bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 181: MIR-18b decreases self-renewal of glioblastoma cancer stem-like cells through targeting NOTCH2, NEDD9, and MEKK1
Authors: He Xiaobing , DiMeco Francesco , Vescovi Angelo , Heth Jason , Muraszko Karin , Fan Xing 
Published: August 2012

Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in human with extremely poor prognosis and new treatment for this deadly disease is desperately needed. Cancer Stem-like cells (CSCs) have been prospectively isolated from GBM and shown required for tumor propagation. We and others have demonstrated recently that differentiation of GBM neurospheres decreases GBM cell propagation both in vitro and in vivo (Zhu et al, Cancer Research, 71:6061-72, 2011). In the current study, we found that miR-18b was up-regulated upon differentiation of GBM neurosphere. When we introduced miR-18b into GBM neurospheres by lentivirus, we found that miR-18b decreases clonogenesis and growth of three different GBM neurosphere lines, indicating that GBM CSC population was reduced by miR-18b. Mechanistically, we found that miR-18b down-regulates luciferase activity of 3′-UTR reporters of NOTCH2, NEDD9, and MEKK1. Furthermore, protein expression of NOTCH2, NEDD9, and MEKK1 are also decreased by miR-18b, suggesting that NOTCH2, NEDD9 and MEKK1 are the direct targets of miR-18b in GBM CSCs. In addition, we have demonstrated previously that NOTCH regulates GBM CSC propagation through pAKT (Fan et al, Stem Cells, 28:5-16, 2010). Here, we found that pAKT and pERK1/2 were also down-regulated in miR-10b infected GBM neurosphere lines, indicating that miR-18b reduces GBM CSC propagation through NOTCH2/pAKT pathways. Taken together, we have demonstrated that miR-18b functions as a tumor suppressor and decreases GBM CSC propagation through targeting NOTCH2, NEDD9, and MEKK1, indicating that miR-18b can be a potential therapeutic molecule to target GBM CSCs and improve GBM treatment.
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 181. doi:1538-7445.AM2012-181
Abstract 1814: Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1
Authors: Lin Xinjian , Shang Xiying , Manorek Gerald , Howell Stephen 
Published: August 2012

Abstract
Cell adhesion complexes play a central role in controlling the behavior of epithelial cells, and loss of cell-cell adhesion is a characteristic of virtually all epithelial malignancies. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells including an increase in in vivo growth rate and metastatic potential. However, the role of claudins in controlling sensitivity of ovarian cancer cells to the platinum-containing drugs, and the mechanisms by which they regulate the sensitivity, remain largely unknown. The effect of CLND3 and CLDN4 on cisplatin cytotoxicity, cellular accumulation and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 or CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). CLDN3KD cells were 3.1-fold resistant to cisplatin whereas CLDN4KD cells were 8.0-fold resistant compared to the parental 2008 cells. The net accumulation of platinum in CLDN3KD and CLDN4KD cells was reduced to 66% and 49% of that in the parental cells after exposure to 30 μM cisplatin for 1 h. Likewise, the DNA adduct levels dropped to 65% and 41% of control when CLDN3 and CLDN4 were knocked down. Given that transporters and chaperones that manage copper homeostasis regulate platinum drug accumulation and efflux, their expression was measured by qRT-PCR. Among these, only the expression of CTR1 was significantly reduced (p&lt;0.01) in the knockdown cells while there was no appreciable change in CTR2, ATP7A, ATP7B or ATOX1 mRNA levels. Consistent with the decrease in CTR1 level, the average steady-state copper level in the 2008 cells was 6.4 ± 1.26 ng Cu/μg S whereas the CLDN3KD and CLDN4KD cells contained only 4.2 ± 0.87 and 4.0 ± 0.74 ng Cu/μg S resulting in a 34% (p=0.008) and 38% (p=0.004), respectively, loss of intracellular copper. Copper-dependent tyrosinase activity was also markedly reduced in those CLDN knockdown cells when incubated with the substrate L-DOPA. These results indicate that CLDN3 and CLDN4 affect sensitivity to the cytotoxic effect of cisplatin by regulating expression of the copper transporter CTR1 that we have previously shown to play a central role in the influx of cisplatin.
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 1814. doi:1538-7445.AM2012-1814
Abstract 1823: AZ20, a novel potent and selective inhibitor of ATR kinase with in vivo antitumour activity
Authors: Jacq Xavier , Smith Lisa , Brown Elaine , Hughes Adina , Odedra Rajesh , Heathcote Dan , Barnes Jen , Powell Steve , Maguire Sharon , Pearson Victoria , Boros Joana , Caie Peter , Thommes Pia A. , Nissink Willem , Foote Kevin , Jewsbury Philip J. , Guichard Sylvie M. 
Published: August 2012

Abstract
The DNA damage response (DDR) comprises a range of mechanisms that ensure the integrity of the genome. As part of the DDR and in response to specific DNA damage, the master kinases ATM, ATR and DNA-PK are activated in a coordinated fashion inducing cell cycle arrest and repair of the damage before resuming DNA replication. Alternatively they may induce apoptosis if the DNA damage is incompatible with cell viability. Due to their genetic instability, tumour cells may be more reliant on the DNA damage response and so inhibiting specific DDR components may lead to antitumour activity while minimizing toxicity in normal tissue. ATR (Ataxia telangectasia and Rad 3 mutated) is recruited at specific sites of DNA damage, namely ssDNA (single stranded DNA) coated with RPA (Replication Protein A). ATR activates downstream substrates that regulate replication fork progression, cell cycle checkpoint, and DNA repair proteins. Here we report the discovery of AZ20, a novel potent and selective inhibitor of ATR kinase identified by screening a subset of the AZ compound collection against the target enzyme. In vitro, AZ20 decreases pChk1 Ser345, pChk1 Ser317 and pChk1 Ser296 levels in a concentration-dependent manner. Prolonged exposure with AZ20 increases γH2AX pan-nuclear staining, indicative of replication stress. This is associated with S-phase arrest and increase in phospho-histone H3. AZ20 induces growth inhibition and cell death in vitro and its profile of activity is distinct from other cytotoxic agents such as platinum derivatives, permetrexed or docetaxel. The cytotoxic effect of AZ20 can be increased in combination with the selective ATM inhibitor KU-60019. AZ20 induces significant tumour growth inhibition in vivo at well tolerated doses. This is associated with a persistent elevation of γH2AX pan-nuclear staining in xenograft tissue, but a transient increase in mouse bone marrow at therapeutic doses, suggesting a favourable therapeutic index.
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 1823. doi:1538-7445.AM2012-1823
Abstract 1828: Identification of MUC16/CA125-specific therapeutics through dual fluorescence high throughput screening
Authors: Thapi Dharmarao , Thapi Sahityasri , Rosales Nestor , Antczak Christophe , Ouerfelli Ouathek , Spriggs David R. , Djaballah Hakim 
Published: August 2012

Abstract
BACKGROUND: The MUC16 gene encodes the CA125 ovarian cancer antigen. This glycoprotein is expressed in the majority of Epithelial Ovarian Cancers (EOC) but has limited expression elsewhere in the adult human. Expression of the carboxy-portion of MUC16 results in increased invasion, soft agar growth and in vivo growth. OBJECTIVES:. We seek to identify MUC16 specific small molecules as chemotherapy candidate drugs for development in ovarian cancer. METHODS: Our previously reported study of dual fluorescence isogenic high content screening for MUC16/CA125 selective agents (Mol.Can.Ther, 2011) was extended to a library of 74,942 compounds from NCI, to identify small molecules which have a differential effects against MUC16 positive cells compared to isogenic MUC16 negative ovarian cancer cell lines Carboxy-terminus portions of the human MUC16 gene were introduced into A2780 EOC cell lines labeled with mCherry and compared to GFP labeled isogenic controls in a 384 well co-culture assay for cellular viability by computerized fluorescence intensities and compared for the relative toxicity against MUC16+/MUC16- isogenic cell lines. Compounds with differential activity were selected, resupplied and examined by Vi Cell counting and Alamar Blue cytotoxic assays for confirmation in SK-OV-3 cell line pairs. RESULTS: A2780 isogenic pair was initially used and thirty compounds which selectively targeted MUC16 positive cells were identified. These 30 compounds were tested for growth inhibition with a secondary SKOV3 isogenic screen for confirmation. Two compounds were among the screen identified in the secondary SKOV3 isogenic pair testing. These compounds were studied using Alamar Blue Assay with a panel of ovarian cell lines including CAOV3; OV433; OV432; SKOV8 (WT and MUC16 knockdown and an isogenic T80 MUC16+/− pair (in vitro transformed normal ovarian surface epithelial cell line) and IGROV1-R10. We are in the process of examining the Structural Activity Relationship around these 2 compounds and will present their response. CONCLUSIONS: These MUC16 +/− dual fluorescence screens can be used as an example of single gene target, high throughput screening strategies to identify potentially specific therapeutics for key oncogenic targets.
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 1828. doi:1538-7445.AM2012-1828
Abstract 1855: Jab1/CSN5 a negative regulator of p27 plays a role in the pathogenesis and cisplatin sensitivity of nasopharyngeal carcinoma
Authors: Pan Yunbao , Zhang Qingxiu , Tian Ling , Wang Xin , Fan Xiaohang , Zhang Huizhong , Yang Huiling , Claret Francois X. 
Published: August 2012

Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Previous studies have reported that genetic susceptibility is associated with NPC. Jab1/CSN5 promotes cell growth and proliferation. Recent studies have shown that Jab1/CSN5 is aberrantly expressed, is correlated with low expression of p27, and is associated with advanced tumor stage and poor prognosis in several human cancers. In this study, we examined the functional role and correlation between Jab1/CSN5 and p27 protein expression in NPC tissue samples and cell lines, the association of their expression with clinical outcome and the antitumor effects of cisplatin in NPC cells. Immunohistochemical analysis showed that Jab1/CSN5 aberrant expression was inversely associated with p27 expression in NPC tissue samples, and Jab1/CSN5 overexpression was correlated with poor survival (p&lt;0.01). Further analysis showed that Jab1/CSN5 mediated p27 degradation in a proteasome-dependent manner, and Jab1/CSN5 directly interacted with p27 in NPC cells. In addition, inactivation of Jab1/CSN5 by small interfering RNAs resulted in a remarkable increase in p27 levels and in the inhibition of cell proliferation, thereby indicating that Jab1/CSN5 controls the stability of p27 by targeting it for degradation in NPC. Moreover, suppression of Jab1/CSN5 enhanced the antitumor effects of cisplatin in NPC cells. To our knowledge, these findings are the first to suggest that Jab1/CSN5 overexpression is involved in NPC pathogenesis via Jab1-mediated p27 degradation, thus explaining the low p27 levels seen in NPC. Therefore, Jab1/CSN5 could be a diagnostic marker and a novel therapeutic target in patients with NPC.
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 1855. doi:1538-7445.AM2012-1855
Abstract 187: Down-regulation of microRNA34 induces cell proliferation and invasion of human mesothelial cells
Authors: Tanaka Norimitsu , Toyooka Shinichi , soh junichi , Tsukuda Kazunori , Shien Kazuhiko , Furukawa Masashi , Muraoka Takayuki , Maki Yuho , Ueno Tsuyoshi , Asano Hiroaki , Otsuki Takemi , Miyoshi Shinichiro 
Published: August 2012

Abstract
Purpose: In the recent half-decade, many studies have shown that microRNAs (miRNAs) can act as oncogenes or tumor suppressors and that the widespread alteration of miRNA expression patterns is highly relevant to various human malignancies. We previously reported that microRNA-34s (miR-34s) are methylated and down-regulated in malignant pleural mesothelioma and might play an important role in the carcinogenesis of mesothelioma. In this study, in contrast to our previous study, we down-regulated miR-34s in the human mesothelial cells to investigate cellular effect of miR-34s knockdown. Material and methods: Two human mesothelial cell lines, MeT-5A derived from human pleura and LP-9 derived from human peritoneum, and three human primary cultured mesothelial cells from pleura were used in this study. Antisense mimics of miR-34a, b, and c (Anti-miR miRNA InhibitorR, Ambion) were transfected to these cells and effect of proliferation and invasion was estimated. Control scramble transfected cells were used as control. The protein expression status was estimated using Western Blotting. Results: Antisense miR-34a, b, and c down-regulated each miR-34s in introduced human mesothelial cells. Cell proliferation significantly increased in each antisense of miR-34s transfected human mesothelial cells than in control for all examined cells (p &lt; 0.0001 for miR-34s with all cells). Invasion ability also increased in antisense transfected cells than in control for MeT-5A and LP-9 (P &lt; 0.0001 for 2 cell lines). Human primary cultured mesothelial cells did not obtain invasion ability in this experiment. Western blotting confirmed up-regulation of c-Met and p-c-Met protein. Conclusion: We confirmed that down-regulation of miR-34s up-regulated oncogenic phenotype of mesothelial cells. The present study together with our previous report strongly suggests miR-34s play an important role in early carcinogenic process of human mesothelial cells to malignant mesothelioma.
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 187. doi:1538-7445.AM2012-187
Abstract 188: EphrinA1 induces microRNA-302b expression in malignant mesothelioma cells and suppresses tumor growth via repression of Mcl-1 gene
Authors: Khodayari Nazli , Mohammed Kamal A. , Goldberg Eugene P. , Jantz Michael A. , Nasreen Najmunnisa 
Published: August 2012

Abstract
Introduction: EphA2 is a receptor tyrosine kinase (RTK) and is over expressed in malignant mesothelioma (MM). In earlier studies we demonstrated that receptor EphA2 activation with ephrinA1 suppressed growth of MM. In addition there is evidence that ephrin ligand induces some MicroRNAs expression in cancer cells. MicroRNAs belonging to the miR-302 family are emerging as key players in the control of proliferation and cell fate determination during differentiation. However, the mechanisms whereby EphrinA1 activation attenuates the MM cell growth are not clear. Our study identified a novel mechanism of Ephrin-A1 tumor suppressor signaling in MM cells. Ephrin-A1 activation up regulates miR-302b expression in MM cells and attenuates tumor growth via repression of Mcl-1. Methods: MM cell lines (CRL-2081 and CRL-5830) were activated with recombinant-Ephrin-A1 for the indicated period of time. The expression of miR-302b was analyzed by quantitative real time RT-PCR, and the expression Mcl-1 was analyzed by RT-PCR, immuno-blotting and Immunofluorescence staining. To confirm that Ephrin-A1 regulates the expression of Mcl-1 mRNA through miR302-b up regulation, cultured cells were transfected with and without miR302-b and miR-302b inhibitor prior to activation. The cell proliferation and tumor growth was measured by WST-1 and 3 D matrigel assay in vitro assays respectively. Luciferase assay was performed to confirm the binding of miR-302b to the 3′UTR of Human Mcl-1. Results: Ephrin-A1 activation induced several fold increases of miR-302b expression in MM cells when compared to resting cells. In Ephrin-A1 activated MM cells, Mcl-1 expression was significantly down regulated when compared to resting cells. Moreover, Ephrin-A1 activation significantly inhibited MM cell proliferation and tumor growth. The present data suggests that Ephrin-A1 targets MM cells by inducing the expression of miR-302b and inhibits MM cell and tumor growth by targeting Mcl-1 protein. Conclusion: Our data suggest that over expression of Mcl-1 enhances tumor proliferation in MM cells. During Ephrin-A1 activation miR-302b expression is up regulated in MM cells. The up regulation of miR-302b leads to repression of Mcl-1 gene and attenuation of tumor growth. EphrinA1 could be a promising therapeutic agent for the treatment of MM. Funding Source: NIR and RC1 Department of Health Florida; VA Merit Review
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 188. doi:1538-7445.AM2012-188
Abstract 1897: RAS signaling pathway gene mutations and acquired resistance to EGFR tyrosine-kinase inhibitors in EGFR mutant lung cancer
Authors: Ohashi Kadoaki , Chmielecki Juliann , Lin Ya-Lun , Pan Helen , Vnencak-Jones Cindy , Arcila Maria , Wang Lu , Fernandez Lynnette , Keisuke Aoe , Shien Kazuhiko , Yamamoto Hiromasa , Toyooka Shinichi , Kiura Katsuyuki , Thomas Roman , Yang James Chih-Hsin , Miller Vincent , Ladanyi Marc , Politi Katerina , Pao William 
Published: August 2012

Abstract
EGFR mutant lung cancers are highly sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), but in the metastatic setting, acquired drug resistance is inevitable. Second-site EGFR mutations, MET amplification, PIK3CA mutations, and histologic changes (transformation to small cell lung cancer, epithelial-mesenchymal transition (EMT)) have been reported as resistance mechanisms. Up to 40% of cases are still mechanistically unexplained. Surprisingly, despite the importance of the RAS signaling pathway downstream of EGFR, no RAS pathway signaling gene mutations have been reported to occur in acquired resistance. Here, we investigated further the significance of this pathway in preclinical models and tumor specimens. First, we screened 21 lung tumors from 11 mice with acquired resistance to erlotinib (Politi et al. Dis Model Mech. 2010; 3(1-2): 111-9) and found one tumor with a KrasG12V mutation. Next, we established 6 new cell-line based models of acquired erlotinib resistance in 5 different drug-sensitive EGFR mutant cell lines. While 5 lines developed known mechanisms of resistance (i.e. EGFR T790M, MET amplification, EMT), 1 (11-18 cells) developed de novo a NRASQ61K mutation. Single cell cloning suggested that both the EGFR mutation (L858R) and NRASQ61K mutations were in the same cell. Consistent with these findings, NRAS activity was higher in 11-18 resistant cells (11-18R) compared to parental cells. In growth inhibition assays, 11-18R were sensitive only to combined EGFR inhibition with siRNA knockdown of NRAS or with MEK inhibitors. Expression of NRASQ61K in drug-sensitive PC-9 cells conferred resistance to erlotinib. Finally, we screened 127 tumor samples from patients with acquired resistance patients to EGFR-TKIs. No NRAS or KRAS mutations were found, but one patient's tumor harbored in addition to EGFR L858R both EGFRT790M and BRAFV600E mutations. BRAFV600E expression also conferred resistance to EGFR inhibition, both in PC-9 (EGFR exon 19 deletion) and PC-9R cells (EGFR exon 19 deletion plus T790M). Collectively, these data shown that mutations in RAS pathway signaling genes may be infrequent but occur and could influence therapeutic outcomes in trials for patients with acquired resistance to EGFR TKIs.
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 1897. doi:1538-7445.AM2012-1897
Abstract 1902: Sorafenib overcome irinotecan resistance in colorectal cancer
Authors: Mazard Thibault , Causse Annick , Leconet Wilhem , Assenat Eric , Ychou Marc , Rio Maguy Del , Martineau Pierre , Robert Bruno , Gongora Céline 
Published: August 2012

Abstract
Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. In the last decade, several studies have shown that cetuximab, an anti-EGFR monoclonal antibody, can overcome acquired resistance to irinotecan chemotherapy, but only in KRAS non mutant tumors. Thus, new treatment options are needed to improve survival in patients with irinotecan refractory and KRAS mutated colorectal cancer. In this study, we examined if treatment with sorafenib, a potent inhibitor of Raf kinase and VEGF receptor, could reverse the resistant phenotype in tumor, thereby enhancing the therapeutic efficacy of currently used irinotecan treatment. We used both in vitro and in vivo models to test the efficacy of sorafenib either as a single agent or in combination with irinotecan. We have first tested these different combinations on seven colorectal cancer cell lines displaying different molecular characteristics (mutated or not for KRAS, BRAF, p53 and PIK3CA). We have shown that sorafenib, as a single agent, showed antitumor properties and the effects were more pronounced when it was used in combination with the active metabolite of irinotecan, SN38. Then we have tested these treatments on SN38-resistant clones derived from the colon adenocarcinoma HCT-116 (KRAS mut) and SW48 (KRAS WT) cell lines, that show various levels (6 to 60 fold) of resistance to SN-38 as compared to the corresponding parental cells. Sorafenib has improved the anti-tumoral activity of SN-38 on all the SN38 resistant clones in vitro. Moreover, sorafenib sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Signalling pathways involved in this effect have been identified on xenografts using the proteome profiler array. Altogether, our results show for the first time that sorafenib can inhibit resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in colorectal cancer, particularly in KRAS mutated tumors.
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 1902. doi:1538-7445.AM2012-1902