bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1195: Erk activity promotes Notch-dependent HES1 expression in pancreatic cancer cells
Authors: Tremblay Isabelle , Bintz Jennifer , Boucher Marie-Josee 
Published: August 2012

Abstract
The oncogene Ras is well-recognized for its involvement in tumorigenesis in part through activation of downstream pathways including the PI3K/Akt and Mek/Erk pathways. Recent studies have suggested that the ability of Ras to transform cells also depends on cooperation with the Notch signalling pathway. However, the molecular and cellular mechanisms involved in this cooperation remain largely unknown. The aim of this study was to evaluate whether specific activation of the Ras/Raf/Mek/Erk pathway impacts Notch-dependent signalling. METHODS. Experiments were done using the pancreatic cancer cells MIA PaCa-2 and BxPC-3. Both cell lines express endogenous levels of the activated Notch1 (NIC). To inhibit Mek/Erk activity, cells were treated with the Mek inhibitor U0126 (10uM). Activation of the Mek/Erk pathway was achieved by treatment with phorbol 12-myristate 13-acetate (PMA, 100nM). The hes1-luciferase reporter gene was used to evaluate Notch-dependent transcriptional activity. The gamma-secretase inhibitor DAPT (25µM) was used to inhibit Notch activation. RESULTS. 1- Treatment of pancreatic cancer cells with U0126 reduced the activity of the hes1-luciferase reporter gene to the same extent than treatment with the gamma-secretase inhibitor DAPT. 2- Combined treatment (U0126 + DAPT) did not result in an additive inhibition of hes1-luciferase activity suggesting a Notch-dependent impact of the Mek inhibitor on hes1 transcription. 3- Increased HES1 mRNA expression levels were observed following treatment with PMA, an effect prevented by addition of U0126. 4- Massive activation of the Notch receptors by treatment with EGTA promoted HES1 protein expression. 5- Interestingly, strong stimulation of Erk activity by PMA promoted the EGTA-induced HES1 protein expression. 6- Conversely, inhibition of Erk activity completely prevented both the EGTA-induced and EGTA+PMA-induced HES1 protein expression. CONCLUSION. Taken together, our results suggest that Erk activity promotes Notch-dependent transcriptional activity and consequently promotes the expression of Notch target genes such as HES1.
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 1195. doi:1538-7445.AM2012-1195
Abstract 1197: Soluble uPAR plays a critical role in the progression of meningioma by autocrine signaling
Authors: Gogineni Venkateswara Rao , Nalla Arun Kumar , Velpula Kiran Kumar , Rao Jasti S. 
Published: August 2012

Abstract
In previous studies, we have reported on the vital role of the uPA-uPAR system in the progression of meningioma. Recent studies on the molecular structure of uPAR confirm that its shedding characterizes a further level of regulation in cellular processes. Here, we show that malignant meningioma cells release higher levels of soluble uPAR (SuPAR). Further, SuPAR concentration increased with radiation treatment (7 Gy) while uPAR knockdown diminished it. Deglycosylation analysis illustrated the existence of both SuPAR and cleaved SuPAR in vitro and in vivo. The cells shed SuPAR and phospholipase C mediates radiation-induced shedding of uPAR. SuPAR had a physical interaction with uPA and influences its activity in a concentration-dependent manner. Nonetheless, SuPAR did not adversely influence cell proliferation or cell cycle characteristics, but instead activated the MEK- ERK pathway. Receptor tyrosine kinase arrays and function blocking assays revealed the role of FPRL 1 receptors in SuPAR-mediated signaling. Further, SuPAR acted as a chemo-attractant for the invasion and migration of meningioma cells. Tumor bearing mice showed a significant rise in serum SuPAR concentrations, which also correlated with radiation treatment and morbidity. In conclusion, our results demonstrate the pro-invasive role and prognostic significance of SuPAR in the progression of meningioma.
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 1197. doi:1538-7445.AM2012-1197
Abstract 1198: Conversion of triple negative breast cancer cells into HER2 positive cells - a novel therapeutic approach
Authors: Bernemann Christof , Hülsewig Carolin , Kiesel Ludwig , Liedtke Cornelia 
Published: August 2012

Abstract
Introduction: Triple negative breast cancer (TNBC) is defined by the lack of estrogen-receptor alpha (ERα) and progesterone receptor (PGR) expression as well as absence of human epidermal growth factor receptor2 (HER2/neu) overexpression. This type of breast cancer is characterized by a poor prognosis and significantly reduced survival rate compared to other breast cancer subtypes. This is mostly due to the lack of targeted agents like endocrine or anti HER2 targets. Breast cancers which express HER2 are usually treated by chemicals targeting the human epidermal growth factor receptor; either by blocking the extracellular domain of HER2 through trastuzumab or the intracellular domain of HER2 through the small molecule lapatinib. Both therapeutics lead to inhibition of downstream signaling pathways like MAPK and PI3K signaling, resulting in increased apoptosis as well as reduced proliferation. Methods: We hypothesize that downstream effects e.g. reduced proliferation or apoptosis might be induced in triple negative breast cancer cells when HER2 is artificially overexpressed by transfection and cells get treated as HER2 positive cells. Therefore, triple negative breast cancer cell lines were stably transfected with HER2. These cells will be treated with anti-HER2 agents. Molecular analyses will demonstrate whether transfection with HER2 will yield a HER2 positive breast cancer phenotype in that all downstream signaling mechanisms act similarly to a priori HER2 positive cells. Results: Preliminary experiments suggest that proliferation of breast cancer cells transfected with HER2 does not change significantly. Treatment with HER2-specifically blocking antibody trastuzumab leads to significant decrease of proliferation in HER2 transfected, initially triple negative MDA-MB-231 breast cancer cells. Only a moderate decrease in proliferation was observed when lapatinib, a small molecule directed against both EGFR and HER2, was used in both MDA-MB-231 wildtype and HER2-transfected cell lines. Additional results will be presented. Conclusion: We surmise that firstly, transdifferentiation of cancer might become a clinical tool to treat cancer of poor prognosis and secondly that our results might shed light on future therapeutic approaches e.g. small molecule compound screening for endogenous HER2 reactivation / overexpression and subsequent targeted treatment of cancers.
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 1198. doi:1538-7445.AM2012-1198
Abstract 1214: Effects of dovitinib on fibroblast growth factor receptor-2 (FGFR2) expressing pancreatic cancer
Authors: Zhang Hao , Hylander Bonnie , LeVea Charles , Repasky Elizabeth , Straubinger Robert , Adjei Alex , Ma Wen Wee 
Published: August 2012

Abstract
Introduction. FGF signaling has been implicated in pancreatic cancer (PC) tumorigenesis and tumor-stromal interactions. Dovitinib is a potent inhibitor of the FGF receptors. We examined the effect of dovitinib in pancreatic cancer in relation to tumor FGFR2 expression using cell lines and patient-derived primary PC models. Methods. FGFR2 expression in 6 PC cell lines (L3.6PL, Panc4.30, AsPC1, Panc2.13, SU86.86, Panc02.03) and 13 patient-derived primary PC tumors was assessed using immunoblotting and RT-PCR. Dovitinib efficacy was assessed in vitro following FGF2 stimulation (IC50 &lt; 10 μM). Contribution by FGF signaling inhibition was evaluated by knockdown and constitutive activation of FRS2, Mcl-1 and Akt. Effects on downstream signaling pathways were evaluated by immunoblotting. Tumor-bearing mice were treated with dovitinib 40mg/kg (daily oral gavage) and tumor growth was measured. Effects of dovitinib in tumors were evaluated by immunohistochemistry (H&E, ki67, TUNEL, CD34, aSMA, collagen IV). Results. Dovitinib and FRS2 shRNA induced significant in vitro cell kill in bFGF-stimulated PC cell lines that had elevated FGFR2 mRNA expression. This was associated with inhibition of p-Akt and decreased Mcl-1 level in sensitive PC cells. Ectopic Mcl-1 and constitutively active Akt1 overexpression reversed the sensitivity whereas Mcl-1 knockdown sensitized resistant PC cells to dovitinib-induced apoptosis. In in vivo xenograft studies, compared to controls, dovitinib caused significant growth inhibition in high FGFR2 mRNA expressing PC (L3.6PL; T/C=0 after 10 days) but not low expressing PC (SU86.86; T/C=0.8 after 28 days). We then selected a primary tumor with high FGFR2 mRNA expression (#12424), which dovitinib exerted anti-proliferative and pro-apoptotic effects, causing significant growth inhibition (T/C=0.1 after 28 days), with reduced tumor-associated stroma and microvessel density at ≤ 20 mg/kg in a dose-dependent manner. Dovitinib caused only moderate tumor growth inhibition in #10978 (T/C= 0.78), a low FGFR2 mRNA expressing primary tumor. Conclusions. Dovitinib demonstrated significant anti-tumor efficacy that was mediated via the Akt/Mcl-1 pathway, and this effect was dependent on FGFR2 activity. We propose that FGFR2 mRNA level may be a predictive marker for efficacy of dovitinib in PC, and will be evaluated in an on-going clinical trial using a dovitinib-containing regimen.
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 1214. doi:1538-7445.AM2012-1214
Abstract 1231: Differential roles of trans-phophorylated EGFR, HER2, HER3 and RET as heterodimerization partenrs of MET in lung cancer with MET amplification
Authors: Tanizaki Junko , Okamoto Isamu , Sakai Kazuko , Nakagawa Kazuhiko 
Published: August 2012

Abstract
Background: MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumor types. We investigated the roles and mechanisms of RTK heterodimerization in lung cancer with MET amplification. Methods: With the use of an RTK array, we identified several phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays. Results: We identified EGFR, HER2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor, but not by treatment with their spcific inhibitors. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signaling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signaling. Conclusion: Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET play differential roles in tumor development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerization partners of MET in lung cancer with MET amplification.
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 1231. doi:1538-7445.AM2012-1231
Abstract 1234: GRK2 negatively regulates IGF-1R signaling pathway and cyclins in HepG2 cells
Authors: Wei Zhengyu , Hurtt Reginald , Bodzin Adam S. , Gu Tina , Doria Cataldo 
Published: August 2012

Abstract
G protein-coupled receptor kinase 2 (GRK2) plays a central role in the regulation of a variety of signaling pathways associated with many important cellular processes. Alternation of GRK2 expression has profound effects on cell physiological functions and induces diseases such as heart failure, rheumatoid arthritis, and cancer. In this study, we investigated the role of GRK2 in human hepatocellular carcinoma (HCC) HepG2 cells. We created a GRK2 knockdown cell line using a lentivirus containing GRK2 specific shRNA. Under IGF-1 (50 ng/ml) stimulation, HepG2 cells with reduced GRK2 expression showed increased tyrosine phosphorylation of IRS1 at the residue 612 and increased phosphorylation of Akt. We then treated the cells with gefitinib, an EGFR inhibitor. We found HepG2 cells displayed gefitinib sensitiveness with the increase of drug concentration. Moreover, gefitinib treated cells with reduced expression of GRK2 showed decreased phosphorylation of Akt in a dose dependent manner, but had relatively more IGF-1R expression. However, HepG2 cells with reduced expression of GRK2 did not display any growth difference in culture as compared with the scramble control cells. We further detected that reduced expression of GRK2 induced a small G2/M phase arrest by overexpressing cyclin A, B1, and E. DNA microarray analysis showed decreased transcription levels of IGF binding protein 1 and 4, which were confirmed by quantitative PCR analysis. Our results demonstrated that GRK2 has a role in the regulation of IGF-1R signaling pathway and involves in cell cycle progression in HCC HepG2 cells.
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 1234. doi:1538-7445.AM2012-1234
Abstract 127: miR-141 confers anoikis resistance of ovarian cancer cells by targeting KLF12
Authors: Mak Sze Ling 
Published: August 2012

Abstract
Anoikis resistance is one of the fundamental capacities of metastatic cancer cells to survive during invasion and dissemination. Emerging evidences have documented that deregulation of miRNAs have been associated with different aspects of tumorigenesis. In this study, we aimed to identify putative miRNA candidates that govern this process during metastasis of ovarian cancers. Using miRCURY™ LNA Array profiling (1264 miRNAs) analyze on two categories of ovarian cancer cell lines: high and low anchorage-independent growth ability. We firstly sorted out a list of 9 miRNAs which were upregulated and associated with high anchorage-independent growth ability in ovarian cancer cells. Amongst these candidates, miR-141 retained the strongest anchorage-independent growth ability examined by soft agar assay. Further real-time Q-PCR analysis found that miR-141 was frequently upregulated in ovarian cancer cell lines (n = 6) and clinical samples (n = 49) as compared with normal ovaries (n = 12). Functional studies showed that enforced expression of miR-141 increased both number and size of colonies formed in soft agar assay, and cell growth in focus formation assay. Moreover, miR-141 could enhance cell survival and proliferation in ovarian cancer cells in low serum media. Conversely, inhibition of miR-141 expression by miR-141 inhibitor could abrogate the above tumorigenic functions in ovarian cancer cells. On the other hand, by computational miRNA target prediction and pMIR-REPORT miRNA luciferase assay, we identified a tumor suppressor, Krüppel-related zinc finger protein AP-2rep (KLF12), was post-transcriptionally downregulated by miR-141. Previous studies have documented that KLF12 is a tumor suppressor in inhibiting AP2-induced tumorigenicity including anoikis resistance. Indeed, our biochemical analyses using luciferase reporter assays in combination with mutational analyses and Western blotting confirmed that miR-141 specifically targeting KLF 3′UTR and its expression. Taken together, our findings suggest that miR-141 is an oncogene that can enhance anoikis resistance in ovarian cancer cells through downregulation of KLF12. However, further investigation in delineating molecular mechanism of miR-141 and KLF12 in mediating ovarian cancer oncogenesis is warranted.
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 127. doi:1538-7445.AM2012-127
Abstract 1273: Identification of differentially expressed proteins in human papillary thyroid carcinoma using proteomic analysis
Authors: Sugimoto Chizuru , Susuki Dai , Kimura Yuichi , Narita Norihiko , Fujieda Shigeharu 
Published: August 2012

Abstract
Papillary thyroid carcinoma (PTC) is one of the most common malignant tumors of the thyroid glands. It tends to grow slowly but is associated with a poor prognosis when metastasis happens. To better understand basic mechanisms of tumor development and identify potential new biomarkers of PTC, we examined protein expression profiling in clinical PTC tissue and matched normal thyroid tissue using fluorescence two-dimensional difference gel electrophoresis (2D-DIGE). To identify the proteins, peptide mass fingerprinting via MALDI-TOF mass spectrometry was carried out. Using these strategies, 85 up-regulated or down-regulated proteins were found in PTC. Imaging software determined 26 proteins to be differentially expressed at the two-fold (or greater) level. Among them, Cathepsin B and Lamin A/C were selected for further analyses. Western blotting and immunohistochemical staining showed a higher expression of these proteins in clinical PTC tissue compared to normal thyroid tissue. We are presently investigating those roles in PTC. Proteomic analysis of PTC using 2D-DIGE and mass spectrometry could provide novel potential biomarkers and insights into global pathophysiologic changes in PTC.
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 1273. doi:1538-7445.AM2012-1273
Abstract 1276: Application of high-throughput proteomics Micro-Western array in studying molecular mechanism of anticancer effect of liver X receptor agonists against human colon cancer cells
Authors: Lin Ching-Yu , Huo Chiech , Lin Hui-Ping , Jiang Shih Sheng , Chuu Chih-Pin 
Published: August 2012

Abstract
We recently developed a high-throughput proteomics technology, the Micro-Western arrays (Ciaccio MF, Nature Methods 2010). Micro-Western array is a nano-litter scale array-based Western blotting assay. This method allowed us to measure 96 to 384 different phosphosites on multiple proteins of a set of 6 to 15 different samples simultaneously. We applied this technology in investigating molecular mechanism of anticancer effect of small molecular compound. Colon cancer is the third leading cause of cancer-related death in the world. Previously, we reported that agonists for liver X receptors (LXRs) suppressed the proliferation of several human cancer cell lines. LXRβ and LXRβ are nuclear receptors and are important regulators of cholesterol, fatty acid, and glucose homeostasis. 96-well proliferation assay and colony formation assay showed that three commonly used LXR agonists 22(R)-hydroxycholesterol, T0901317, and GW3965 suppressed proliferation of HT-29 and HCT-116 human colon cancer cells dose-dependently. Flow cytometry analysis indicated that LXR agonists induced G1 cell cycle arrest but not apoptosis in colon cancer cells. We then used gene overexpression and shRNA/siRNA knockdown to verify that LXRβ and LXRβ were directly involved in the growth inhibition caused by LXR agonists. To understand the molecular mechanism, we used gene array and Micro-Western Array with more than 240 phosphorylated antibodies targeting signaling network regulating receptor tyrosine kinases (RTKs), cell cycle, cell stress, and PI3K/Akt to systematically investigate signaling proteins being affected by LXR agonists in multiple time points. With help of bioinformatics modeling, our result revealed a potential mechanism how nuclear receptor LXR regulating cell cycle in human colon cancer cells via EGFR/PI3K/Akt and ABCA1/SREBP-1/LDLR signaling. Effect of LXR agonists treatment with or without chemotherapy agents on HT-29 xenograft model and validation of target proteins for LXR agonists in patients’ tissues are currently ongoing. Our observations suggested that LXR agonists treatment may be a potential adjuvant therapy for colon cancers.
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 1276. doi:1538-7445.AM2012-1276