bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3048: The genome-wide contribution of microRNAs to gene regulation in Ewing sarcoma.
Authors: Herrero-Martin David , Kauer Maximilian , Emdal Kristina B. , Sienski Grzegorz , Fourtouna Argyrou , Kralovics Robert , Olsen Jesper V. , Kovar Heinrich 
Published: August 2014

Abstract
The identification of microRNA (miR) targets within a given cellular context still poses a largely unsolved problem. MiR targets are predicted based on the presence of seed sequences in the 3'UTR of mRNAs. Target candidate lists are filtered assuming mRNA destabilization, and validated by artificially forcing ectopic expression of miR analogs, or by interfering with miR expression by antagomirs. However, the expression level and amplitude of physiological miR variations is much smaller than experimentally induced miR perturbations. Crosslinking and immuno precipitation (CLIP) followed by sequencing of bound RNA allows monitoring of dynamic changes in miR/mRNA occupancy of RISC. However, it is unclear if increased miR activity will lead to increased target read counts due to elevated RISC occupancy or to decreased read counts as a consequence of target destabilization.
Ewing sarcoma (ES) expresses an oncogenic transcription factor, EWS/FLI1.To study the impact of miRs to the gene regulatory network downstream of EWS/FLI1, we used a combination of mRNA and miR expression profiling, ChIP-seq, PAR-CLIP of AGO2, AGO2 knockdown, and SILAC monitoring of proteome changes in an inducible EWS/FLI1 knockdown ES cell line. Our data suggest that EWS/FLI1 perturbs gene regulation primarily on the transcriptional level and miRs play only a modulatory role for gene expression. Furthermore EWS/FLI1 affects the expression of many miR biogenesis and miR activity as well as RISC associated proteins. Knockdown of EWS/FLI1 results in pronounced changes of miR specific PAR-CLIP spectra. Disabled RISC activity lead to only minor changes in genome-wide mRNA expression. Our results are consistent with a complex role of the miRNome in the fine tuning of gene regulatory networks in Ewing sarcoma.
Supported by grants EU-FP7 259348 and Austrian Science Fund FWF 24708-B21.
Citation Format: David Herrero-Martin, Maximilian Kauer, Kristina B. Emdal, Grzegorz Sienski, Argyrou Fourtouna, Robert Kralovics, Jesper V. Olsen, Heinrich Kovar. The genome-wide contribution of microRNAs to gene regulation in Ewing sarcoma. [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 3048. doi:10.1158/1538-7445.AM2013-3048
Abstract 3059: MicroRNA-140 dysfunction leads to hepatocarcinogenesis through NF-κB activation by impairing the regulation of NF-κB coactivator.
Authors: Takata Akemi , Otsuka Motoyuki , Yoshikawa Takeshi , Kishikawa Takahiro , Ohno Motoko , Yoshida Haruhiko , Koike Kazuhiko 
Published: August 2014

Abstract
Nuclear factor κB (NF-κB) is a transcriptional factor that regulates a set of genes that are critical to many cellular biological processes, including liver tumorigenesis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate specific target gene expression.To determine the miRNAs which are involved in regulating NF-κB activation in the liver, we screened for 60 kinds of miRNAs expressing in hepatocytes that can modulate NF-κB activation. We identified that miRNA-140 suppressed NF-κB activation significantly.Because miRNA-140 dysfunction was frequently observed in human hepatocellular carcinomas, it was hypothesized that the impairment of miRNA-140 function may be involved in hepatocarcinogenesis through NF-κB activation. Nuclear receptor interacting protein 1 (NRIP1) which is coactivator of NF-κB was identified as a target of miRNA-140 and the increased NRIP1 in hepatocellular carcinoma cells this led to enhanced NF-κB activation and hepatocarcinogenesis. MiRNA-140 knockout mice were indeed prone to hepatocarcinogenesis and had a phenotype similar to results in vitro. These results indicate that miRNA-140 acts as a liver tumor suppressor and the impairment of miRNA-140 function may also lead to hepatocarcinogenesis.
Citation Format: Akemi Takata, Motoyuki Otsuka, Takeshi Yoshikawa, Takahiro Kishikawa, Motoko Ohno, Haruhiko Yoshida, Kazuhiko Koike. MicroRNA-140 dysfunction leads to hepatocarcinogenesis through NF-κB activation by impairing the regulation of NF-κB coactivator. [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 3059. doi:10.1158/1538-7445.AM2013-3059
Abstract 3070: Suppression of tumor cell invasiveness and in vivo tumor growth by microRNA-874 in non-small cell lung cancer.
Authors: Kesanakurti Divya , Maddirela Dilip , Chittivelu Subramanyam , Rao Jasti S. , Chetty Chandramu 
Published: August 2014

Abstract
MicroRNAs are a family of small non-coding RNAs that regulate expression of many genes involved in normal development as well as human disorders including cancer. Here, we show that miR-874 plays a tumor suppressor role in non-small cell lung cancer (NSCLC) in vitro and in vivo. Interestingly, in silico target prediction analysis revealed numerous pro-oncogenes associated with tumor initiation, angiogenesis, invasion and migration, including MMP-2, uPA, NFAT5, PAK3, PAK7, LIMD, PECAM1, VEGF-A, Stat3, CUX1 and FGF1 as the putative target genes of miR-874. Our preliminary in situ hybridization experiments demonstrated the diminution of miR-874 expression in lung cancer tissues as compared to its normal counterparts. Overexpression of miR-874 in CD133-positive NSCLC cancer stem cell (CSC) population led to a significant loss in CSC phenotype and enhanced sphere de-differentiation into epithelial-like morphology. Restoration of miR-874 expression drastically reduced the invasive ability of cells in comparison to mock and control-miR treated cells by suppressing the protein levels of MMP-2 and uPA. Further, miR-874 treatment decreased orthotopic tumor growth in nude mice as compared to mock and control-miR treatments. Further, in vivo orthotopic tumor experiments in nude mice revealed the significant decrease in the immunoreactivity of human anti-MMP-2 and anti-uPA in miR-874-treated tumor sections. In conclusion, our study highlights the possible tumor suppressor role of miR-874 in NSCLC-initiating cells and suggests miR-874 as a potential target in the future treatment of NSCLC.
Citation Format: Divya Kesanakurti, Dilip Maddirela, Subramanyam Chittivelu, Jasti S. Rao, Chandramu Chetty. Suppression of tumor cell invasiveness and in vivo tumor growth by microRNA-874 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 3070. doi:10.1158/1538-7445.AM2013-3070
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3079: Estrogen signaling promotes cancer stem cell expansion via microRNA-140 targeting of pluripotency-associated factor SOX2 in ERα positive breast cancer cells.
Authors: Zhang Yongshu , Eades Gabriel L. , Yao Yuan , Li Qinglin , Zhou Qun 
Published: August 2014

Abstract
Multiple reports indicate that the prospective tumor suppressor miR-140 is down regulated in breast tumors compared to normal breast tissues; however, the role of miR-140 in breast tumorigenesis remains unclear. We have identified a novel target for miR-140 in mammary epithelium, the core pluripotency transcription factor SOX2. It is well known that SOX2 regulates the self-renewal of embryonic stem cells, however, less is known concerning possible oncogenic roles of SOX2 in breast cancer. We found that miR-140 and SOX2 target mRNA exhibited inverse expression in breast tumors and normal breast tissues, which was also correlated with estrogen receptor alpha (ERα) status. We investigated the role of ERα signaling in the regulation of miR-140 and SOX2 in breast tumors and found that estrogen stimulation resulted in decreased miR-140 and increased SOX2 expression in mammary epithelium and breast cancer cells. We performed bioinformatics promoter analyses of the miR-140 promoter revealing several predicted estrogen response elements (ERE) in the miR-140 promoter. We examined estrogen-induced activation of these prospective EREs using luciferase reporters for a miR-140 promoter deletion series. Furthermore, we used chromatin-immunoprecipitation to reveal that ERα binds to an ERE flanking the miR-140 promoter, consequently suppressing miR-140 transcription. As estrogen signaling was previously implicated in the regulation of breast cancer stem cells (CSCs), we investigated whether the miR-140/SOX2 pathway might provide a mechanistic link between ERα signaling and CSC maintenance. We found that forced activation of the miR-140/SOX2 pathway decreased mammosphere formation (a surrogate measure of CSC self-renewal) and opposed estrogen-induced expansion of the well-characterized CD44(high)/CD24(low) CSC subpopulation in ERα+ breast cancer cells. These results indicate that an ERα/miR-140/SOX2 pathway critically regulates breast CSC maintenance in ERα+ breast tumors.
Citation Format: Yongshu Zhang, Gabriel L. Eades, Yuan Yao, Qinglin Li, Qun Zhou. Estrogen signaling promotes cancer stem cell expansion via microRNA-140 targeting of pluripotency-associated factor SOX2 in ERα positive breast 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 3079. doi:10.1158/1538-7445.AM2013-3079
Abstract 3083: A novel method of sonic hedgehog signaling activation in the chemoresistance of glioblastoma: A ligand-independent mechanism.
Authors: Munoz Jessian L. , Rameshwar Pranela 
Published: August 2014

Abstract
Glioblastoma Multiforme (GMB) is the most common and lethal adult primary tumor of the central nervous system. Despite current chemotherapy with concomitant surgical resection and radiotherapy, GBM 5-year survival is ∼3%. A better understanding of the cellular pathways in tumor proliferation and survival is required for the development of new treatments. Previously, the Sonic Hedgehog pathway has been shown to be dysregulated in chemoresistant GBM. Pharmacological inhibition of SHH signaling with Cyclopamine enhanced GBM chemosensitivity to temozolomide (TMZ). SHH receptor, PTCH1, is tonically repressed by the ligandbut is activated by by receptor-mediated endocytosis of SHH. Here we show SHH signaling in GBM is ligand-independent and is initiated by post-transcriptional regulation of PTCH1. MicroRNA are small non-coding RNA molecules known to regulate a number of cell processes such as development and oncogenesis. As far as we are aware there is no report on microRNA in the regulation of PTCH1. Knockdown of Dicer, a Type III RNAase, which is required for microRNA synthesis, increased the cellular toxicity to TMZ, thus revealing the importance of microRNA in GBM chemoresistance. We have indentified and characterized PTCH as a functional target of microRNA-9 (miR-9) in both non-neural cell lines as well as GBM cell lines. Overexpression of miR-9 in GBM cells results in downstream pathway activation and resistance to TMZ treatment. We also explored a number of mir-9/PTCH1-dependent mechanisms of chemoresistance and uncovered downstream upregulation of ATP-binding cassette drug efflux transporters, MDR1 and ABCG2. Taken together, our data indicate a role for miRNA9 in the acquisition of chemoresistance in GBMs and may serve as novel therapeutic targets.
Citation Format: Jessian L. Munoz, Pranela Rameshwar. A novel method of sonic hedgehog signaling activation in the chemoresistance of glioblastoma: A ligand-independent mechanism. [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 3083. doi:10.1158/1538-7445.AM2013-3083
Abstract 3097: microRNA-21 inhibitor potentiates anti-tumor effect of radiation therapy in vitro and in vivo.
Authors: Cho Bong Jun , Choi Eun Jung , Kim Hans H. , Lee David J. , Chun Sun Ha , Kim In-Ah 
Published: August 2014

Abstract
microRNA-21 (miR-21) plays significant roles in carcinogenesis and is highly expressed in diverse human cancers. In this study, we evaluated the potential of targeting miRNA-21 to overcome the radioresistance of human cancer cells having an activated PI3K-Akt signaling and also aimed to elucidate the mechanisms of radiosensitization, and the effect on epithelial- mesenchymal transition (EMT).
A panel of human cancer cells (U251, U87, A549, MDA-MB-468, SKBR-3 cells) were transfected with miR-21 led to up-regulation of PI3K-Akt signaling and increased radioresistance compared with the cancer cells that were treated with nonspecific control. In contrast, a specific inhibitor of miR-21, an antipeptide nucleic acid (PNA) attenuated PI3K-Akt signaling and radiosensitized a panel of human cancer cells we tested. Inhibition of miR-21 was associated with persistent γH2AX foci formation and down-regulation of p-DNA-PKcs. While ectopic overexpression of miR-21 exhibited higher invasion and migration potential and increased vascular tube formation, inhibitor of miR-21 decreased these typical features of EMT. Treatment of anti-miR-21 significantly decreased tumor burden in nude mice bearing intracranial U251 xenografts compared to control as measured by bioluminescence. Combined treatment of anti-miR-21 and radiation further decreased tumor burden compared to each treatment alone.
In summary, miR-21 is an important onco-miR which confers radioresistance and diverse features of EMT. Inhibition of miR-21 could be a potential strategy for improving the efficacy of radiation therapy via unique modulation of PI3K-Akt signaling and EMT.
Citation Format: Bong Jun Cho, Eun Jung Choi, Hans H. Kim, David J. Lee, Sun Ha Chun, In-Ah Kim. microRNA-21 inhibitor potentiates anti-tumor effect of radiation therapy in vitro and in vivo. [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 3097. doi:10.1158/1538-7445.AM2013-3097
Abstract 3098: MiRNA-145 is a master regulator of the hallmarks of thyroid cancer.
Authors: Boufraqech Myriem , Zhang Lisa , Jain Meenu , Gulati Neelam , Nilubol Naris , Kitano Mio , Xiong Yin , Kebebew Electron 
Published: August 2014

Abstract
microRNA-145 (miR-145) in an important member of the family of microRNAs which are downregulated in several types of tumors. However, miR-145 expression and function in thyroid cancer and in cellular differentiation is unknown. In our study, we performed miRNA profiling in normal, benign and malignant thyroid cancers including undifferentiated tumors with validation of differentially expressed miRNAs by quantitative RT PCR. We found significant downregulation of miR-145 in differentiated and undifferentiated thyroid cancer. We performed functional studies in thyroid cancer cell lines and found that miR-145 decreases cell proliferation, induces cell cycle arrest, decreases cell invasion and targets the PI3K/Akt pathway, one of the most commonly activated pathways in thyroid cancer and which is associated with epithelial-mesenchymal transition (EMT). Overexpression of miR-145 in cell lines also decreased the expression of EMT markers vimentin and N-cadherin. Furthermore, inhibition of miR-145 in normal primary thyroid cultured cells decreased NIS and PAX8 expression, key regulators of thyroid cell differentiation. miRNA-145 expression in tumor tissue was inversely correlated with VEGF serum levels in the same patients and overexpression of miR-145 in vitro decreased angiogenesis and VEGF secretion.
MiRNA-145 has important regulatory effects on the hallmarks of thyroid cancer cells and thus may be involved in thyroid cancer progression.
Citation Format: Myriem Boufraqech, Lisa Zhang, Meenu Jain, Neelam Gulati, Naris Nilubol, Mio Kitano, Yin Xiong, Electron Kebebew. MiRNA-145 is a master regulator of the hallmarks of thyroid 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 3098. doi:10.1158/1538-7445.AM2013-3098
Abstract 3103: Overexpression of homeoprotein six1 activates non-canonical TGF-beta signaling to induce epithelial-mesenchymal transition in human papillomavirus type 16-immortalized human keratinocytes.
Authors: Xu Hanwen , Pirisi Lucia , Creek Kim E. 
Published: August 2014

Abstract
Inappropriate expression of embryonic genes, particularly homeodomain transcription factors, contributes to tumorigenesis and tumor progression. The overexpression of Six1, a member of the Six family of homeodomain transcription factors, has been found in various human cancers, and is associated with increased tumor progression and metastasis. Previous studies in our laboratory discovered that the expression of Six1 mRNA and protein increased during in vitro progression of human papillomavirus type 16 (HPV16)-immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. However, the precise mechanisms of how Six1 promotes tumor onset at early and late stages of HPV16-mediated transformation remain unknown. In this study, we found that HKc/HPV16 and HKc/DR overexpressing Six1 exhibited a more mesenchymal phenotype compared to vector controls, as characterized by a fibroblastic morphology, and increased migration and invasion. We utilized Whole Human Genome Microarrays (4x44K from Agilent Technologies) to explore the gene expression changes associated with Six1 overexpression in HKc/HPV16 and HKc/DR. We found that overexpression of Six1 down-regulated epithelial-related genes (ex., E-cadherin and occludin) and up-regulated mesenchymal-related genes (ex., N-cadherin, vimentin, and snail), which strongly suggests that Six1 overexpression induces epithelial-mesenchymal transition (EMT). Gene expression changes determined by microarray analysis were confirmed by real time PCR and western blotting. Increased expression of TGF-beta receptors in response to overexpression of Six1 in HKc/DR did not lead to increased Smad-dependent signaling but did activate the Mitogen-activated protein kinase (MAPK) pathway, suggesting that MAPK non-Smad TGF-β signaling may be involved in Six1-mediated EMT. In conclusion, our study demonstrates that Six1 overexpression induces EMT, possibly by activation of the MAPK non-canonical (non-Smad) TGF-β pathway, during HPV16-mediated transformation of human keratinocytes.
Citation Format: Hanwen Xu, Lucia Pirisi, Kim E. Creek. Overexpression of homeoprotein six1 activates non-canonical TGF-beta signaling to induce epithelial-mesenchymal transition in human papillomavirus type 16-immortalized human keratinocytes. [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 3103. doi:10.1158/1538-7445.AM2013-3103
Abstract 3109: SOX4 and POU2F1 synergistically regulate metastasis-associated NRP1 in HCC metastasis.
Authors: Tsou Ann-Ping , Liao Yu-Lun , Sun Yi-Ming , Horng Jorng-Tzong , Hsiao Michael 
Published: August 2014

Abstract
Gene regulation by SOX proteins depends on the presence of requisite partners which provides target specificity and combinatorial control. Previously, we have shown that SOX4 is an oncogenic transcription factor involved in human hepatocarcinogenesis. By bioinformative prediction, we identified that POU2F1 is an SOX4 co-factor and further showed that SOX4 and POU2F1 synergistically regulate metastasis-associated NRP1 expression in HCC cells. Using co-immunoprecipitation experiments, SOX4 and POU2F1 were shown to participate in direct protein-protein interaction in vitro involving assembly into a complex that required the N-terminus and HMG domain of SOX4 interacting with POU2F1. In addition, RNAi knockdown of SOX4 expression of HCC cell lines drastically reduced the expression of epithelial-mesenchymal transition (EMT) related genes, N-cadherin, MMP2 and MMP9. SOX4 knockdown also reduced the expression of VEGF related genes VEGFC, FLT1 and FLT4 and blood vessel distribution in subcutaneous tumors was decreased in shSOX4, shPOU2F1 and shNRP1-infected Mahlavu tumor cells. Our results suggest that SOX4 and POU2F1 may play a critical role in the regulation of genes involved in tumor invasion. These results support a new regulatory network from SOX4 and POU2F1 to NRP1 that occurs during liver tumor metastasis. This investigation provides relevant gene targets that are regulated by SOX4 and POU2F1 in liver tumors and these results could be used to develop effective diagnostic and alternative therapeutic strategies for the treatment of intrahepatic HCC.
Keywords: SOX4; POU2F1; hepatocellular carcinoma
Citation Format: Ann-Ping Tsou, Yu-Lun Liao, Yi-Ming Sun, Jorng-Tzong Horng, Michael Hsiao. SOX4 and POU2F1 synergistically regulate metastasis-associated NRP1 in HCC metastasis. [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 3109. doi:10.1158/1538-7445.AM2013-3109
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.