robust apoptosis of colon cancer cells in culture and strong decrease of tumor development in mice xenografted with colon cancer cells in vivo. OX1R represent a new promising target in colorectal cancer therapy and/or for metastases imaging. 1 J.Biol.Chem, 279: 45875 (2004) 2 Can. Res. 71: 3341 (2011) 3 FASEB J. 22: 1993 (2008) 4 FASEB J. 23: 4069 (2009)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1215. doi:1538-7445.AM2012-1215
Abstract 1221: Microscopy based high throughput screen for the mechanistic analyses of ErbB2 degradation in response to Hsp90-targeted therapeutics
Authors: Bailey Tameka A. , Luan Haitao , Wells Amy L. , Kelly David L. , Naramura Mayumi , Raja Srikumar , Band Vimla , Band Hamid 
Published: August 2012

Abstract
ErbB2 expression is observed in 25 - 30 % of invasive breast cancers and is associated with reduced response to chemotherapy, and shorter time to relapse and reduced overall survival of breast cancer patients. Malignant mammary epithelial cells that overexpress ErbB2 exhibit enhanced proliferation, invasion of mammary tissue and metastasis. The stability of overexpressed mature ErbB2 at the plasma membrane of mammary epithelial cells is critically dependent on its interaction with the chaperone protein, heat shock protein 90 (Hsp90). Thus, Hsp90 promotes the proliferation and survival of malignant mammary epithelial cells and interruption of this interaction is expected to inhibit the growth of ErbB2-overexpressing tumors. 17-AminoAllyl-Geldanamycin (17-AAG), an Hsp90 inhibitor, is a semi-synthetic ansamycin antibiotic currently in phase II clinical trials for breast cancer treatment (www.clinicaltrials.gov). Because it preferentially binds to Hsp90 of the chaperone complex in malignant mammary epithelial cells, treatment of ErbB2-overexpressing breast cancer with 17-AAG is expected to destabilize ErbB2 and inhibit tumor growth. While a number of Hsp90 client proteins have been identified, ErbB2 is amongst the most sensitive to Hsp90 inhibition. These facts provide strong rationale for using 17-AAG as a part of the targeted therapy against ErbB2-overexpressing breast cancer. However the cellular machinery responsible for 17-AAG induced degradation of ErbB2 is not completely understood. At present it is unclear whether internalization of ErbB2 occurs via Clathrin-dependent or -independent endocytosis. Furthermore it is unresolved if the degradation of ErbB2 is dependent upon proteasomal or lysosomal proteolysis. And although C-terminus of Hsp70 Interacting Protein (CHIP) and Cullin 5 were identified as E3 ligases responsible for the ubiquitination of ErbB2, it is unknown if these ligases are the sole E3s responsible for the ubiquitnation of ErbB2. Also vague is if the rerouting of ErbB2 from the recycling pathway to the degradative pathway in response to 17-AAG is exclusively dependent upon ubiquitnation. In this current work we attempt to bridge these critical gaps in our knowledge of the mechanisms of 17-AAG induced degradation of ErbB2 using an automated microscopy-based analysis to identify genes whose siRNA-dependent suppression reduces 17AAG-induced ErbB2 degradation. We expect that this work will identify additional targets for therapeutic intervention and potential biomarkers of response to breast cancer drug therapy with Hsp90 inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1221. doi:1538-7445.AM2012-1221
Abstract 1229: Fibroblast growth factor signaling in ovarian cancer
Authors: Brantner Manuel , Wagner Renate , Grusch Michael , Berger Walter , Holzmann Klaus , Marian Brigitte , Grunt Thomas W. 
Published: August 2012

Abstract
Epithelial ovarian cancer (OC) is a rapidly progressive, highly lethal disease. It is the fifth leading cause of cancer-related death among women. Over the last decades, there has been only modest improvement in the treatment of OC. Nevertheless, recent clinical trials with inhibitors of transmembrane receptor tyrosine kinases such as fibroblast growth factor (FGF) receptors (FGFRs) yielded some promising results in OC. FGFRs are involved in malignant transformation, angiogenesis and chemoresistance. Inhibition of FGFR-dependent signaling can overcome resistance to standard therapies. Thus, FGFRs represent potential targets for cancer therapy. Unfortunately, however, the biological and therapeutic relevance of the FGF-FGFR system has not been elucidated yet in OC. The aim of this study was to characterize the FGF-FGFR system, its influence on malignancy-related cell properties and its potential role as a druggable signaling pathway in OC cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that expression of FGFs and FGFRs, leading to autocrine signaling loops with a strong mitogenic potential, is a common event in OC. Immunoblotting proved that the FGF signaling system is functionally active in these cells. Conditioned growth medium was able to induce phosphorylation of ERK1/2. Moreover, recombinant FGF-2 significantly elevated the growth rate in approximately 50% of the OC cell lines as demonstrated by formazan dye assay, whereas FGF-1 markedly induced migration in 66% of the cell lines. The dependency of OC cells on FGFR signaling was further evaluated by growth inhibition assays using the two small molecular FGFR inhibitors PD173074 and dovitinib (TKI-258, CHIR-258). A-2780 cells were found to be extremely sensitive to FGFR inhibition, while HEY and SKOV-3 cells showed moderate sensitivity. In contrast, OVCAR-3 cells were not inhibited by these compounds. Together, our data suggest that FGFR inhibitors reveal anticancer activity in a significant proportion of OC cells even as single drugs. Thus, combination of conventional cytotoxic intervention with blockade of the FGF-FGFR system might represent a promising future strategy for the treatment of OC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1229. doi:1538-7445.AM2012-1229
Abstract 1230: Syntaxin 6- and microtubule-mediated intracellular trafficking contributes to Golgi and nuclear translocation of EGFR
Authors: Du Yi , Shen Jia , Hsu Jennifer L. , Han Zhenbo , Wang Ying-Nai , Yamaguchi Hirohito , Miller Stephanie A. , Hung Mien-Chie 
Published: August 2012

Abstract
Receptor mediated endocytosis is well known for its degradation and recycling trafficking. Recent evidence shows that these cell surface receptors translocate from cell surface to different cellular compartments, including the Golgi, mitochondria, endoplasmic reticulum (ER) and the nucleus to regulate physiological and pathological functions. Although some trafficking mechanisms have been resolved, the completed mechanism of intracellular trafficking from cell surface to the Golgi is still unknown. Herein, we report a mechanism of the Golgi translocation of EGFR in which EGF-induced EGFR travels to the Golgi via microtubule (MT)-dependent movement by interacting with dynein and fuses with the Golgi through syntaxin 6 (Syn6) mediated membrane fusion. We also demonstrate that the Golgi translocation of EGFR is necessary for its consequent nuclear translocation and transcriptional activity. Interestingly, foreign protein such as bacterial cholera toxin, which is known to activate its pathological function through the Golgi/ER retrograde pathway, also utilizes the MTs/Syn6 pathway. Thus, the MTs/Syn6/Golgi/ER pathway defines a comprehensive retrograde trafficking route for both cellular and foreign molecules to travel from cell surface to the Golgi and the nucleus.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1230. doi:1538-7445.AM2012-1230