bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1455: Therapeutic synergy between novel tumor suppressor miR-520d-3p and EphA2-targeting siRNA in ovarian cancer
Authors: Shah Maitri , Lopez Gabriel Berestein , Sood Anil , Calin George 
Published: May 2015

Abstract
EphA2 has emerged as an important target for ovarian cancer therapy in recent years. In the present study, we identified miR-520d-3p as an independent favorable prognostic marker for epithelial ovarian cancer patients. We demonstrate that dual targeting of EphA2 in vitro using EphA2-siRNA and miR-520d-3p exhibits synergistic downregulation of EphA2 and inhibits cell proliferation, migration and invasion. In vivo treatment using DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) nano-liposomes conjugated with miR-520d-3p and EphA2-siRNA showed synergistic therapeutic efficacy and superior inhibition of tumor proliferation and angiogenesis than either monotherapy alone. We also identified that EphA2(low)/EphB2(low)/miR-520d-3p(high) gene signature predicts favorable clinical prognosis for ovarian cancer patients. This study addresses a new concept of RNA inhibition therapy by combining miRNA and siRNA to target oncogenic pathways altered in ovarian cancer.
Citation Format: Maitri Shah, Gabriel Berestein Lopez, Anil Sood, George Calin. Therapeutic synergy between novel tumor suppressor miR-520d-3p and EphA2-targeting siRNA in ovarian 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 1455. doi:10.1158/1538-7445.AM2014-1455
Abstract 1456: MicroRNA improves the efficacy of imatinib on the treatment of chronic myeloid leukemia
Authors: Yi Bin , Ma Ruixia , Feng Xiangling , Xing Zhiwei , Zhang Xiaoguo , Piazza Gary , Xi Yaguang 
Published: May 2015

Abstract
Human chronic myelogenous leukemia (CML) is a malignancy of pluripotent hematopoietic cells that is caused by the deregulated activity of the tyrosine kinase that is encoded by the chimeric bcr-abl oncogene. Given that CML cells are usually highly resistant to chemotherapy, novel and more efficacious strategies against this disease are urgently needed. MicroRNA (miRNA) is a set of newly discovered 20-22 nucleotides RNA molecules, and they broadly repress their cognate target genes at post-transcriptional/trans-lational level. To date, there are approximately 2,500 human miRNA transcripts have been characterized, which are estimated to modulate more than 30% human genes by being involved in many essential normal biological and pathological processes including differentiation, proliferation, apoptosis, and tumorigenesis as well. In this study, we studied let-7a, a miRNA with tumor suppressive signature, for its therapeutic potential in CML. When treating CML K562 and KU812 cell by imatinib, let-7a can be significantly induced. Overexpression of let-7a can sensitize K562 and KU812 cells to imatinib, while knock-down of let-7a can increase the resistance of these cells towards this drug. The functional studies found that let-7a was able to promote apoptosis of CML cells, inhibit the tumor cell proliferation, and lead to a cell cycle arrest in the G0/G1 phase. These results demonstrate that let-7a is a potential target for treating CML by imatinib and/or other anti-cancer drugs. The pro-apoptosis and anti-proliferation roles of let-7a in CML cells may provide novel insights into discovery and development of more efficacious drugs for treating this malignant disease.
Citation Format: Bin Yi, Ruixia Ma, Xiangling Feng, Zhiwei Xing, Xiaoguo Zhang, Gary Piazza, Yaguang Xi. MicroRNA improves the efficacy of imatinib on the treatment of chronic myeloid leukemia. [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 1456. doi:10.1158/1538-7445.AM2014-1456
Abstract 1457: Development of miRNA-loaded polymeric nanoformulation for pancreatic cancer therapy
Authors: Arora Sumit , Swaminathan Suresh K. , Srivastava Sanjeev K. , Singh Seema , Panyam Jayanth , Singh Ajay P. 
Published: May 2015

Abstract
MicroRNAs (miRNAs) are small (18-22 nucleotide long) non-coding RNAs that play important roles in biological processes through post-transcriptional regulation of gene expression. Their aberrant expression and functional significance are reported in several human malignancies, including pancreatic cancer (PC). Recently, we identified miR-150 as a novel tumor suppressor microRNA in PC and demonstrated that its overexpression inhibits growth and malignant behavior of PC cells suggesting that restoration of miR-150 could serve as an effective therapeutic approach for pancreatic cancer. In the present study, we have developed a nanoparticle-based miR-150 delivery system and tested its therapeutic efficacy by in vitro assays. Using double emulsion solvent evaporation method, we developed a poly (D, L-lactide-co-glycolide) (PLGA)-based nanformulation (NF) of miR-150 (miR-150-NF). Polyethyleneimine (a cationic polymer) was incorporated in PLGA matrix to increase the encapsulation of miR-150. Physical characterization of miR-150-NF demonstrated that miR-150-loaded nanoparticles were spherical in shape, had high encapsulation efficiency (&gt;75%), were stable at room temperature and exhibited sustained release profile. miR-150-NF efficiently delivered miR-150 mimics to PC cells and led to the downregulation of its target gene (MUC4) expression. Downregulation of MUC4 correlated with a concomitant decrease in the expression of its interacting partner, HER2, and repression of its downstream signaling. Furthermore, treatment of PC cells with miR-NF suppressed their growth, clonogenicity, motility and invasion. Together, these findings suggest that PLGA-based nanovector platform could be a potential candidate for systemic delivery of miR-150 to the pancreatic tumor cells and can be a step forward in miRNA-based cancer therapeutics.
Citation Format: Sumit Arora, Suresh K. Swaminathan, Sanjeev K. Srivastava, Seema Singh, Jayanth Panyam, Ajay P. Singh. Development of miRNA-loaded polymeric nanoformulation for pancreatic cancer therapy. [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 1457. doi:10.1158/1538-7445.AM2014-1457
Abstract 146: Combining molecular targeted drugs to inhibit both cancer cells and activated stromal cells in colon cancer
Authors: Yuge Ryo , Kitadai Yasuhiko , Shinagawa Kei , Onoyama Mieko , Tanaka Yuichiro , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: May 2015

Abstract
Recent studies have shown that tumor growth and metastasis are not determined by cancer cells alone but also by a variety of stromal cells. We have shown previously that platelet-derived growth factor receptors (PDGF-Rs) are overexpressed by various stromal cell populations, but not by cancer cells themselves in human colon cancer tissues. Blockade of PDGF-R signaling pathways in tumor-associated stromal cells has been shown to inhibit the stromal reaction. Activation of phosphoinositide 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling is frequently observed in many cancer types and has been implicated in the pathogenesis of various diseases. mTOR is a central regulatory kinase that increases the production of proteins that stimulate key cellular processes such as cell proliferation, metabolism, survival, and angiogenesis. However, the effects of mTOR inhibitors on the stromal component of tumor tissues have not been studied.
In the present study, the effects of nilotinib (PDGF-R tyrosine kinase inhibitor) and everolimus (mTOR inhibitor) on tumor development and metastasis, were examined using orthotopic and experimental liver metastatic models of human colon cancer, whereby KM12SM cells were implanted into the cecum and spleen of nude mice, respectively. Groups of mice received saline (control), nilotinib (100mg/kg/day) or everolimus (1mg/kg/day), or a combination of nilotinib (100mg/kg/day) and everolimus (1mg/kg/day) by daily oral gavage. After 4 weeks of treatment, primary tumors and metastatic lesions were resected, and specimens were analyzed histologically and immunohistochemically for comparison between the treatment group and control group.
After treatment with nilotinib, the stromal reaction was significantly decreased. After treatment with everolimus, the stromal reaction was not decreased, but tumor cell proliferation and microvessel density were decreased. With the combination therapy, both tumor cell proliferation and the stromal reaction were decreased and apoptosis of tumor cells was increased, resulting in a remarkable decrease in tumor size and the number of metastatic liver lesions.
Therefore, concurrent inhibition of tumor cells and activated stromal cells by combination therapy may represent a novel molecular-targeted approach for patients with colon cancer.
Citation Format: Ryo Yuge, Yasuhiko Kitadai, Kei Shinagawa, Mieko Onoyama, Yuichiro Tanaka, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Combining molecular targeted drugs to inhibit both cancer cells and activated stromal cells in colon 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 146. doi:10.1158/1538-7445.AM2014-146
Abstract 1461: A miR-221 multigene pharmacodynamic signature for assessing miR-221 inhibition
Authors: Pavlicek Adam , Vincent Thomas , Guicherit Oivin , Chau Nelson , Zabludoff Sonya , Gibson Neil , Lee Edmund C. 
Published: May 2015

Abstract
miR-221 targets key cancer pathways, inhibits translation of important tumor suppressors, and is overexpressed in hepatocellular carcinoma (HCC). Aberrant miR-221 expression has been linked to HCC progression, while inhibition of miR-221 has been shown to reduce tumor growth. In preclinical models, miR-221 inhibition can be assessed by measuring de-repression of known miR-221 target genes such as p27. However, changes in individual microRNA target genes are often small and model-dependent; and comprehensive assessment of pharmacodynamic (PD) effects following microRNA inhibition is often challenging. Herein, we present a miR-221 multigene PD signature that can assess miR-221 target engagement with a large dynamic window and work across different human HCC models following miR-221 inhibition. In the first stage, we transfected five different human HCC lines with two chemically-modified oligonucleotides that inhibit miR-221 functions (miR-221 anti-miRs) and a microRNA-duplex that mimics miR-221/222 functions (mimic). The resulting global mRNA expression changes were compared to mock treated cells using GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix). Ninety unique human genes with transcripts containing conserved and/or 8-mer target seeds (TargetScan), that significantly went up and down after anti-miR-221s and mimic treatment respectively, were further profiled with qPCR in the second stage. Out of the 90 tested transcripts, 62 of them were significantly up-regulated by anti-miR-221s but not by control oligonucleotides (either mismatch or targeting unrelated microRNAs). From the 62 genes, an optimal multigene signature consisted of 13 unique human genes normalized by 6 reference housekeeping genes was identified. We also devised a “miR-221 signature score” and demonstrated that our multigene signature can separate miR-221 anti-miRs treatment from control oligonucleotides with a high degree of sensitivity and specificity. We further validated this multigene signature by demonstrating that it correctly distinguished miR-221 anti-miRs treatment from controls in three additional HCC cell lines in vitro and one HCC model in vivo. In summary, our miR-221 multigene PD signature analysis provided a comprehensive assessment of miR-221 inhibition, with significantly larger dynamic window compare to individual gene analysis, that may be used to discover, rank order and guide the development of novel miR-221 anti-miRs for the treatment of human cancers.
Citation Format: Adam Pavlicek, Thomas Vincent, Oivin Guicherit, Nelson Chau, Sonya Zabludoff, Neil Gibson, Edmund C. Lee. A miR-221 multigene pharmacodynamic signature for assessing miR-221 inhibition. [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 1461. doi:10.1158/1538-7445.AM2014-1461
Abstract 1463: Long non-coding RNA RoR and microRNA-145 regulate tumor cell invasion in triple-negative breast cancer via targeting of ADP-ribosylation factor 6
Authors: Eades Gabriel L. , Zhou Qun 
Published: May 2015

Abstract
Triple-negative (ER-, HER2-, PR-) breast cancer (TNBC) is an aggressive disease with a poor prognosis. Currently, there is no available molecularly targeted therapy for TNBC. MicroRNA-145 (miR-145) silencing was identified as a defining marker of TNBC by molecular profiling using deep sequencing. Previous reports indicate that miR-145 may function as a growth suppressor in some breast cancers. However, we find that in TNBC miR-145 does not regulate proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Since metastatic breast cancer remains an incurable disease we investigated miR-145 regulated pathways to identify new potential biomarkers or therapeutic targets. Here we identify a novel target of miR-145, the small GTPase ADP-ribosylation factor 6 (Arf6). We find that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in triple-negative and metastatic breast tumors. We find that ARF6 can regulate E-cadherin localization and impact cell-cell adhesion. Finally, we examined the molecular mechanism behind miR-145 down-regulation in TNBC. We find that when compared to ER+ disease, TNBC shows dramatic downregulation of mature miR-145, but not pri-miR-145 or pre-miR-145, indicating that loss of miR-145 is occurring post-transcriptionally and following Drosha and Dicer processing. We find that overexpression of the long non-coding RNA, lincRNA-ROR, functions as a competitive endogenous RNA sponge in TNBC. We find that lincRNA-ROR is dramatically upregulated in TNBC and in metastatic disease. Finally, we find that knockdown of lincRNA-ROR restores miR-145 expression and reduces breast tumor cell invasion. These results reveal a lincRNA-ROR / miR-145 / ARF6 pathway that is a critical regulator of invasion in TNBCs.
Citation Format: Gabriel L. Eades, Qun Zhou. Long non-coding RNA RoR and microRNA-145 regulate tumor cell invasion in triple-negative breast cancer via targeting of ADP-ribosylation factor 6. [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 1463. doi:10.1158/1538-7445.AM2014-1463
Abstract 1466: Regulation of colon cancer metastasis by sprouty-2
Authors: Zhang Qiong , Vaish Vivek , Khare Sharad 
Published: May 2015

Abstract
Introduction: We earlier established that sprouty-2 is overexpressed in human colon cancer and up-regulates c-met and thereby increases the growth phenotype and metastatic potential of colon cancer cells (Oncogene, 29: 5241-53, 2010). To our knowledge, this was the first study to demonstrate the tumor oncogene phenotype of sprouty-2 in colon cancer metastasis. On the contrary, cancer protective role of sprouty-2 was noted in breast, liver and prostate cancers. However, a recent report on non-small cell lung cancer (NSCLC) discovered that silencing of sprouty-2 reduced c-met expression and thus confirmed our findings in colorectal cancer (PNAS, 110: 8573-78, 2013). We further extended our studies to demonstrate that this pathway modulates gastrointestinal specific microRNAs (miRNAs) and regulates various oncogenes and tumor suppressor genes in colon cancer cells. Methods: RNA from control and shRNA sprouty-2 transfected cells were labeled with Hy5 and Hy3 respectively and hybridized to miRCURY LNA arrays. Unsupervised miRNA clustering was carried out and a heat map prepared with Java TreeView. MicroRNA targets were identified by Real-time PCR, western blotting and 3′UTR luciferase assays. Migratory phenotype of colon cancer cells was confirmed by cell migration and invasion assays in trans-well chambers. Cancer cells were transfected by miRNA mimics to assess the expression levels of target genes. Human colon cancer tissue microarrays were utilized to assess the expression of miRNA target genes. Human tumor sections were evaluated by immunofluorescence and immunohistochemical staining. Results: Sprouty-2 shRNA transfected stable cell lines demonstrated upregulation of tumor suppressive miRNAs and down-regulation of oncogenic miRNAs. Overexpression of gastrointestinal specific miRNA mimics inhibits colon cancer cells proliferation and metastasis. On the contrary, overexpression of miRNA inhibitor in colon cancer cells promotes proliferation and colonization. Studies further indicated that miRNA down-regulates expression of CDK7, RB1, AKT, FASL, IGF1R, EGFR and N-cadherin and up-regulates expression of P21 and E-cadherin. MiRNA regulated genes were responsible for cell cycle arrest, enhanced apoptosis and decreased metastasis. AKT was upregulated whereas E-cadherin was downregulated at the invasive fronts in human colon tumors. Conclusion: Sprouty-2/miRNA expression levels could be used to risk-stratify patients for CRC recurrence and sprouty-2 axis regulation may lead to the development of therapeutics in colon and lung cancer.
Citation Format: Qiong Zhang, Vivek Vaish, Sharad Khare. Regulation of colon cancer metastasis by sprouty-2. [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 1466. doi:10.1158/1538-7445.AM2014-1466
Abstract 1477: Evaluation of microRNA-10b prognostic significance in a prospective cohort of breast cancer patients
Authors: Parrella Paola , Barbano Raffaela , Pasculli Barbara , Fontana Andrea , Copetti Massimiliano , Valori Vanna Maria , Poeta Maria Luana , Perrone Giuseppe , Coco Michelina , Balsamo Teresa , Pellegrini Fabio , Muda Andrea Onetti , Maiello Evaristo , Murgo Roberto , Fazio Vito Michele 
Published: May 2015

Abstract
Several prognostic factors are currently used to stratify breast cancer patients based on the risk of disease progression. However, even patients classified as at low risk can progress and die for the disease. MicroRNA-10b (miR-10b) has a prominent role in regulating tumor invasion and metastasis by targeting the HOXD10 transcriptional repressor and has been found up-regulated in several tumor types including breast cancer.
We evaluated the expression of miR-10b in paired tumor and normal specimens obtained from a prospective cohort of breast cancer patients with at least 36 months follow-up enrolled according to the REMARK guidelines (n=150). RNA quality was measured and only samples with RNA Integrity Number (RIN) ≥7.0 were analyzed. The relative expression of miR-10b in tumor as compared to its normal counterpart (RER) was determined by RT-qPCR. miR-10b RERs were higher in the subgroup of patients with synchronous metastases (n=11, Median 0.25; IQR 0.11-1.02) as compared with patients without metastases (n=90, Median 0.09; IQR 0.04-0.29) (p=0.028). In the subgroup of patients without synchronous metastases (n=90), higher miR-10b RERs were associated with increased risk of disease progression and death in both univariable (HR 4.35, p=0.021 and HR 6.02, p=0.015 respectively) and multivariable (HR 13.37, p&lt;0.001, and HR 15.39, p=0.003 respectively) Cox regression models. The addition of miR-10b RERs to the Nottingham Prognostic Index (NPI) provided an improvement in discrimination power and risk reclassification abilities for the clinical outcomes at 36 months. Survival C-indices significantly increased from 0.849 to 0.889 (p=0.009) for OS and from 0.735 to 0.767 (p=0.050) for DFS.
Our results provide evidences that the addition of miR-10b RERs to the prognostic factors used in clinical routine could improve the prediction abilities for both overall mortality and disease progression in breast cancer patients.
Citation Format: Paola Parrella, Raffaela Barbano, Barbara Pasculli, Andrea Fontana, Massimiliano Copetti, Vanna Maria Valori, Maria Luana Poeta, Giuseppe Perrone, Michelina Coco, Teresa Balsamo, Fabio Pellegrini, Andrea Onetti Muda, Evaristo Maiello, Roberto Murgo, Vito Michele Fazio. Evaluation of microRNA-10b prognostic significance in a prospective cohort of breast cancer patients. [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 1477. doi:10.1158/1538-7445.AM2014-1477