bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4312: E3 ligase activity of XIAP RING domain is required for XIAP-mediated cancer cell migration but not for its RhoGDI binding activity
Authors: Yu Yonghui , Liu Jinyi , Zhang Dongyun , Luo Wenjing , Yu Jianxiu , Li Jingxia , Zhang Xinhai , Chen Jingyuan , Huang Chuanshu 
Published: August 2012

Abstract
Although an increased expression level of XIAP is associated with cancer cell metastasis in individuals with various types of cancer, the molecular mechanism linking XIAP to cancer metastasis remains unexplored. Here we show that in XIAP depletion HCT116 cells (XIAP−/−), cell migration, invasion and actin polymerization are decreased, which could be rescued either by the introduction of XIAP RING domain or knockdown of RhoGDI. Subsequent studies demonstrate that this function of the XIAP RING domain depends on its inhibition of RhoGDI SUMOylation at K138. Furthermore, SUMO1-RhoGDI, but not un-sumoylated RhoGDI preferentially binds to Rho GTPase and downregulates the activities of GTPases, including RhoA, Cdc42 and Rac1, by which RhoGDI inhibits cancer cellular actin polymerization and motility. Taken together, our study reveals a novel post-translational modification (SUMOylation) of RhoGDI, and its physiological regulation by the RING domain of XIAP, which may account for XIAP modulation of cancer cell motility.
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 4312. doi:1538-7445.AM2012-4312
Abstract 4313: A novel endoplasmic reticulum protein promotes cancer invasion/metastasis
Authors: Evensen Nikki A. , Kuscu Cem , Pulkoski-Gross Ashleigh , Nguyen Hoang-Lan , Zucker Stanley , Cao Jian 
Published: August 2012

Abstract
Although considerable progress has been made in our understanding of cancer cell invasion, much of this complex cellular process remains a mystery, ultimately hindering advancements in treatment strategies targeting metastasis. Here we report the vital role of a novel endoplasmic reticulum (ER) resident protein identified by a PCR-subtraction hybridization technique, designated Cancer ER Invasion Gene (CERIG), in cancer cell migration and invasion. Clinical relevance of CERIG is highlighted by upregulation of CERIG in human invasive breast cancer specimens examined by immunohistochemistry and real-time RT-PCR, as well as increased expression in various forms of human cancer as determined by data mining. This up-regulation of CERIG correlates with poor prognosis of patients with breast cancer assessed by a DNA microarray data-mining approach from three publicly available cohorts containing a total of 696 breast cancer patients. Mechanistically, increased CERIG in solid tumors is linked to hypoxia-induced activation of CERIG promoter via the hypoxia-inducible factor-2α. Silencing of CERIG in an aggressive breast cancer cell line disrupted mesenchymal morphogenesis in vitro, resulting in a mesenchymal-to-epithelial transition, and interfered with cancer metastasis in vivo. Employing both gain- and loss-of-function approaches, CERIG was found to induce cancer cell migration and invasion. Enhanced cell migration required CERIG retention within the ER, where this 160 kDa protein forms a complex with an ER chaperone protein, GRP78/BiP. The minimal protein domain required for ER retention was identified using a mutagenesis approach. Furthermore, fusion of the ER-retention domain to a soluble matrix metalloproteinase (MMP) prevents the secretion of the MMP and retained it in the ER. Overexpression of CERIG in cells results in diminished ER and increased cytoplasmic calcium levels, suggesting a role for CERIG in ER calcium leakage. Furthermore, chelating intracellular calcium abrogates CERIG induced cell migration. The induction of cell migration via CERIG was found to involve a CERIG-BiP-ER calcium leakage-PKC-MAPK pathway. Our data indicate that CERIG, as a novel ER resident protein, plays an important role in cancer progression, serving as a novel cell migration-promoting gene.
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 4313. doi:1538-7445.AM2012-4313
Abstract 4315: A novel role for the high affinity IL13 receptor in glioblastoma multiforme
Authors: Prasol Melanie S. , Moon Kyung-Sub , Lesniak Maciej S. , Balyasnikova Irina V. 
Published: August 2012

Abstract
IL13 Receptor alpha 2 (IL13Ra2) is one of two receptors for IL13 and is found to be highly expressed in a number of cancers including, ovarian, head and neck, pancreatic and glioblastoma multiforme (GBM). IL13Ra2 has been found to be expressed mostly in high grade GBMs but not in low grade gliomas or normal brain tissue. IL13Ra2 has a short intracellular domain that lacks a signaling domain and possesses a high affinity for IL13. It is thought that in GBMs IL13Ra2 acts primarily as a decoy receptor for IL13. However, recent evidence from pancreatic and ovarian cancer lines indicates that IL13Ra2 initiates signaling pathways that influence cell invasion and adhesion properties of cancer cells. We hypothesize the IL13Ra2 might play a role in GBMs distinct for its decoy receptor function. This study is designed to determine if IL13Ra2 possess functional properties and can modulate the behavior of glioma cells through its interaction with IL13. We examined the effect of IL13 interaction with IL13Ra2 in multiple glioma cell lines in vitro. A BrdU based proliferation assay was utilized to determine the effect of IL13 on the proliferation rate of glioma cells. Migration of glioma cells was also examined over a 24 hour period following exposure to IL13. A shRNA mediated knockdown of IL13Ra2 in glioma cells was also produced and the resultant phenotype analyzed by phalloidin staining for cytoskeletal actin and in the migration assay. Treatment of IL13Ra2 expressing glioma cell lines with IL13 did not influence their proliferation rates in vitro. However, cells that had been treated with IL13 demonstrated an increased migration response. Knockdowns were found to have decreased migration rates, both in the presence and absence of IL13. Knockdowns were also found to have dramatic changes in phenotype with increased cellular adhesion and altered actin structure. When the actin structure was examined following IL13 treatment, normal cells appeared to have an increase in peripheral actin and filopodia, while in knockdown cells treated cells did not appear different from untreated controls. Our data indicate that IL13 interaction with IL13Ra2 might contribute to changes in the phenotype of glioma cells that promote their invasive properties. Further research is needed to determine the underlying mechanism.
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 4315. doi:1538-7445.AM2012-4315
Abstract 4317: Stim1 and Orai1 are critical regulators of melanoma invasion and anoikis
Authors: Yang Shengyu , Sun Jianwei , He Huifang 
Published: August 2012

Abstract
Store-operated calcium (SOC) influx is the major calcium entry mechanism in non-excitable cells regulating a plethora of physiological and pathological processes. The internal store calcium sensor and plasma membrane pore-forming unit are recently identified to be Stim1 and Orai1, respectively. We were the first to demonstrate the critical roles of Stim1 and Orai1 in breast tumor cell migration and metastasis (Cancer Cell, 2009, 15:124). There are still a few important questions remained to be answer: Whether Stim1 and Orai1 play a role in the dissemination of other tumors? How do Stim1 and Orai1 dysregulate and reorganize actin cytoskeleton to promote tumor cell invasion and metastasis? Do Stim1 and Orai1 contribute to tumor progression in cancer patients? Our recent data suggested that Stim1 and Orai1 were important regulators of tumor cell migration and invasion in multiple tumors. SOC inhibitors block cell migration and invasion in all the tumors tested. Stim1 and Orai1 promote tumor cell invasion and degradation of extracellular matrix by promoting the formation of invadopodia. Stim1 and Orai1 regulate invadopodia formation through facilitating SOC calcium influx and activation of non-receptor tyrosine kinase Src. The activation of Src by SOC influx also contributes to anoikis resistance in tumor cells. We were able to further demonstrate that the expression levels of Stim1 correlate with tumor progression and metastasis in multiple solid tumors. Therefore, our data suggested that Stim1 overexpression in tumors may promote tumor metastasis through calcium influx and Src activation, which facilitate extracellular matrix degradation and promote anchorage-independent growth.
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 4317. doi:1538-7445.AM2012-4317
Abstract 432: Differences in molecular background of colorectal liver and lung metastases
Authors: Knijn Nikki , van Lin Simone , Vink-Borger Elisa , van Vliet Shannon , Mekenkamp Leonie , Riemersma Sietske , Tebar Maria , Klomp Marjolein , Meijer Jos , Teerenstra Steven , Punt Kees , Nagtegaal Iris 
Published: August 2012

Abstract
BACKGROUND: Mutations in the KRAS oncogene occur in 30-60% of the patients with colorectal cancer (CRC). Constitutively activation of the KRAS protein leads to growth, proliferation, and survival of CRC cells. KRAS mutation is an early event during colorectal carcinogenesis, therefore all tumor cells including metastatic cells are expected to have the same mutation status. We investigated the KRAS mutation status in primaries and metastatic tissue of patients with liver and lung metastasis. METHODS: Patients with histological confirmed CRC who underwent surgical resection of the primary tumor and biopsy or surgical resection of the corresponding liver (n = 304) or lung metastasis (n = 90) were included. KRAS mutation analysis was performed for codons 12 and 13 using sequencing analysis. We used Next Generation Sequencing (NGS) to further evaluate a patient with a discordance in KRAS mutation status between the primary and metastasis. RESULTS: KRAS mutations were detected in 35.3% of the 304 primary tumors with liver metastases. In 11 cases (3.6%), we found a discordance between primary tumor and metastasis: 5 primary tumors had a KRAS mutation with a wild-type metastasis, 1 primary tumor was wild type with a KRAS mutation in the metastasis, and in 5 cases the primary tumor and the metastasis had a different KRAS mutation. NGS of the patient with a wild type primary tumor and a KRAS mutation in the liver metastases revealed a KRAS mutation in 7.5% of the primary tumor cells. KRAS mutations were detected in 46.7% of the 90 primary tumors with lung metastases. The KRAS mutation frequency in lung metastases was 55.6%. A discordance in KRAS mutation status between primary tumors and metastasis was observed in 8 cases (8.9%). In all these patients the primary tumors had a KRAS wild-type while the lung metastasis showed a KRAS mutation. CONCLUSION: We observed a higher KRAS mutation frequency in primary CRC with lung metastases compared to primary CRC with liver metastases (p=0.038). Increased discordance in the lung metastases might indicate that these originate in very small subclones of the primary.
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 432. doi:1538-7445.AM2012-432
Abstract 4322: Iron increases the invasiveness of prostate cancer cells in vitro: Mechanisms and inhibition by the antioxidant ebselen
Authors: Guo Wenji , Schlicht Michael , Kucynda Theresa , Zhou Ping , Valyi-Nagy Klara , Kajdacsy-Balla André 
Published: August 2012

Abstract
The effect of iron on PC-3 prostate cancer cell invasiveness was investigated using Neuroprobe filter membrane transmigration assays. PC-3 cells were pre-incubated with ferric ammonium citrate (FAC) for 6 hours. Excess iron was removed before the assay. The PC-3 cells were placed on an extracellular membrane preparation (Matrigel®) in the upper wells of the chamber and allowed to migrate onto the underside of a porous membrane that allowed cell transmigration. The number of cells migrating to the underside of the membrane was determined and used as a marker of cell invasion. Pre-treatment with 100 µM FAC caused a 4-fold increase in PC-3 cell invasion when measured at 24 hours (P&lt; 0.05). The FAC concentrations that induced PC-3 invasion were 100 times smaller than concentrations which interfered with cell viability or proliferation rate. Western blot analysis suggested that the effect of FAC exposure on PC-3 cell invasion was mediated by p42/44 MAP kinase activity. Furthermore, the antioxidant ebselen, a hydrogen peroxide inhibitor, decreased FAC-induced PC-3 cell invasion. We also examined the mRNA expression of invasion-related genes using a cDNA array and found a positive correlation between the exposures to FAC and the invasion phenotype of prostate cancer cells. The data demonstrated that the upregulation of genes, such as fractalkine and plasminogen, after FAC treatment may be associated with iron-induced invasion of prostate cancer. Our data suggest that iron overload may be detrimental to patients with prostate cancer and that the effect of iron on invasion may be inhibited by ebselen.
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 4322. doi:1538-7445.AM2012-4322
Abstract 4325: CD99 suppresses osteosarcoma cell migration by favouring the oncosoppressor N-cadherin/beta-catenin signalling pathway in contrast to ezrin.
Authors: Manara Maria Cristina , Zucchini Cinzia , Pinca Simona , de Sanctis Paola , Guerzoni Clara , Scotlandi Katia 
Published: August 2012

Abstract
CD99 is a 32-kDa highly glycosylated transmembrane protein encoded by MIC2 gene which shares no homology with any known family of proteins except Xga and mouse CD99L2 proteins. Located in the pseudoautosomal region of chromosomes X and Y, MIC2 encodes two distinct products by alternative splicing of gene transcripts: a long form (32-kDa), corresponding to the full-length protein (CD99wt) and a short form harbouring a deletion in the intracytoplasmic domain (CD99 sh). CD99 is involved in multiple cellular events including cell adhesion, apoptosis, differentiation of T- cells and thymocytes, transendothelial migration of leukocytes, maintenance of cellular morphology and regulation of intracellular membrane protein trafficking either in physiology and in pathological conditions. In osteosarcoma, CD99 is expressed at low levels and functions as a tumor suppressor. The two alternative spliced isoforms are associated to distinct functional outcomes: CD99sh expression increases, whereas wtCD99 significantly inhibits migration, invasiveness and metastasis of osteosarcoma cells (Manara MC, 2006; Scotlandi K 2007). In this study, we specifically analyzed modulation of cell-cell contacts, reorganization of the actin cytoskeleton, and modulation of signalling pathways by comparing osteosarcoma cells characterized by different metastasis capabilities and CD99 expression, to identify molecular mechanisms responsible for metastasis. Our data indicate that expression of CD99wt induces recruitment of beta-catenin to adherens injunctions through N-cadherin up-regulation. In addition, forced expression of CD99wt inhibits the expression of several molecules crucial to remodeling the actin cytoskeleton, such as ACTR2 (also named ARP2), ARPC1A and ROCK II as well as ezrin, an ezrin/radixin/moesin (ERM) family member that has been clearly associated with tumor progression and metastatic spread either in experimental models and clinical samples of osteosarcoma. Functional studies by siRNA and/or specific inhibitors point to ROCKII as a crucial intracellular mediator regulating osteosarcoma metastasis capabilities.
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 4325. doi:1538-7445.AM2012-4325
Abstract 4327: Loss of the APC tumor suppressor alters breast cancer cell migration and invasion
Authors: Odenwald Matthew A. , Prosperi Jenifer R. , Goss Kathleen H. 
Published: August 2012

Abstract
Metastasis is responsible for the majority of deaths attributable to cancer, but the molecular events that drive the metastatic phenotype are not completely understood. The adenomatous polyposis coli (APC) tumor suppressor is frequently inactivated in colorectal cancer as well as other tumor types, such as breast cancer, and has been implicated specifically in early tumor progression. However, it is not known whether APC also plays an important role in the later stages of cancer pathogenesis, including invasion and metastasis. Preliminary data indicated that transient knockdown of APC in 4T07 mouse mammary tumor cells led to marked morphological changes from mesenchymal-like to epithelial-like phenotypes, leading to the hypothesis that APC can effect the mesenchymal-to-epithelial transition and may alter cancer metastasis. To test this hypothesis, 4T07 cells were stably infected with lentiviral APC short-hairpin (sh)RNAs, and knockdown of APC expression was verified by quantitative real-time PCR and immunofluorescence (IF) with an APC antibody. We found that APC depletion altered the mesenchymal morphology of these cells to a more epithelial phenotype. The localization of β-catenin at the ends of cell protrusions was dependent on APC; however, APC knockdown did not result in cytosolic or nuclear accumulation of β-catenin. Consistent with the observed morphology change, APC depletion significantly impaired the ability of 4T07 cells to migrate in wound-filling assays and invade through a Matrigel-coated membrane. Together, these results suggest that APC loss impacts the morphology, migration and invasion of breast cancer cells, all key features of metastatic capacity. Current efforts are aimed at uncovering the mechanism by which APC alters these properties and translating these findings to our understanding of breast cancer metastasis in vivo.
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 4327. doi:1538-7445.AM2012-4327
Abstract 4328: Specific epidermal growth factor receptor autophosphorylation sites promote epithelial cell chemotaxis and restitution
Authors: Yamaoka Toshimitsu , Frey Mark , Polk D.Brent , Oki Yasunari , Murata Yasunori , Sugiyama Tomohide , Kusumoto Sojiro , Ishida Hiroo , Shirai Takao , Nakashima Masanao , Okuda Kentaro , Ohnishi Tsukasa , Hirose Takashi , Ohmori Tohru , Adachi Mitsuru 
Published: August 2012

Abstract
BACKGROUND: Cell migration is required for the physiological processes of wound repair, resolution of inflammation, and organogenesis, but is also involved in the pathology of tumor invasion. Thus, investigation of the regulatory mechanisms of cell migration is important for both understanding basic intestinal biology and identifying potential therapeutic targets for disorders such as inflammatory bowel diseases and colon cancer. HYPOTHESIS: Upon ligand binding, epidermal growth factor (EGF) receptor (R) autophosphorylates on c-terminal tyrosines, generating docking sites for signaling partners that stimulate proliferation, restitution, and chemotaxis. Specificity for individual EGFR tyrosines in cellular responses has been hypothesized but not well documented. Here we tested the requirement for particular tyrosines, and associated downstream pathways, in mouse colon epithelial cell chemotactic migration. We compared these requirements to those for the phenotypically distinct restitution (wound healing) migration. METHODS: Wild-type, Y992/1173F, Y1045F, Y1068F, and Y1086F EGFR constructs were expressed in EGFR-/- cells; EGF-induced chemotaxis or restitution were determined by Boyden chamber or modified scratch wound assay, respectively. Pharmacological inhibitors of p38, phospholipase C (PLC), Src, MEK, JNK/SAPK, phosphatidylinositol 3-kinase (PI 3-kinase), and protein kinase C (PKC) were used to block EGF-stimulated signaling. Pathway activation was determined by immunoblot analysis. RESULTS: Unlike wild-type EGFR, Y992/1173F and Y1086F EGFR did not stimulate colon epithelial cell chemotaxis towards EGF; Y1045F and Y1068F EGFR partially stimulated chemotaxis. Only wt EGFR promoted colonocyte restitution. Inhibition of p38, PLC, and Src blocked chemotaxis; JNK, PI 3-kinase, and PKC inhibitors blocked restitution but not chemotaxis. All four EGFR mutants stimulated downstream signaling in response to EGF, but Y992/1173F EGFR was partially defective in PLCγ activation while both Y1068F and Y1086F EGFR failed to activate Src. CONCLUSIONS: Specific EGFR tyrosines play key roles in determining cellular responses to ligand. Chemotaxis and restitution, which have different migration phenotypes and physiological consequences, have overlapping but not identical EGFR signaling requirements.
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 4328. doi:1538-7445.AM2012-4328