bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 182: Tumor suppressor microRNA-493 decreases cell motility and migration ability in human bladder cancer cells by down-regulating RhoC and FZD4
Authors: Ueno Koji , Hirata Hiroshi , Majid Shahana , Yamamura Soichiro , Shahryari Varahram , Tabatabai Z. Laura , Hinoda Yuji , Dahiya Rajvir 
Published: August 2012

Abstract
Introduction and Objective: The purpose of this study was to identify new tumor suppressor microRNAs in bladder cancer to carry out functional analysis of their suppressive role and identify their specific target genes. Methods: To identify tumor suppressor microRNAs in bladder cancer, microRNA microarray was performed using SV-HUC-1, T24, J82 and TCCSUP cells. Based on the microRNA microarray, 10 microRNAs were selected and expression levels confirmed using real-time PCR. The function of miR-493 was measured by MTS, cell cycle, migration, and wound healing assays using T24 and J82 cells. Based on the observation that miR-493 affects cell motility and migration, we searched for target genes of miR-493 related to motility and migration using a target scan algorithm, identified RhoC and FZD4 and performed 3′UTR luciferase assays. To examine whether RhoC and FZD4 affects T24 and J82 cell migration, RhoC siRNA, FZD4 siRNA or control siRNA was transfected into T24 and J82 cells and migration, and wound healing assays were performed. We also analyzed whether over-expression of miR-493 affects the binding of RhoC to Rock-1by immunoprecipitation at 72 hr after transfection in T24 cells. Results: Expression of miR-493 in bladder cancer (T24, J82 and TCCSUP) cells was down-regulated compared to normal SV-HUC-1 cells. Also the expression of miR-493 was significantly lower in human bladder cancer tissues than in their corresponding non-cancerous tissues. Transfection of miR-493 into T24 and J82 cells decreased cell growth and migration abilities. To identify potential miR-493 target genes, we used target scan algorithms to identify target oncogenes (FZD4 and RhoC) related to invasion and migration. MiR-493 decreased 3′UTR luciferase activity and protein expression of FZD4 and RhoC. Cell migration was significantly decreased by 35 to 50% in RhoC and FZD4 siRNA transfectants compared with control cells. MiR-493 also decreased binding of RhoC and Rock-1. Conclusions: MiR-493 is a new tumor suppressor microRNA in bladder cancer and inhibits cell motility through down-regulation of RhoC and FZD4.
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 182. doi:1538-7445.AM2012-182
Abstract 1824: Functional characterization of DOG1 in Gastrointestinal Stromal Tumors (GIST)
Authors: Simon Susanne , Fererra Loretta , Galietta Luis , Grabellus Florian , Breitenbücher Frank , Schuler Martin , Fletcher Jonathan , Bauer Sebastian 
Published: August 2012

Abstract
Introduction: DOG1, a calcium-dependent chloride channel, has been shown to be strongly and specifically expressed in GIST and is commonly used as diagnostic marker. Notably, KIT-negative GIST cell lines do not express DOG1. We have therefore sought to investigate the role of DOG1 for KIT expression and GIST growth and its potential as therapeutic target. Methods: GIST cell lines (GIST882: K642E, IM-sensitive, GIST-T1: del558-614, IM-sensitive, GIST48: V560D/D820A, IM-resistant) were transduced with lentiviral particles containing DOG1 sh-RNA. Expression of KIT and DOG1 was measured by immunoblotting. Effects of DOG1 knock-down on proliferation (with/without imatinib) were studied by BrdU incorporation assays and effects on chloride currents using patch clamp technique. Xenografts from transduced cells (and scrambled control) were generated and evaluated for tumor growth and expression of DOG1, KIT and Ki-67. Expression profiles from cell lines and xenograft tumors were compared using microarrays. Results: Lentiviral knock-down of DOG1 resulted in a near-complete inhibition of DOG1 while expression of KIT or the KIT-depending signalling pathways were not affected. Patch clamp measurements showed a strong inhibition of chloride currents in the majority of cells (DOG1-knock-down) tested compared to scrambled control. No difference was found in the growth rate of cells with DOG1-knockdown alone or in the presence of imatinib compared to cells transduced with scrambled sh-RNA. Xenografts generated from transduced cell lines retained DOG-1 knockdown as well as strong KIT-expression. Notably, xenografts with knock-down of DOG1 showed a lower proliferative activity (Ki-67: immunoreactivity score 12 (strongly positive) versus 6 (moderately positive)) with a reduction of tumor size of 43% after 19 days of tumor growth (n=8; p=0.003) when compared with the scrambled control. Expression analyses revealed MNK1 (MAP kinase-interacting serine/threonine-protein kinase 1) to be down-regulated in DOG1 negative GIST xenografts compared to scrambled control. Conclusion: DOG1 knock-down results in a reduction of intracellular chloride currents but does not affect KIT-expression or sensitizes cells to imatinib treatment. Proliferation is not affected by DOG1 knock-down in vitro but DOG1 appears to contribute to tumor growth 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 1824. doi:1538-7445.AM2012-1824
Abstract 1833: A large-scale synthetic lethal RNAi screening identifies unique sensitizing targets for anti-inflammatory CDDO-Me in metastatic melanoma
Authors: Ekmekcioglu Suhendan , Qin Yong , Deng Wuguo , Grimm Elizabeth A. 
Published: August 2012

Abstract
Metastatic melanoma is the most lethal form of skin cancer strongly associated with the inflammatory process by secreting high levels of proinflammatory cytokines and producing reactive oxygen and nitrogen species. Chronic inflammation is considered as a major factor to promote the tumor microenvironment in advantage of resistance to radiation, chemotherapy, and biotherapy for metastatic melanoma. CDDO-Me, a novel synthetic triterpenoid, has been shown to exert potent anti-inflammatory and antitumor activity by decreasing oxidative stress and the production of pro-inflammatory molecules, such as Nrf2 and iNOS, in several tumor models. CDDO-Me is presently under evaluation in clinical studies for chronic kidney disease and pancreatic cancer. Here, we used CDDO-Me as a primary agent to inhibit metastatic melanoma growth. In order to improve CDDO-Me response in melanoma cells, we utilized a large-scale synthetic lethal RNAi screen with 24,000 siRNAs targeting ∼6,000 human druggable genes to identify targets that when silenced would sensitize melanoma cells to CDDO-Me. Results from the screens identified twenty of siRNA pools that significantly potentiated the growth inhibitory effects of CDDO-Me in A375 cells. We selected five unique genes, GNPAT, SUMO1, SPUNT2, FLI1, and SSX1, which have not been addressed as drug targets in melanoma before, for target validation and functional analysis in four metastatic melanoma and control cell lines. Specific siRNA against each of these five genes could substantially sensitize four tested melanoma cells to CDDO-me by increasing the growth inhibition and induction of apoptosis, while treatment with nontarget siRNA resulted in no change compared to the treatment with CDDO-Me only. Further studies of downstream signaling revealed that these five genes involved in regulating melanoma cell proliferation and cell death. We identified for the first time that the levels of phosphorylated Erk1/2, Akt, GSK-2, and PRAS40, were dramatically decreased by individual siRNA against GNPAT, SUMO1, SPUNT2, FLI1, and SSX1. Our findings indicate that GNPAT, SUMO1, SPUNT2, FLI1, and SSX1 may play critical roles in synergy with inflammation pathways in modulating melanoma cell survival, which could serve as sensitizing targets to enhance CDDO-Me efficacy in melanoma. Supported by MDACC SPORE in Melanoma P50CA093459.
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 1833. doi:1538-7445.AM2012-1833
Abstract 1847: SNRPE is involved in cell proliferation and the progression of high-grade prostate cancer through the regulation of AR expression
Authors: Anchi Takashi , Tamura Kenji , Furihata Mutsuo , Satake Hirofumi , Kamei Maiko , Shimamoto Tsutomu , Fukuhara Hideo , Ashida Shingo , Karashima Takashi , Nishikawa Hiroshi , Yamasaki Ichiro , Yasuda Masaharu , Kamada Masayuki , Inoue Keiji , Shuin Taro 
Published: August 2012

Abstract
Clinically high-grade prostate cancers (PC) with high Gleason scores of 8-10 tend to grow quickly and are more likely to spread beyond the prostate. They show a poor response to androgen deprivation therapy and eventually acquire a castration-resistant phenotype. To identify novel molecular cancer drug targets, we previously analyzed the gene expression profiles of high-grade PC using a cDNA microarray combined with laser microbeam microdissection and found a number of genes that are transactivated in high-grade PC. Among them, we report the identification of a novel molecular target, small nuclear ribonucleoprotein polypeptide E (SNRPE). Semi-quantitative RT-PCR confirmed that SNRPE is overexpressed in high-grade PC cells compared with normal prostatic epithelial cells (NP). Knockdown of SNRPE expression by short interfering RNA (siRNA) resulted in the marked suppression of PC cell proliferation. In contrast, SNRPE overexpression promoted PC cell proliferation, indicating its oncogenic effects. Furthermore, we demonstrated that SNRPE regulates androgen receptor (AR) mRNA expression in PC cells. Knockdown of SNRPE expression by siRNA resulted in the marked suppression of AR and its downstream target genes at the mRNA level. We suggest that the regulation of AR expression by SNRPE is essential for the cell proliferation and progression of high-grade PC and that it could be a novel molecular target for cancer drugs.
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 1847. doi:1538-7445.AM2012-1847
Abstract 1851: A role for heat-shock protein 40 YDJ1 in the protection from anthracycline exposure
Authors: Flores-Rozas Hernan , Mazu Tryphon 
Published: August 2012

Abstract
Doxorubicin is an anthracycline antibiotic commonly used as an antineoplastic agent for the treatment of both solid tumors and hematological cancers. Although there is a dose-dependent response in the use of anthracyclines, there is also a dose-related toxicity associated to them, namely chronic cardiotoxicity. To increase our knowledge of the pathways that protect cells from the cytotoxic effects of anthracyclines, we carried out a genetic screening in the eukaryotic model organism S. cerevisiae, to identify gene defects that generate cells hypersensitive to doxorubicin. Our findings indicate that inactivation of the heat-shock protein 40 encoded by the genes YDJ1 and ZUO1, as well as the heat-shock protein 70 encoded by the gene SSZ1, render cells highly sensitive to the toxicity of doxorubicin. Further analysis of the YDJ1 defective strain revealed that it is also sensitive to daunorubicin and cisplatin, but not to other DNA damaging agents such as alkylating agents, the topoI inhibitor campthotecin or replication blocks from hydroxyurea. YDJ1 mutant displayed different sensitivity to DNA-double-strand breaks and oxidative damage, both of which are generated by anthracyclines. Complementation of the ydj1 mutation with the human DNAJA2 gene rescues the sensitivity of the deletion strain, suggesting a potential role of DNAJA2 in the protection to doxorubicin and implying that this mechanism also applies to higher eukaryotes.
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 1851. doi:1538-7445.AM2012-1851
Abstract 1867: Gene expression profiles obtained from ex vivo human scalp hair to determine the effects of drug response following exposure to HDAC inhibitors.
Authors: Reed Benjamin J. , Forslund Ann , Casneuf Tineke , Miele Gino , Grimes Emma , Mefo Tim , Harrison Elliott , Meyer-Turkson Lydia , Brady Ged , McClue Steve , Winkler Hans 
Published: August 2012

Abstract
Background Plucked human scalp hair represents an ideal surrogate tissue to enable non-invasive monitoring of drug response in clinical trials. Congruence of patterns of transcriptome activity within the bulb region of plucked scalp hair show high concordance and to that of primary target tumour tissues. The ex vivo plucked scalp hair culture technique involves exposing healthy normal volunteer hair to different concentrations of a number of HDAC inhibitors and ascertain the effects that they have on gene expression. This technique is an ideal approach to identifying desirable non-invasive transcriptional biomarkers to demonstrate target engagement and define a PK/PD relationship, as well as enabling the monitoring of a well tolerated dose schedule with maximal biological effect. Materials and Methods In this study, we deployed our proprietary ex vivo culture technique to ascertain the effects that three different HDAC inhibitors had on gene expression in plucked hair. Three different concentrations of each HDAC inhibitor were incubated in culture for a period of 18 hours. RNA was extracted from the hair bulb following the culture technique and gene expression was assessed following microarray analysis. Statistically significant biomarkers (p&lt;0.05) were identified along with genes with a greater than 2 fold change from the vehicle group. Direct comparisons in the profiles obtained following exposure to the three different HDAC inhibitors were conducted to evaluate differences in the mechanism of action of each compound. Results We were able to demonstrate from the ex vivo plucked hair study, a panel of transcriptional markers that exhibited a similar response to drug treatment following exposure to the three different HDAC inhibitors. The differentially expressed genes identified were biologically relevant as they are consistent with pathways that are known to be associated with HDAC inhibition. The results also demonstrated the potency of each of the HDAC inhibitors and provided an insight into the different mechanisms of action of each compound. The differentially expressed biomarkers identified in this study may be used in clinical settings to monitor pharmacodynamic responses in plucked scalp hair obtained from patients. Conclusions We conclude that plucked human scalp hair represents an ideal minimally invasive surrogate tissue to monitor drug response in patients receiving treatment with HDAC inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1867. doi:1538-7445.AM2012-1867
Abstract 1870: Association of prostaglandin-endoperoxide synthase 2 (PTGS-2) polymorphisms with colorectal cancer risk and immunohistochemical detection of PTGS-2 in Chinese colorectal cancer patients
Authors: Lim Rachel Liyu , Lim Jia Qi , Yip Fong Ee , Niah Weixin , Sandanaraj Edwin , Singh Onkar , Koilan Subramaniyan , Chowbay Balram 
Published: August 2012

Abstract
PTGS-2 is an rate-limiting enzyme that can be induced by several factors including mitogens, cytokines, growth factors and tumor promoters. It catalyzes the formation of Prostaglandin E2 (PGE2) that favors carcinogenic processes. Overexpression of PTGS-2 gene encoding PTGS-2 enzyme was observed in several human malignancies including colorectal cancer. Various functional genetic polymorphisms present in the PTGS-2 gene were shown to influence the expression level of the PTGS-2 protein and affect the individuals’ susceptibility to developing colorectal cancer. Whole gene screening in the healthy local Chinese subjects had identified 26 SNPs, which were tagged by 15 tag SNPs. Among these tag single nucleotide polymorphisms (SNPs), two were found in the 5′ upstream region [−1424 A&gt;G (rs689465), −1329 A&gt;G (rs689466)], five were in the intronic region [IVS1+145A&gt;G (rs11567820), IVS2-22C&gt;G (rs20427), IVS3+36C&gt;T, IVS9+146C&gt;T and IVS9-164G&gt;T], two were in the coding region [306G&gt;C (rs5277) and 1759G&gt;A(rs3218625)], four were in the 3′ untranslated region (UTR) [*427T&gt;C (rs5275), *2267G&gt;T (rs4648302), *2358T&gt;A (rs13306038), *2368_*2369insA] and two were located in the 3′ downstream region [*+2868G&gt;A (rs4648308), *+4038_*4039insTA] of the PTGS-2 gene. This study aimed to investigate the association between fifteen PTGS-2 tag SNPs and one functional SNP [-899G&gt;C (rs20417)] with (1) the risk of developing colorectal cancer and (2) the expression level of PTGS-2 protein in the tumor resections in Chinese colorectal cancer patients (N=90). The genetic association analysis indicated that patients harboring the heterozygous genotype (TC) of *427T&gt;C (rs5275) SNP had a significant reduced risk in colorectal cancer predisposition (codominant model: Odds Ratio (OR)=0.51; 95% Confidence Interval (CI)=0.25-1.03; P=0.033 and overdominant model: OR=0.47; 95% CI=0.24-0.95; P=0.033). However, this SNP was not found to be significantly associated with the PTGS-2 expression in the tumor resections of the patients (N=48). No significant correlation was observed between other investigated tag SNPs with colorectal cancer risk and PTGS-2 protein expression. The findings of this study suggest that *427T&gt;C (rs5275) might be a biomarker for colorectal cancer predisposition in the local Chinese colorectal cancer patients. Further conformational investigations in larger cohort should be performed to validate the findings of the present study.
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 1870. doi:1538-7445.AM2012-1870
Abstract 1888: MM-111, a bispecific HER2 and HER3 antibody, inhibits trastuzumab-resistant tumor cell growth
Authors: Zhang Bo , Nguyen Stephanie , Huhalov Alexandra , Nielsen Ulrik B. , Niyikiza Clet , McDonagh Charlotte F. , Kudla Arthur J. , Onsum Matthew 
Published: August 2012

Abstract
Amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 25% of breast cancers and is associated with increased disease recurrence and poor prognosis. Trastuzumab, a monoclonal antibody targeting HER2, has demonstrated clinical benefit in HER2 over-expressing tumors. However, acquired resistance and disease progression is widely observed in patients treated with trastuzumab. In this experiment our objectives were to dissect the dynamic, molecular mechanisms involved in acquired resistance to trastuzumab and to determine whether MM-111, a novel bispecific antibody fusion protein that specifically targets the HER2/HER3 heterodimer and blocks heregulin binding to HER3, has activity in trastuzumab-resistant tumor cells. BT474 cells were cultured in the presence of trastuzumab and cells were periodically tested for response to trastuzumab and MM-111. Samples were also collected for protein and RNA analyses. Resistance to trastuzumab gradually increased in BT474 cells after four months of exposure to trastuzumab, as measured by a cell proliferation assay. Quantitative flow cytometry analysis showed EGFR, HER2, and HER3 levels on the cell surface of resistant cells were similar to the parental cells. Phospho-protein kinase antibody arrays revealed that signaling pathways associated with the ERK cascade were activated during the development of drug resistance. Western blotting further confirmed that phosphorylation of EGFR, ERK, CREB, c-Jun, and AFT-1 was increased in the resistant cells. Real-time polymerase chain reaction also showed transcript levels of HER ligands, including HRG1α, HRG1α, betacellulin, amphiregulin, epigen, TGFβ, and HB-EGF, dramatically increased in tumor cells that acquired resistance to trastuzumab. Compared to the BT474 parental cells, MM-111 showed a greater inhibition in trastuzumab-resistant cells in a spheroid growth assay. Furthermore, trastuzumab-resistant cells became more sensitive to gefitinib and erlotinib, both EGFR inhibitors. The combination of gefitinib or erlotinib with MM-111 showed greater inhibition than either drug alone. In conclusion, our data suggest that one mechanism by which HER2 overexpressing breast cancer cells develop resistance to trastuzumab is to up-regulate ligand-dependent EGFR and HER3 signaling pathways. The use of MM-111 and EGFR inhibitors may provide an effective therapeutic strategy for the treatment of trastuzumab-resistant cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1888. doi:1538-7445.AM2012-1888
Abstract 1891: NF-κB signaling plays a certain role in apoptosis resistance in 3D-cultured EGFR-mutant lung adenocarcinoma cells
Authors: Sakuma Yuji , Miyagi Yohei 
Published: August 2012

Abstract
It is generally thought that suspended tumor cells show reduced proliferative activity and are more resistant to conventional chemotherapy compared with adherent tumor cells. Two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858R + T790M), cultured in suspension, however, undergo apoptosis much more easily than these two cell lines cultured in conventional monolayer dishes, i.e. anchorage dependent conditions, when the kinase activity of EGFR is completely inhibited by treatment with EGFR tyrosine kinase inhibitors (TKIs) regardless of suspension or monolayer culture conditions. These findings indicate that attached EGFR-mutant lung adenocarcinoma cells appear less dependent on constitutive EGFR signaling for survival than detached cells, probably because integrin ligation enhances cell survival in adherent cells. However, the microenvironment of cells in monolayer culture conditions is considerably different from that of cells in vivo. We thus tested whether EGFR-mutated lung adenocarcinoma cells in three dimensional (3D) conditions using Matrigel resist EGFR TKIs-induced apoptosis compared with suspended cells. We uncovered three major findings in this study as follows: 1) both HCC827 cells and H1975 cells cultured in 3D conditions were significantly less sensitive to EGFR TKIs-induced apoptosis than suspended cells. 2) Marked degradation of IαBβ, the inhibitor of NF-κB pathway, was observed only in 3D-cultured EGFR-mutated lung adenocarcinoma cells, resulting in NF-κB signaling activation. 3) TPCA-1, a potent IKKα inhibitor, can enhance the levels of apoptosis in 3D-cultured EGFR-mutant cells treated with EGFR TKIs. These results suggest that combined EGFR and NF-κB inhibition is required to induce apoptosis effectively in EGFR-mutated lung adenocarcinoma cells 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 1891. doi:1538-7445.AM2012-1891