bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1151: SIRT6 induces EMT and promotes cancer cell invasion and migration in prostate cancer
Authors: Xie Qian , Wong Alice S. , Xia Weiliang 
Published: May 2015

Abstract
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer related death in males in the developed countries. One of the major clinical challenges is the propensity for advanced PCa to metastasize to bone or other organs, which is primarily responsible for its effect on patient mortality. SIRT6, one of Sirtuins family members, is an important histone modifying protein that regulates diverse physiological functions such as aging and metabolism. Recently there is much evidence showing an involvement of SIRT6 in tumorigenesis. At present, relatively little is known about the role of SIRT6 in regulating prostate cancer or metastasis. In our study, we have used both prostate tumor tissues and prostate cancer cell lines to study the roles of SIRT6 in the development and progression of PCa. From deposited gene profiling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal prostate tissues. Tissue microarray studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Depletion of SIRT6 by siRNA inhibited PCa cell proliferation. Bioinformatics analysis of the databases revealed that the high SIRT6 expression was associated with markedly shorter window of clinical recurrence, and the expression level of SIRT6 was significantly higher in PCa tissue with Gleason grade greater than seven. Further analysis indicated that SIRT6 expression increased along with the metastasis of PCa. We used PC-3 and DU145 cells to study whether SIRT6 could play a role in the migration and invasion of PCa cells. Indeed, SIRT6-deficiency markedly reduced cell migration and invasion. Compared with control siRNA treated cells, the protein level of N-cadherin reduced while E-cadherin level showed an increase after SIRT6 knockdown. We further revealed that SIRT6 regulated EMT-inducing transcription factor expression in PCa cells. Taken together, our findings indicate that SIRT6 is up-regulated in PCa, and the high expression of SIRT6 plays an important role in the progression of PCa as it facilitates cancer cell migration and invasion, and possibly metastasis. These data also suggest the therapeutic value of targeting SIRT6 in the treatment of metastatic PCa.
Citation Format: Qian Xie, Alice ST Wong, Weiliang Xia. SIRT6 induces EMT and promotes cancer cell invasion and migration in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1151. doi:10.1158/1538-7445.AM2014-1151
Abstract 1159: A novel HGF-MET paracrine signaling pathway promotes growth and resistance to chemotherapy in lung cancer
Authors: Choi Hyejin , Gao Ding Cheng , Lee Sharrell B. , Durrans Anna , Ryu Seongho , Elemento Olivier , Wong Stephen , Altorki Nasser K. , Mittal Vivek 
Published: May 2015

Abstract
Lung cancer is a leading cause of deaths from cancer among men and women worldwide with an estimated 1.5 million deaths each year. Available molecularly targeted therapies benefit a limited number of patients and even in these patients acquired resistance is a major impediment to effective therapeutic response. To address the need for additional therapeutic targets, we used a unique approach to identify and target tumor-stroma paracrine crosstalk pathways in non-small cell lung cancer (NSCLC).
To explore paracrine crosstalk in NSCLC, we analyzed transcriptomes of specific stromal and epithelial compartments that were sorted from Kras driven mouse model of NSCLC. Transcriptome analysis and computational modeling of multi-cellular network identified potential tumor-stroma crosstalk signaling pathways. We have selected the hepatocyte growth factor (HGF)-MET tyrosine kinase receptor signaling pathway because both HGF and MET are associated with poor survival in many cancer types including lung cancer. Notably, we identified reprogrammed intratumoral macrophages as unique source of HGF, while the expression of MET receptor was confined to tumor epithelial compartment. Importantly, we have observed elevated HGF in chemoresistant tumors both in mouse and human. Previous studies have implicated MET receptor amplification or mutations as the main mechanism of acquired resistance to EGFR TKIs, but little is known about the contribution of HGF ligand-dependent activation of MET signaling in NSCLC growth and resistance to chemotherapeutic regimens that are widely used. We have used a combination of culture experiments and in vivo genetic approaches to show that macrophage-derived HGF interacts with the MET receptor on tumor epithelial cells in a paracrine fashion, to activate downstream signaling pathways that promote tumor progression and mediate resistance to standard chemotherapies. Our investigations on this relatively unexplored HGF-MET paracrine interaction as a key mechanism of resistance to standard-of-care chemotherapeutic regimens-and not just EGFR targeted therapies-have the potential to benefit the NSCLC population as whole rather than a small subset of patients.
Citation Format: Hyejin Choi, Ding Cheng Gao, Sharrell B. Lee, Anna Durrans, Seongho Ryu, Olivier Elemento, Stephen Wong, Nasser K. Altorki, Vivek Mittal. A novel HGF-MET paracrine signaling pathway promotes growth and resistance to chemotherapy in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1159. doi:10.1158/1538-7445.AM2014-1159
Abstract 1251: Repurposing antipsychotic drug Penfluridol for cancer treatment
Authors: Ranjan Alok , Srivastava Sanjay K. 
Published: May 2015

Abstract
Repurposing of old drugs as new anti-cancer drugs is important as it can save time and cost of drug development. Penfluridol is a first generation, highly potent antipsychotic drug. In this study, we determined the anticancer effects of Penfluridol in pancreatic cancer cells. Penfluridol treatment inhibited the growth of Panc-1, BxPC-3 and AsPC-1 pancreatic cancer cells in a concentration-dependent manner. Panc-1 , BxPC-3 and AsPC-1 cells treated with Penfluridol exhibited apoptosis as evaluated by Annexin/FITC assay and cleavage of caspase-3 and PARP. Our results showed that Penfluridol treatment induced ER stress in pancreatic cancer cells through the up regulation of ER stress markers like Bip/Grp78, CHOP and IRE. Penfluridol treatment also induced autophagy in pancreatic cancer cells as observed by acridine orange assay. Western blot analysis of Panc-1, BxPC-3 and AsPC-1 cells treated with Penfluridol exhibited up regulation of autophagy markers like LC3B, and p62. Microscopic analysis revealed punctate LC3B after Penfluridol treatment in pancreatic cancer cells confirming autophagy. Further mechanistic studies are in progress to establish the role of ER stress and autophagy in pancreatic cancer cells and correlate it with cell growth suppression. [Supported in part by R01 grant CA129038 awarded by NIH.]
Citation Format: Alok Ranjan, Sanjay K. Srivastava. Repurposing antipsychotic drug Penfluridol for cancer treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1251. doi:10.1158/1538-7445.AM2014-1251
Abstract 1371: Histone lysine trimethylation or acetylation in sporadic breast tumor and matched normal tissue
Authors: Gallon-Bernard Dominique J. , Judes Gaëlle , Dagdemir Aslihan , Echegut Maureen , Karsli-Ceppioglu Seher , Ngollo Marjolaine , Lebert Andre , Penault-Llorca Frederique , Bignon Yves-Jean 
Published: May 2015

Abstract
Breast cancer is responsible of cancer mortality in women worldwide. The challenge in carcinogenesis is to predict tumor progression. Epigenetics open new perspectives in this field. It was demonstrated that epigenetic alterations are involved in cancer. DNA methylation or histone modifications can regulate gene transcription. Our goal was to determine the role of different histone marks, such as H3K27me3, H3K4ac and H3K9ac on the expression of a panel of genes involved in breast cancer: BRCA1, ERβ, EZH2, P300, SRC3, ERα and PGR. For this study, we used less than one hundred sporadic breast tumors and matched normal tissues. We performed chromatin immunoprecipitation and Q-PCR. After that, we checked the gene expression assaying RNA with RT-QPCR and proteins with Western blotting. Finally, we demonstrated that H3K4ac marks behaved like H3K27me3 repressive marks. The increase of H3K9ac marks resulted in the overexpression of ERα and P300 genes in the tumors. For the underexpressed genes BRCA1 and ERβ, we found that their repression did not pass through the repressive marks H3K27me3 nor H3K4ac but by other mechanisms perhaps DNA methylation.
Then, we used variance analysis and studied interactions between the studied different marks and intrinsic subtypes of breast cancer according to St Gallen International Expert Consensus. Finally, we defined gene-mark couples in each subtypes. At the end, a decision tree was drawn and determined 4 genes (BRCA1, ERα, ERβ, and PGR) and 2 marks (H3K27me3 and H3K4ac) that separated subtypes in the present study.
Citation Format: Dominique J. Gallon-Bernard, Gaëlle Judes, Aslihan Dagdemir, Maureen Echegut, Seher Karsli-Ceppioglu, Marjolaine Ngollo, Andre Lebert, Frederique Penault-Llorca, Yves-Jean Bignon. Histone lysine trimethylation or acetylation in sporadic breast tumor and matched normal tissue. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1371. doi:10.1158/1538-7445.AM2014-1371
Abstract 1390: Interferon-gamma potentiates the targeted phenotypic reversion of erbb2/her2/neu transformed human tumor cells
Authors: Runkle Edwin Aaron , Young Peter , Nagai Yasuhiro , Tsuchiya Hiromichi , Zhang Hongtao , Greene Mark I. 
Published: May 2015

Abstract
Oncogenic erbB2/HER2 is a major transforming determinant of human breast cancer and its amplification is prognostic of poor survival. Monoclonal antibody (mAb)-based therapy to specifically target erbB2/HER2 has been effective in patients with HER2-positive breast cancer; however, some patients do not respond and those who do frequently relapse despite ongoing therapy. The evolution of tumors that resist targeted therapy is complex and involves the emergence of complex transcriptional functions. Snail is overexpressed in recurrent tumors of transgenic HER2/neu mice and snail expression participates in tumor recurrence. Previous studies from our laboratory and others have revealed that targeted therapy requires cooperation with elements of the endogenous immune system for optimal tumor regression activity. The cytokine interferon-gamma (IFN-γ) is relevant to the regression process although the mechanism by which IFN operates on targeted cells remains undefined and the effects of IFN on the transformed cell have not been studied during phenotypic reversion. In the present study, we utilized cell biological and biochemical-based assays to define if targeted therapy could be improved through the addition of IFN-γ and unexpectedly defined a unique mechanism operative to achieve this end. Cell culture model systems were used to examine the co-treatment of erbB2/HER2 targeting with IFN-γ to eliminate issues such as aberrant immune responses, which arise as a consequence of adding IFN-γ to cells. We defined that while mAb targeting of erbB2 reversed the transformed phenotype of HER2-positive breast cancer cells reversion of phenotype was increased upon inclusion of IFN-γ. Co-treatment with the erbB2 mAb and IFN-γ resulted in a greater reduction of snail protein levels compared to either modality alone. Snail degradation was dependent on GSK3-β and active proteasome dependent elimination processes. Furthermore, IFN-γ activated GSK3-β in mAb treated cells to the extent of that observed in cells treated with specific small molecule inhibitors to erbB receptors. Our findings provide a mechanistic explanation as to how to use IFN-γ to optimize mAb-mediated tumor regression. The implication of this study is improvement of targeted efficacy could lead to more comprehensive therapy options that may eliminate tumor recurrence.
Citation Format: Edwin Aaron Runkle, Peter Young, Yasuhiro Nagai, Hiromichi Tsuchiya, Hongtao Zhang, Mark I. Greene. Interferon-gamma potentiates the targeted phenotypic reversion of erbb2/her2/neu transformed human tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1390. doi:10.1158/1538-7445.AM2014-1390
Abstract 140: The role of Abl kinases in breast cancer bone metastasis
Authors: Wang Jun 
Published: May 2015

Abstract
Abl kinases are a family of non-receptor tyrosine kinases consisting of two members, Abl1 and Abl2 (Arg). In recent years, accumulating data support a role of Abl kinases in breast cancer that harbor enhanced expression and/or activation of these kinases. The Cancer Genome Atlas has recently reported that Abl2 is among the most highly amplified genes and overexpression of Abl2 correlates with poor survival in invasive breast cancer. In addition, Abl kinases are activated downstream of receptor tyrosine kinases, chemokine receptors and src family kinases, all of which are deregulated in breast cancer and drive tumor proliferation and invasion. In this study, we have uncovered a critical role of Abl kinases in the regulation of breast cancer metastasis to the bone. We found that the incidence of bone metastasis is significantly greater in breast cancer patients with high Abl expression. Using global transcriptome analysis (RNAseq) of breast cancer cells we uncovered a novel role for Abl kinases in regulating the expression of multiple pro-bone metastasis genes. Furthermore, both pharmacological inhibition and RNA interference mediated knockdown of Abl kinases resulted in markedly decreased osteolytic metastasis in vivo and decreased osteoclast activation in vitro. Together these findings support a role for Abl kinases in promoting osteolytic metastasis and suggest that Abl dependent signaling may be targeted to inhibit this process.
Citation Format: Jun Wang. The role of Abl kinases in breast cancer bone metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 140. doi:10.1158/1538-7445.AM2014-140
Abstract 1406: Evoking potent RNAi response using novel 2′-OMe-phosphorodithioated modified siRNAs
Authors: Wu Sherry , Yang Xianbin , Egli Martin , Ghaupure Kshipra , Hatakeyama Hiroto , McGuire Michael , Rupaimoole Rajesha , Miyake Takahito , Taylor Morgan , Pradeep Sunila , Nagaraja Archana , Sierant Malgorzata , Singhania Richa , Rodriguez-Aguayo Cristian , McMillan Nigel , Lopez-Berestein Gabriel , Ram Prahlad , Nawrot Barbara , Sood Anil K. 
Published: May 2015

Abstract
Improving small interfering RNA (siRNA) efficacy in target cell populations remains a critical challenge to bringing siRNA therapy into the clinic. There is currently an unmet need to develop a reliable strategy to globally enhance siRNA stability and potency. Here, we report a novel chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on a single nucleotide, that significantly enhances potency and resistance to nuclease degradation for a variety of siRNA sequences. We show a 3.5-fold improvement in gene silencing in tumors following systemic delivery of MePS2-modified siRNAs using DOPC nanoliposomes compared to unmodified counterparts. We found that this enhanced potency stems from an unforeseen increase in loading of siRNAs to the RNA-induced silencing complex (RISC), likely due to the unique interaction between 2′-OMe and PS2 moieties. We subsequently demonstrate the therapeutic utility of MePS2 siRNAs in orthotopic mouse models of chemoresistant ovarian cancer, focusing on targeting GRAM domain containing 1B (GRAMD1B), a protein whose role in taxane resistance is first reported here. Efficient silencing of GRAMD1B (&gt;80%) was achieved in tumors following systemic delivery of these MePS2-modified siRNAs and a synergistic anti-tumor effect was observed when combined with paclitaxel treatment. Given that limited success has been achieved thus far toward broadly enhancing siRNA potency with chemically modified siRNAs, our finding represents an important step forward in bringing siRNA therapeutics into the clinic.
Citation Format: Sherry Wu, Xianbin Yang, Martin Egli, Kshipra Ghaupure, Hiroto Hatakeyama, Michael McGuire, Rajesha Rupaimoole, Takahito Miyake, Morgan Taylor, Sunila Pradeep, Archana Nagaraja, Malgorzata Sierant, Richa Singhania, Cristian Rodriguez-Aguayo, Nigel McMillan, Gabriel Lopez-Berestein, Prahlad Ram, Barbara Nawrot, Anil K. Sood. Evoking potent RNAi response using novel 2′-OMe-phosphorodithioated modified siRNAs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1406. doi:10.1158/1538-7445.AM2014-1406
Abstract 1438: Targeting metabolic enzyme with locked nucleic acids in non-small cell lung cancer
Authors: Zhang Wen Cai , Lim Bing 
Published: May 2015

Abstract
Despite advances in our knowledge of genetics of cancer and some progress in cancer treatment over the last few decades, lung cancer remains the leading cause of cancer mortality worldwide. Recently cancer metabolomics have been widely applied into cancer research, including of cancer diagnosis and therapy. Our recent work has identified tumor initiating cells (TICs) derived from non-small cell lung cancer (NSCLC) patients and shown that metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in NSCLC. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients. Those findings provide potential diagnostic markers and/or therapeutic target for NSCLC. Locked nucleic acids (LNAs) are novel high-affinity DNA analogs that can be used as genotype-specific drugs. In this study we tested NSCLC patient-derived xenograft tumor growth inhibition by GLDC LNAs antisense oligonucleotides. These LNAs antisense oligonucleotides strongly reduce GLDC protein levels. The osmotic minipumps were filled with GLDC LNAs antisense oligonucleotides at 0.5,1 and 5 mg/kg/day dose and implanted dorsally into tumor-bearing NOD/SCID Il2rγ-/- mice. Tumor growth was inhibited at dosages from 1 mg/kg/day. LNAs antisense oligonucleotides appeared to be non-toxic at dosages of 5 mg/kg/day. Furthermore, we found significant changes of serum metabolomics in lung cancer patients compared to normal donors. Our data show that GLDC LNAs antisense oligonucleotides are potent genotype-specific drugs that can inhibit lung tumor growth in vivo.
Note: This abstract was not presented at the meeting.
Citation Format: Wen Cai Zhang, Bing Lim. Targeting metabolic enzyme with locked nucleic acids in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1438. doi:10.1158/1538-7445.AM2014-1438
Abstract 1474: Integrated microRNA network analyses identify a poor prognosis subtype of gastric cancer characterized by the miR-200 family
Authors: Song Fengju , Chen Kexin 
Published: May 2015

Abstract
Purpose:
Our aim was to investigate whether microRNAs can predict the clinical outcome of patients with gastric cancer (GC). We used integrated analysis of microRNA and mRNA expression profiles to identify GC microRNA subtypes and their underlying regulatory scenarios.
Experimental Design:
MicroRNA-based GC subtypes were identified by consensus clustering analysis of microRNA profiles of 90 GC tissues. Activated pathways in the subtypes were identified by gene expression profiles. Further integrated analysis was performed to model a microRNA regulatory network for each subtype. RNA and protein expression were analyzed by RT-PCR and tissue microarray, respectively, in a cohort of 385 GC cases (including the 90 cases for profiling) to validate the key microRNAs and targets in the network. Both in vitro and in vivo experiments were performed to further validate the findings.
Results:
MicroRNA profiles of 90 GC cases identified two microRNA subtypes significantly associated with survival. The poor-prognosis GC microRNA subtype was characterized by overexpression of epithelial-to-mesenchymal transition (EMT) markers. This GC “mesenchymal subtype” was further validated in a patient cohort comprising 385 cases. Integrated analysis identified a key microRNA regulatory network likely driving the GC mesenchymal subtype. Three of the microRNAs (miR-200c, miR-200b, and miR-125b) targeting the most genes in the network were significantly associated with survival. Functional experiments demonstrated that miR-200b suppressed ZEB1, augmented E-cadherin, inhibited cell migration, and suppressed tumor growth in a mouse model.
Conclusions: We have uncovered a key microRNA regulatory network that defines the mesenchymal GC subtype significantly associated with poor overall survival in GC.
Citation Format: Fengju Song, Kexin Chen. Integrated microRNA network analyses identify a poor prognosis subtype of gastric cancer characterized by the miR-200 family. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1474. doi:10.1158/1538-7445.AM2014-1474
Abstract 1483: Biological and clinical significance of miR-224 in colorectal cancer
Authors: LING HUI , Calin George , Nicoloso Milena , Ikuo Mariko 
Published: May 2015

Abstract
MicroRNAs (miRNAs) not only participate to cancer initiation and tumor growth, but also play roles in tumor metastasis. The aims of this study were to identify specific miRNAs involved in colorectal cancer (CRC) metastasis, and study their biological functions. We initially assessed by microarray global miRNA expression profile in primary CRC tissues from patients with or without metastasis. The most differentially expressed miRNAs were validated in a large set of CRC patient samples by real time PCR (qRT-PCR). We identified 7 miRNAs that were significantly upregulated in stage III-IV primary CRC compared with stage I-II cancer, among which miR-224 expression increased consistently with tumor burden. We used transwell-based cell motility analysis in CRC cell lines to test the biological activities of studied miRNAs, and showed that miR-224 and miR-141 promote CRC cell motility. By using qRT-PCR, western blot and luciferase assay, we identified SMAD4 as a direct miR-224 target mediating miR-224's effect on cell motility in CRC cells. We conclude that MiR-224 is associated with CRC malignancy, and functions as a metastasis activator by negative regulation of SMAD4.
Citation Format: HUI LING, George Calin, Milena Nicoloso, Mariko Ikuo. Biological and clinical significance of miR-224 in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1483. doi:10.1158/1538-7445.AM2014-1483