bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5189: The transcriptional regulation of the long non-coding RNA HOTAIR in ovarian cancer.
Authors: Ozes Ali R. , Miller Dave , Guo Cong , Bhattrai Anurag , Liu Yunlong , Nephew Kenneth P. 
Published: August 2014

Abstract
The Polycomb Group (PcG) Repressive Complexes 1 and 2 (PRC1 and PRC2) maintain gene expression patterns by epigenetically modifying chromatin. PRC2 suppresses transcription by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), a hallmark of repressed chromatin. Although overexpression of PRC2 components has been implicated in cancer initiation, progression and metastasis how PRC2 is recruited to its target genes remains poorly understood. Recent work suggests the interaction of PRC2 with the long-non coding (lnc) RNA HOX transcript antisense intergenic RNA (HOTAIR) could serve as a potential guide to silence target genes, but the mechanism has yet to be defined. In this study, we performed whole transcriptome RNA-seq analysis of isogenic cisplatin- sensitive and -resistant A2780 ovarian cancer (OC) cell lines. Of the lncRNA examined, HOTAIR was markedly induced in the cisplatin resistant cells (5-fold upregulation compared to the cisplatin-sensitve A2780 parental line). shRNA depletion of HOTAIR resensitized the drug-resistant cells to cisplatin. Based on analysis of the HOTAIR promoter using luciferase assays, we identified two putative NF-κB binding sites and three E-box binding sites. To further investigate whether these sites contributed to HOTAIR expression, platinum-sensitive cells were treated with different growth factors and cytokines (0 to 48hrs) and analyzed for changes in HOTAIR expression. Treatment with TNF-α, a well-known inflammatory cytokine and established activator of NF-κB, resulted in 16 fold-induction of HOTAIR. In accord with these results, we observed significant enrichment of both NF-κB and cMYC on the HOTAIR promoter using ChIP assay. Pharmacological inhibition of cMYC and NF-κB reduced HOTAIR expression by 2-fold, and siRNA depletion of the NF-κB p65 subunit or cMYC similarly reduced (P&lt;0.01) HOTAIR expression. Based on these results, we hypothesize a positive feedback loop for HOTAIR transcriptional regulation: HOTAIR inhibits Iκ-Bα (an inhibitor of NF-κB) allowing the lncRNA to enter the nucleus and activate not only its own expression but also cMYC expression to further drive HOTAIR expression as well as cMYC-inducible genes. We are currently testing this hypothesis. We believe this novel pathway, whose components have been implicated in numerous other cancers, may be involved in cisplatin-resistant OC.
Citation Format: Ali R. Ozes, Dave Miller, Cong Guo, Anurag Bhattrai, Yunlong Liu, Kenneth P. Nephew. The transcriptional regulation of the long non-coding RNA HOTAIR in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5189. doi:10.1158/1538-7445.AM2013-5189
Abstract 5199: The biological importance of LRIG1 in lung cancer.
Authors: Kvarnbrink Samuel , Edlund Karolina , Botling Johan , Micke Patrick , Henriksson Roger , Hedman Håkan , Johansson Mikael 
Published: August 2014

Abstract
Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is an endogenous inhibitor of epidermal growth factor receptor (EGFR) signaling. LRIG1 is down-regulated in several forms of human cancer. The LRIG gene family also includes LRIG2 and LRIG3. EGFR signaling is important in non-small cell lung cancer (NSCLC) and EGFR tyrosine kinase inhibitors are today considered standard treatment in patients with advanced disease. Since smoking recently was reported to down-regulate LRIG1 gene expression in lung epithelium and squamous cell carcinoma of the lung, the LRIG family of proteins may be important in lung cancer. The objective of the present study was to investigate if LRIG is a prognostic factor in non-small cell lung cancer (NSCLC) and if LRIG1 have any effects of lung cancer growth in vivo and in vitro.
In the present study we analyzed the LRIG protein expression by immunohistochemistry in a tissue microarray (TMA) from surgically treated patients with NSCLC (n=366). To study the effect of LRIG1 expression on tumor growth, an animal model was used. Transgenic mice with an inducible EGFR L858R mutation were crossbred with LRIG1 knockout mice and tumor growth was assessed with micro-MRI. The impact of ectopic LRIG1 expression on lung cancer cell proliferation was studied in vitro.
In the TMA, patients with high LRIG1 expression had a significantly longer median survival than negative cases (p=0.012). In the animal model, tumor progression was significantly faster in LRIG1 knockout mice 60 days after tumor induction (p=0.025) indicating that LRIG1 is of importance in the early tumor progression. Transient ectopic expression of LRIG1 inhibited lung cancer cell proliferation in vitro.
In summary, LRIG1 was a positive prognostic factor in lung cancer and LRIG1 expression inhibited lung cancer growth in vivo and in vitro. This suggests that LRIG1 is of biological importance in lung cancer and that further studies of LRIG1 as a biomarker and tumor suppressor in lung cancer are warranted.
Citation Format: Samuel Kvarnbrink, Karolina Edlund, Johan Botling, Patrick Micke, Roger Henriksson, Håkan Hedman, Mikael Johansson. The biological importance of LRIG1 in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5199. doi:10.1158/1538-7445.AM2013-5199
Abstract 5223: Elucidating the complex cross-talk between the MAPK and PIK3 pathways.
Authors: Egbert Megan E. , Wynn Michelle L. , Wu Zhi Fen , Schnell Santiago , Merajver Sofia D. 
Published: August 2014

Abstract
Targeted molecular inhibitors have emerged as a leading anti-cancer strategy; however, despite promising pre-clinical data, many targeted inhibitors induce undesirable off-target effects in the clinic. The large number of off-target effects associated with molecular inhibitors was recently termed the ‘‘whack a mole problem’’ because inhibiting one molecular target often unintentionally activates another molecule. It is increasingly clear that the high incidence of off-target effects associated with targeted inhibitors is related to the complex interactions and emergent behaviors inherent to the highly complex and dysregulated intracellular networks of cancer. Both the mitogen activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) pathways are known to be dysregulated in cancer. In previous work, we and others have demonstrated that the MAPK pathway promotes motility, invasion, and angiogenic factors while the PI3K pathway plays an important role in controlling anchorage independent growth. In addition, the PI3K pathway plays an essential role in stimulating glucose metabolism and the Warburg effect. We hypothesize that robust interactions exist between these two pathways that influence efficacy and potentially also acquired resistance to targeted therapies. Using a combination of experimental and theoretical techniques, we developed a predictive network model linking growth factor signaling to the MAPK and PI3K pathways as well as to glucose metabolism. Specifically, we constructed a logic-based network of the cross-talk between MAPK and PI3K signaling that relied on a detailed literature survey to identify known molecular interactions as well as proposed interactions and regulatory feedback connections in the literature. We next performed a set of experiments using a normal-like breast epithelial cell line and a series of pathway specific inhibitors with and without growth factor stimulation to validate our model. Finally, we repeated these experiments using a diverse set of breast cancer cell lines and integrated this data to produce a series of cancer networks representative of different stages of breast cancer progression. Our model was able to recapitulate both our own experimental data and published data in the literature using a smaller subset of regulatory feedback mechanisms than we started with. Together, our results suggest that some proposed interactions and feedback mechanisms attributed to MAPK and PI3K cross-talk in the literature may not be valid.
Citation Format: Megan E. Egbert, Michelle L. Wynn, Zhi Fen Wu, Santiago Schnell, Sofia D. Merajver. Elucidating the complex cross-talk between the MAPK and PIK3 pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5223. doi:10.1158/1538-7445.AM2013-5223
Abstract 523: Chaetoglobosin K inhibits VEGF expression in ovarian cancer cells.
Authors: Chen Yi C. , Luo Haitao , Douglas Zachary , Stewart Shannon , Li Zhaoliang 
Published: August 2014

Abstract
Ovarian cancer is the 5th leading cause of cancer deaths for women in America. In search for an effective reagent for prevention and treatment of ovarian cancers, we looked into a mycotoxin, chaetoglobosin K (ChK), and investigated its potential of angioprevention in two ovarian cancer cell lines. Cell viability and necrosis were checked with MTS- and LDH-based assays, respectively, and expression of several genes was analyzed by ELISA or Western Blotting. We found this mycotoxin dramatically toxic, sharply reducing cell viability at concentrations of 0.6 to 13 microM, and causing necrosis in both OVCAR-3 and A2780/CP70 cells at 2 microM. However, when applied at low concentrations (0.5 -2 microM), ChK effectively reduced expression of VEGF and HIF-1-alpha proteins, and inhibited phosphorylation of Akt signaling molecules. While further study on ChK is underway, we hypothesize a potential mycotoxin for prevention and treatment of ovarian cancers.
Citation Format: Yi C. Chen, Haitao Luo, Zachary Douglas, Shannon Stewart, Zhaoliang Li. Chaetoglobosin K inhibits VEGF expression in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 523. doi:10.1158/1538-7445.AM2013-523
Abstract 5234: Network interrogations on SNAIL inhibitor GN-25 induced perturbations in HMLE-SNAIL cell line models.
Authors: Azmi Asfar S. , Bollig-Fisher Aliccia , Bao Bin , Joon-Park Bum , Lee SH , Song Gyu-Yong , Mohammad Ramzi M. , Sarkar Fazlul H. 
Published: August 2014

Abstract
HMLEs (HMLE-SNAIL and Kras-HMLE-SNAIL pairs) serve as excellent model system to interrogate the effect of SNAIL targeted agents that reverse epithelial-to-mesenchymal transition (EMT). We developed a SNAIL-p53 interaction inhibitor (GN-25) that was shown to suppress SNAIL function. In this report, using pathway network analysis, we show that GN-25 induces the reversal of EMT to mesenchymal-to-epithelial transition (MET) in well recognized HMLE-SNAIL and Kras-HMLE-SNAIL models. GN-25 induced MET was found to be concurrent with growth inhibition, suppression of spheroid forming capacity and induction of apoptosis. We performed systems and pathway network analysis on mRNA expression by microarrays from GN-25 treated Kras-HMLE-SNAIL cells that showed an orchestrated global re-organization of EMT network genes. The expression signatures were validated at the protein level using confocal microscopy, western blot analysis and time lapse videography, and we found down-regulation of mesenchymal markers such as TWIST1, TWIST2, ZEB-1 concurrently with up-regulation of epithelial marker E-Cadherin. Additionally, RNAi studies validated SNAIL dependent mechanism of action of the drug. Most importantly, GN-25 deregulated many major transcription factors (TFs) such as inhibition of oncogenic TFs Myc, TBX2, NR3C1 and enhancement in tumor suppressor TFs such as SMAD7, DD1T3, CEBPA, HOXA5, TFEB, IRF1, IRF7 and XBP1, resulting in MET as well as induction of cell death. Our systems and network investigations provide solid pre-clinical supportive evidence for clinical application of GN-25 for the reversal of EMT phenotype to MET in aggressive cancers.
Citation Format: Asfar S. Azmi, Aliccia Bollig-Fisher, Bin Bao, Bum Joon-Park, SH Lee, Gyu-Yong Song, Ramzi M. Mohammad, Fazlul H. Sarkar. Network interrogations on SNAIL inhibitor GN-25 induced perturbations in HMLE-SNAIL cell line models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5234. doi:10.1158/1538-7445.AM2013-5234
Abstract 5243: The novel calcium-dependent direct binding of S100B to p90 ribosomal S6 kinase (RSK) decreases MAP kinase-mediated RSK activation in malignant melanoma.
Authors: Pierce Adam D. , Hartman Kira G. , Weber David 
Published: August 2014

Abstract
S100B is an effective and extensively used prognostic marker for melanoma, with increasing serum S100B being predictive of disease stage, increased recurrence, and low overall patient survival. Establishing the mechanism by which S100B alters cell signaling provides insight into how it may facilitate the progression of melanoma and aid in developing new pharmacological drugs to inhibit cancer advancement. To evaluate specific roles for S100B in malignant melanoma, our S100B knock-down and over-expression studies established a correlation between S100B expression and cell viability. ERK phosphorylation was also found to correlate with S100B levels. We have discovered RSK, a downstream ERK target, as a novel binding partner of S100B. RSK is known to regulate MAPK signaling in melanoma but the mechanism is unclear. We observed an inverse relationship between activated and phosphorylated RSK and S100B levels. We used a Ca2+-binding mutant of S100B (E31A + E72A) to demonstrate that the S100B-RSK interaction was calcium-dependent. Pull-down experiments revealed the C-terminal domain of RSK to be necessary for S100B binding. In vitro, S100B was found to reduce ERK-dependent phosphorylation of RSK at Thr573. Our cellular fractionation and immuno-fluorescence studies showed that S100B protein prevented nuclear localization of phosphorylated RSK. These data are consistent with a mechanism in which elevated S100B binds directly to RSK in a calcium-dependent manner, preventing ERK-mediated phosphorylation of RSK and inhibiting RSK localization to the nucleus. We have identified the S100B-RSK interaction as a novel drug target in melanoma cells. We are currently screening compounds for inhibitors of the S100B-RSK interaction.
Citation Format: Adam D. Pierce, Kira G. Hartman, David Weber. The novel calcium-dependent direct binding of S100B to p90 ribosomal S6 kinase (RSK) decreases MAP kinase-mediated RSK activation in malignant melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5243. doi:10.1158/1538-7445.AM2013-5243
Abstract 5250: The role of tumor associated macrophage on drug resistant in non-small cell lung cancer .
Authors: Huang Wen-Chien , Chen Yu-Jen 
Published: August 2014

Abstract
Increased evidence suggests that chronic inflammation is associated with cancer development, metastasis, invasion and drug resistant. The possible mechanisms by which inflammation can contribute to carcinogenesis include lymphocytes infiltration, cytokines and chemokines secretion, tissue remodeling and angiogenesis, etc. The inflammatory mediators facilitate the communication between tumor cells and tumor-associated host stromal tissue, thereby accelerating tumor progression. Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. Previous studies found macrophage in non-small cell lung cancer (NSCLC) specimens by immunohistochemistry staining, and also discovered interplay of cancer cells and macrophages would induce secretion of certain cytokines and chemokines. However, the mechanism of cytokines and chemokines involved with tumor drug resistant in NSCLC is still obscure. It is also unclear the regulatory mechanisms in change of macrophages from M1 to M2 phase affected by tumor cells.
In this study, we attempt to investigate the roles of TAM-mediated molecules using different characteristics of NSCLC cell lines (H2126, CL1-1, H1437, H23, H838, CL1-5, and H2009) as the study model. We will explore TAM mediators in NSCLC cell lines to detect and compare the phenotypic characteristics; then, we may investigate the transcriptional signaling pathways that are associated with expression of TAM mediators. Finally, we will correlate the expression of TAM mediators/proteins that are associated with TAM-mediated regulatory signaling in tumor drug resistant to the outcome of NSCLC patients. We believe that these proteins may serve as therapeutic targets for NSCLC patients in the future.
In our pilot study, we analyzed the secretion stimulation of cytokines (MCP-1, IL-6, IL-7, IL-8, IL-10, and TNF-a) and MMPs (MMP-8, MMP-9, MMP-10 and TIMP-1) from cancer cells under the effect of macrophages. In the current study, we will deeply concern that the ambivalent interactions between TAM phenotypes and biological behavior of cancer cells, because the paradoxical responses between cancer cells and TAMs in a to and fro way are potentially evident.
Citation Format: Wen-Chien Huang, Yu-Jen Chen. The role of tumor associated macrophage on drug resistant in non-small cell lung cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5250. doi:10.1158/1538-7445.AM2013-5250
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5252: CC-223, a selective and potent mTOR kinase inhibitor, synergizes with 5-Aza and Erlotinib in eight NSCLC lines in vitro.
Authors: Tran Tam , Hege Kristen , Mortensen Deborah , Raymon Heather , Xu Shuichan 
Published: August 2014

Abstract
CC-223 is a potent and selective mTOR kinase inhibitor currently undergoing Phase 1 clinical evaluation. We evaluated combinatorial effect of CC-223 with 5-Aza and erlotinib at three different ratios of the two combining agents in three different orders of addition in eight NSCLC lines. Combinational indices (CIs) were calculated based upon published method (Chou and Talalay, 1984). CC-223 synergized with azacitidine (CI&lt;0.7) in most of the lines at all ratios of combination when azacitidine was added first to the cells (SeqM2). Synergism (CI&lt;0.7) and moderate synergism (0.7&lt;CI&lt;0.85) was also observed in some cell lines when CC-223 was added first (SeqM1) or simultaneously (Sim) with azacitidine; however, SeqM2 seems to generate better synergistic effect across all lines than SeqM1 and Sim. In SeqM2 addition, no significant difference was observed among different ratios of the two agents. CC-223 synergized with erlotinib (CI&lt;0.7) in most of the cell lines at a ratio of 1:30 (CC-223:erlotinib). Synergism and moderate synergism (0.7&lt;CI&lt;0.85) were also observed at other ratios. Order of addition had no impact on the combinatorial effect for CC-223+erlotinib. Overall, the data demonstrated that CC-223 synergizes with azacitidine and erlotinib in multiple NSCLC cell lines in vitro. Order of addition has an impact for CC-223 combination with 5-Aza but not with Erlotinib. On the other hand, ratio of the two combinatorial agents is important for CC-223+erlotinib combination in vitro.
Citation Format: Tam Tran, Kristen Hege, Deborah Mortensen, Heather Raymon, Shuichan Xu. CC-223, a selective and potent mTOR kinase inhibitor, synergizes with 5-Aza and Erlotinib in eight NSCLC lines in vitro. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5252. doi:10.1158/1538-7445.AM2013-5252
Abstract 5261: PKC alpha is implicated in epithelial to mesenchymal transition and erlotinib resistance in non-small cell lung carcinoma cells.
Authors: Abera Mahlet , Sordella Raffaella , Kazanietz Marcelo 
Published: August 2014

Abstract
Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) play important roles in the pathogenesis of non-small-cell lung cancer (NSCLC). For patients with EGFR activating mutations, EGFR tyrosine kinase inhibitors (TKIs) are given as a primary therapy. However, the majority of these patients eventually develop resistance to TKIs. To address a potential role of PKC isozymes in the resistance to TKIs, we used an isogenic model: the NSCLC H1650 cell line and its erlotinib-resistance derivative H1650-M3. H1650-M3 cells display a mesenchymal-like morphology driven by TGF-β signaling (PNAS 107:15535-15540, 2010). Comparison of the expression of PKC isozymes by Western blot between parental and erlotinib-resistant H1650 cells revealed that the M3 derivative displays remarkably high levels of PKCα and reduced levels of PKCδ. qPCR analysis established that PKCα mRNA levels in H1650-M3 cells are ∼ 40-fold higher than in parental cells. In order to investigate a potential involvement of PKCα in TKI resistance we used RNAi. Upon PKCα depletion H1650-M3 cells display a morphology that is consistent with the epithelial phenotype. Moreover, depletion of PKCα from H1650-M3 cells led to significant changes in the expression of EMT markers. Indeed, mRNA levels of vimentin, Zeb2, SNAIL and TWIST were reduced by more than 50 % in erlotinib-resistant cells when PKCα expression was silenced. Analysis of cell viability in response to erlotinib treatment showed that pretreatment with either the pan-PKC inhibitor GF 109203X or the cPKC inhibitor Gö6976 sensitized H1650-M3 to erlotinib. Furthermore, PKCα RNAi depletion markedly sensitized H1650 cells to the TKI. Therefore, PKCα up-regulation in erlotinib-resistant cells may play an important role in driving the resistance to the drug. Our results also highlight a potential role for PKCα in EMT in lung cancer cells.
Citation Format: Mahlet Abera, Raffaella Sordella, Marcelo Kazanietz. PKC alpha is implicated in epithelial to mesenchymal transition and erlotinib resistance in non-small cell lung carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5261. doi:10.1158/1538-7445.AM2013-5261