bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2338: EGFR-mediated TGM2 overexpression couples acquired TRAIL-resistance and migration involving c-FLIP and MMP9 in NSCLC cells
Authors: Li Zi , Bai Lang , Chen Wenshu , Xu Xiuling , Lin Yong 
Published: June 2012

Abstract
Acquired chemoresistance not only blunts cancer chemotherapy, but may also promote cancer cell migration and metastasis. Our previous studies have revealed that acquired tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in non-small cell lung cancer (NSCLC) cells was associated with Akt-mediated stabilization of cellular FLICE-like inhibitory protein (c-FLIP) and myeloid cell leukemia 1 (Mcl-1). The cells with acquired TRAIL-resistance have significantly increased migration and invasion potential. Gene expression array assay was used to explore the mechanism underlying TRAIL-resistance associated migration, and tissue transglutaminase 2 (TGM2) was identified as one of the genes with the highest expressing increase in TRAIL-resistant cells. Suppressing TGM2 activity or expression dramatically alleviated TRAIL-resistance and cell migration, suggesting TGM2 contributes to the both phenotypes in the TRAIL-resistant cells. TGM2 suppression significantly reduced c-FLIPL but not Mcl-1L expression, suggesting that TGM2 mediates TRAIL-resistance through c-FLIP. The expression of MMP9, a matrix metalloproteinase involved in cancer cell migration, was suppressed when TGM2 was inhibited, suggesting that TGM2 potentiates cell migration through upregulating MMP-9 expression. Furthermore, we found that EGFR was highly upregulated and activated and suppression of which dramatically reduced the expression level of TGM2 in the TRAIL-resistant cells. With chemical inhibitors, we further determined MAPKs (JNK and ERK), but not Akt and NF-κB, are responsible for EGFR-mediated TGM2 expression. Conversely, suppression of TGM2 had no effect on ERK, JNK and Akt activity. These results identify a novel pathway that involves EGFR, MAPK and TGM2 for acquired TRAIL-resistance and cell migration in NSCLC cells. Because TGM2 converges acquired TRAIL-resistance and cell migration, it could be a molecular target for circumventing acquired chemoresistance and metastasis in lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2338. doi:10.1158/1538-7445.AM2011-2338
Abstract 2340: Ribonucleotide reductase subunit M2 promotes cell invasiveness and motility in lung and head and neck cancer cells
Authors: Rahman Mohammad Aminur , Amin A.R.M. Ruhul , Chen Zhuo Georgia , Davis Mark E. , Shin Dong Moon 
Published: June 2012

Abstract
Ribonucleotide reductase subunit M2 (RRM2) has been frequently observed to be aberrantly overexpressed in various tumors. RRM2 is a key enzyme involved in the production of 2′-deoxyribonucleoside 5′-triphosphates required for DNA synthesis. In addition to DNA synthesis, it has been reported that RRM2 modulates cellular invasiveness. However, the mechanisms through which RRM2 affects the invasive phenotype have not been elucidated. In our study, we examined the role of RRM2 in cell invasion and migration of different lung (A549, H460 and H1299) and head and neck (Tu686) cancer cell lines. To explore the mechanism underlying RRM2's activity, we applied small interference RNA (siRNA) to knockdown the RRM2 protein while pcDNA3/RRM2 plasmid was used to establish RRM2 overexpressing stable cell lines. Our results revealed varying degrees of RRM2 expression levels in lung and head and neck cancer cell lines, which were proportionally correlated with the invasive capability of cells. H1299, a cell line that features epithelial-mesenchymal transition (EMT) expressed the highest level of RRM2 protein among the cell lines studied, and exhibited the greatest invasive and migratory abilities as demonstrated by Boyden chamber invasion and wound healing assays. H1299 was 6-fold more invasive than A549, which has lower RRM2 expression. Moreover, gain of function analysis demonstrated that overexpression of RRM2 enhanced cell invasiveness and motility in low RRM2-expressing cell lines A549 and Tu686. Western blots revealed that markers associated with tumor cell invasion and migration such as phospho-Src, phospho-FAK, phospho-calveolin-1, phospho-Akt, phospho-Erk, and MMP-9 secretion were induced whereas E-cadherin protein expression was significantly inhibited in RRM2 overexpressing cell lines. In contrast, loss of function analysis showed that siRNA targeting RRM2 decreased RRM2 expression and attenuated cellular invasiveness and motility in both lung and head and cancer cell lines. Our study demonstrated that RRM2 substantially promoted cell invasion and migration abilities. An elevated RRM2 may serve as a potential biomarker for metastasis of head and neck and lung cancer. Thus, targeting RRM2 and its downstream signaling intermediaries represents a rational approach for developing novel anticancer therapeutics. (This work is supported by grants from NIH U54CA119338-04, P50CA128613 and DOD W81XWH-07-1-0306).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2340. doi:10.1158/1538-7445.AM2011-2340
Abstract 2354: Characterization of three novel splice variants of the RECK tumor and metastasis suppressor gene
Authors: Trombetta-Lima Marina , Winnischofer Sheila M.B. , Carreira Ana C.O. , Demasi Marcos A.A. , Colin Christian , Oba-Shinjo Sueli M. , Marie Suely K.N. , Sogayar Mari C. 
Published: June 2012

Abstract
REversion-inducing Cysteine-rich protein with Kazal motifs (RECK) encodes a membrane-anchored protein which suppresses both invasion and metastasis by negatively regulating at least three MMP′s, namely: MMP-9, MMP-2 and MT1-MMP. Matrix metalloproteinase (MMP) family members belong to the group of Zn2+ dependent proteolytic enzymes, which are key elements responsible for extracellular matrix (MEC) collapse, being, therefore, directly involved in tumor invasiveness and metastasis. MEC degradation by MMPs not only facilitates tumor invasion, but, also, affects the behavior of tumor and adjacent cells, leading to cancer progression. In general, the relative levels of MMPs increase with tumor progression. Other RECK targets have been identified, such as the extracellular metalloproteinases ADAM10 and CD13/ aminopeptidase N. A positive correlation has been observed between the abundance of RECK expression in tumor samples and better prognosis for patients with gastric, lung, pancreatic and colorectal cancers. Recent studies showed mutations in splicing cis regulatory elements and alterations in the cellular splicing regulatory machinery leading to changes in the splicing pattern of several cancer-related genes, such as CD44, BRCA1, APC, p53 and FHT. In the present study, three novel alternative isoforms of the RECK tumor suppressor gene, namely RECK B (1,548b), RECK D (1,737b) and RECK I (1,101b) were isolated by RT-PCR and their expression profiles were investigated using quantitative real time RT-PCR assays in a normal tissue RNA panel and during human glioma progression. Our results show that RECK isoforms display independent expression patterns when compared to the canonical form, indicating a more complex role for both the canonical and the alternative RECK isoforms in glioma progression. Support: FAPESP, CNPq, FINEP, BNDES, MCT, MS
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2354. doi:10.1158/1538-7445.AM2011-2354
Abstract 2356: Investigating the role of mammalian RNA binding protein Musashi-2 (MSI2) in breast cancer invasion and nodal metastasis
Authors: Holzapfel Nick , Nair Ranju , Done Susan J. 
Published: June 2012

Abstract
Previous array comparative genomic hybridization (aCGH) studies in our lab have shown that chromosomal gains on 17q22-24.2 are associated with invasion when detected in duct carcinoma in situ (DCIS) and nodal metastasis when detected in invasive duct carcinoma (IDC). Of nine candidate genes identified within this region, MSI2 was selected for further study. MSI2 is a Musashi family RNA binding protein that translationally regulates target mRNAs. RNAi screens have indicated that MSI2 down regulation impairs hematopoietic stem cell repopulation. Other studies implicate its role in leukemia and colon cancer. Downstream targets of the MSI2 homologue MSI1, have shown a strong correlation with cancer related processes through their roles in cell cycle modulation, proliferation, differentiation, and apoptosis. MSI1 has also been shown to modulate WNT and Notch signaling through its interactions with the Notch inhibitor NUMB and the WNT antagonist DKK3.
Invasion, migration, and proliferation assays were carried out in the breast cancer cell lines MDA231 and MCF7 over-expressing MSI2. These cell lines were also transfected with the TOPflash TCF reporter plasmid to investigate the effect of MSI2 over-expression on WNT signaling. To investigate the effects of WNT signaling on MSI2, MDA231 cell lines were treated with the human WNT agonist WNT-3a and MSI2 levels were quantified via western blotting. RNA immunoprecipitation was performed to analyze the downstream targets of MSI2. To investigate the role of MSI2 in breast stem and progenitor cell populations, cell lines were grown as non-adherent mammospheres. MSI2 RNA levels in mammospheres were compared via qRT-PCR. Lastly, the expression of a panel of stem cell markers was compared between cells over-expressing MSI2 and GFP controls via qRT-PCR.
Our results show MSI2 over-expressing MCF7 and MDA231 cells have increased levels of proliferation, migration, and invasion. MSI2 over-expressing cells also up-regulate several putative stem cell markers including Epithelial Cell Adhesion Molecule (EpCAM), CD133, and Aldehyde Dehydrogenase. MSI2 levels are significantly enhanced in mammosphere culture and MSI2 over-expressing cells have demonstrated an increase in mammosphere forming capabilities.
We believe MSI2 plays an important role in breast cancer through its modulation of RNA translation and subsequent regulation of WNT signaling and stem cell biology. MSI2 represents a promising therapeutic target which could be used to block breast cancer invasion and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2356. doi:10.1158/1538-7445.AM2011-2356
Abstract 2361: The role of thrombomodulin in bladder cancer
Authors: Ding Ann-ann , Su Wen-Pin , Yang Wen-Horng 
Published: June 2012

Abstract
Bladder cancer is one of the most common cancers in the United States and Taiwan. We have discovered that thrombomodulin (TM) is up-regulated in bladder cancer patients and cancer cell lines but not in normal cells. TM is an exclusive endothelial cell surface glycoprotein and an important vascular protective molecule that has anticoagulant, anti-inflammatory and anti-apoptotic properties. TM immunohistochemical analysis of tissue microarray from bladder cancer patients of the United States was performed, and we found that TM staining was more pronounced in high grade and muscle invasive cancers. TM expression by western blot have been examined in 10 bladder cancer tissues from Taiwan in comparison to 3 normal bladder tissues, 80% (8/10) of the cancer group were over-expressed while none showed in normal bladder tissues. In a cell model, we knocked down the TM expression in BFTC905 bladder cancer cells (which was a cell line from invasive TCC) by siRNA. The two stable TM knocked-down cells (C6 and E2) showed a lower proliferation rate than BFTC905 wild type cells and vector control cells (D3). TM knocked-down cells (C6 and E2) also had lower migration and invasion abilities than control cells. Furthermore, TM knocked-down cells have a decreased colony number and size in tumor formation assays. By contrast, SV-HUC-1(immortalized human normal urothelial cell line) enhanced the migration and invasion ability by transient over-expression with TM plasmid. In an animal model, the RT-PCR analysis of the ascites from mice with peritoneal inoculation of MBT-2 cells (mouse bladder tumor cell line), we found that TM expression has higher in the group with tumor formation than the group without. These findings suggest that TM may be involved in the tumor progression of bladder cancer. Thus TM could be a bladder cancer prognosis biomarker and also be a therapeutic target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2361. doi:10.1158/1538-7445.AM2011-2361
Abstract 2364: Regulation of cofilin activity and tumor cell migration through protein kinase D
Authors: Spratley Samantha J. , Storz Peter 
Published: June 2012

Abstract
During early metastatic events in cancer, reorganization of the actin cytoskeleton must occur to allow for cell invasion and migration. A key enzyme initiating actin remodeling at the leading edge is Cofilin, a small actin binding protein of the ADF/cofilin family with actin severing activities. Cofilin activity is tightly regulated by phosphorylation and dephosphorylation events that are mediated by LIM Kinase (LIMK) and the phosphatase Slingshot (SSH), respectively. Protein kinase D (PKD) is a serine/threonine kinase that has previously been shown to regulate actin driven directed cell migration through phosphorylation and thus inactivation of Slingshot. Here we show that PKD can also regulate cofilin activity via activation of LIMK. We further show that PKD-induced regulation of LIMK and the resulting diminished cofilin activity translates to altered cell motility. Our data suggest that PKD inactivates Cofilin through modulation of both of its regulatory pathways. Further elucidation of the mechanisms by which PKD regulates directed cell migration could enable development of a potential treatment strategy for invasive cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2364. doi:10.1158/1538-7445.AM2011-2364
Abstract 237: MET receptor is a potential new target for cervical carcinoma treatment
Authors: Miekus Katarzyna , Pawlowska Marta , Majka Marcin 
Published: June 2012

Abstract
Introduction: Cervical carcinoma (CC) is the major cause of death among women suffering from neoplastic disease especially in the developing countries. The highest mortality is observed in patients with late diagnosis and metastatic disease. MET protooncogene encodes a tyrosine kinase receptor for hepatocyte growth factor (HGF). MET activation triggers a complex biological program including stimulation of cell proliferation, motility and protection from apoptosis. This program plays an important role during embryonic development and wound healing, but abnormal MET activity contribute to cancer development and progression. Therefore, new therapeutic strategies inhibiting MET signaling have been sought.
Objectives: The aim of this study was to examine the influence of MET inhibition on growth and metastatic ability of cervical carcinoma cell.
Materials and Methods: CC cell line (HTB35) was transduced with MET shRNA and LacZ shRNA expressing viruses and selected with blasticidin. To check genes expression real-time PCR, western blot and flow cytometry were used. Proliferation, cell cycle and apoptosis was studied. Stress fibers organization, adhesion and migration were evaluated using using falloidin staining, adhesion assay and chemotaxis assay respectively. The level of various protein phosphorylation was estimated by western blot.
Results: We showed that downregulation of MET expression in HTB-35 cell line causes: (i) the reduction in cell proliferation resulting from altered cell cycle progression, but not from enhanced apoptosis, (ii) changes in actin cytoskeleton organization, (iii) the increased expression of E-cadherin, (iv) the decrease of mRNA levels in the genes responsible for malignant phenotype (such as c-myc, CXCR4 and Slug), and (v) the increased expression of genes involved in EMT and metastasis (including Snail, Slug, Twist, MMP-2, MMP-9 and HIF-1α). Performed in vitro studies have not shown any significant effect of MET inhibition on adhesive ability of HTB-35 cervical carcinoma cell line. However, the decreased migration of MET negative cells was observed.
Summary: Our results strongly, indicate that MET receptor plays an important role in stimulating growth and metastasis of HTB-35 cervical carcinoma cell line. Thus, inhibition of HGF-MET receptor axis could be used in the future as the new therapeutic strategy to block cervical carcinoma development and progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 237. doi:10.1158/1538-7445.AM2011-237
Abstract 2370: Single cell analysis using a microscale migration slide
Authors: Zhou Yi , Moore Cristina , Chu Vi 
Published: June 2012

Abstract
Cell migration occurs in a variety of biological processes including wound healing, embryonic development, and immune responses. Existing chemotaxis assays used to assess cell migration employ the Boyden chamber which lack real-time imaging capability and does not maintain well defined biomolecular gradients. To overcome these limitations, a cell migration assay was developed which enabled real-time monitoring of single cells on a slide-like platform that maintained a stable linear gradient. Fluorescence measurements with albumin (MW=66kDa) conjugated with FITC demonstrated that the concentration profile was linear over the 1 mm observation area. This linear concentration gradient was established after 1 hour incubation and was stable for over 24 hours.
The microscale migration slide was used to assess the effects of serum concentrations (0, 2, 5, 10, and 15%) on the migration propensity of four different cell lines that were grown on collagen. The cell lines included cancer cell lines with known invasive properties (fibrosarcoma cancer cells HT1080 and breast cancer cells MDA-MB-231), along with HUVECs which are angiogenic cells involved in tumor metastasis and a control cell line, NIH 3T3 fibroblast cells. Cells were incubated in the experimental conditions overnight (12 hours) with images captured every 15 minutes. Migration of single cells was monitored and imaged in real-time and the percentage of cells that exhibited positive migration towards the chemotactic source was calculated. Interestingly, we observed that the highest percentage of migratory HUVEC cells was obtained using 2% serum whereas the other three cell lines exhibited increased migration with increasing serum concentration. Under similar culture conditions of either 10 or 15% serum, MDA-MB-231 possessed the highest migration index, followed by NIH 3T3 fibroblasts and HT1080 cells whereas HUVEC cells did not migrate at all under these high serum conditions. Extensive testing over a range of conditions with different users indicated remarkable consistency in the data generated and suggests that the migration slide is a useful tool to monitor the effects of chemoattractants on adherent cell lines. Overall the results provide a reference point from which to build upon future studies aimed at comparing the effects of signaling molecules and growth factors on the migration propensities of cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2370. doi:10.1158/1538-7445.AM2011-2370
Abstract 2388: Targeted expression of BAG3 to the murine mammary gland (MMTV-hBAG3) reveals a role in mammary tumorigenesis
Authors: Casagrande Giovanna , Yu Minshu , Rodriguez-Canales Jaime , Kohn Elise C. , Virador Victoria M. 
Published: June 2012

Abstract
We have previously shown that BAG3 is a pro-survival protein in human cancer lines subject to stress. BAG3 overexpression also mediates a decrease in migration and adhesion to matrix in MDA-435 breast cancer cells; this is reversed in a BAG3 mutant with a deleted proline-rich domain (PXXP). Additionally, BAG3 induces the secreted molecule CCN-1 to regulate in vitro invasion of HeLa cells. This led us to hypothesize that MMTV-driven human BAG3 would contribute to mammary tumorigenesis. This was examined through generation and analysis of a transgenic mouse model of human BAG3 ectopically expressed under the MMTV promoter in FVB/N mice. Five of 14 confirmed founder lines were selected for characterization to rule out integration effects. Each line was shown to express hBAG3 in mammary ductal epithelium, a typical feature of the MMTV-driven transgenes. We next applied chemical carcinogenesis with DMBA (7,12-dimethylbenzanthracene) to eight-week old virgin transgenic females and age-matched FVB/N wild-type females, by weekly orogastric gavage (1 mg DMBA) for 6 weeks. At study end (18 weeks post DMBA-treatment), 5/19 (26%) transgenic animals had pathologically proven atypical hyperplasia [1], and malignant tumors [adenocarcinoma, 1; myoepithelial tumor, 2; adenosquamous carcinoma, 1]. The age-matched non-transgenic controls did not develop premalignant or malignant breast lesions [0/12]. Luminal cell expression of hBAG3 was present in the atypical hyperplasia, but was not observed in highly proliferative, less differentiated regions of tumors where ductal structures are absent. Since the tumors we obtained were both of the myoepithelial and the epithelial lineages, we next investigated whether forced expression of hBAG3 in the ductal epithelium may dysregulate mammary gland development. We collected mammary glands at 5, 7, 10, and 13 weeks of age from transgenic and wild-type animals (n=4 each per time point) for two selected MMTV-hBAG3 transgenic lines. The terminal end buds, epithelial elongation, and glandular differentiation are currently being analyzed. Our preliminary data indicate that the mammary gland of MMTV-hBAG3 mice have a trend to increased epithelial elongation and more secondary acinar structures in the later pubertal stages. A complete analysis of the study cohort will be discussed. The effects of multiple pregnancies and post-lactation involution are under study. Together our findings point to a putative role of BAG3 as contributor to mammary remodeling during puberty and a promoting effect during chemical carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2388. doi:10.1158/1538-7445.AM2011-2388