bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1890: IKBKE is a substrate of EGFR and a therapeutic target in NSCLCs with activating mutations of EGFR
Authors: Challa Sridevi , Guo Jian-Ping , Xu Cheng-xiong , Li Yajuan , Kim Donghwa , Cress Douglas , Haura Eric , Coppola Domenico , Cheng Jin 
Published: July 2016

Abstract
EGFR is one of key driver pathways of non-small cell lung cancer (NSCLC). EGFR inhibitors have shown significant response in patients with EGFR mutation. However, patients develop resistance in short period of time, which results from secondary EGFRT790M mutation and other mechanisms. Here, we demonstrated that activating mutations of EGFR significantly activated IKBKE, an IκB kinase family member previously shown to activate Akt and NF-κB pathways. Furthermore, we showed that EGFR directly interacts with and phosphorylates IKBKE on tyrosine 153 and tyrosine 179 residues. IKBKE-Y153F/179-F, a mutant that could not be phosphorylated by EGFR, largely reduced its kinase activity and failed to activate Akt and NF-κB as well as inhibited EGFR signaling. Furthermore, phospho-IKBKE-Y153 correlated with EGFR activation in NSCLC patients. Notably, depletion of IKBKE by either small molecule inhibitor amlexanox or shRNA selectively inhibited cell viability in NSCLC cells with EGFR mutations. Moreover, we observed that inhibition of IKBKE led to feedback activation of the MAPK pathway. Combination of amlexanox with MEK inhibitor AZD6244 significantly inhibits cell survival and tumor growth in NSCLC cells driven by activating EGFR mutations including EGFRT790M. Thus, our findings not only identify IKBKE as a direct downstream target of EGFR but also provide a potential therapeutic strategy for EGFR-TKI resistant NSCLC driven by secondary EGFR mutation.
Citation Format: Sridevi Challa, Jian-Ping Guo, Cheng-xiong Xu, Yajuan Li, Donghwa Kim, Douglas Cress, Eric Haura, Domenico Coppola, Jin Cheng. IKBKE is a substrate of EGFR and a therapeutic target in NSCLCs with activating mutations of EGFR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1890.
Abstract 1895: Metastasis-associated protein 1 drives prostate cancer progression and metastasis through regulation of onco-epimicroRNAs
Authors: Dhar Swati , Butt Nasir A. , Kumar Avinash , Zhang Xu , Levenson Anait S. 
Published: July 2016

Abstract
Our recent studies in prostate-specific tumor suppressor Pten gene compromised transgenic mice, revealed a strategic role for Metastasis Associated protein 1 (MTA1), a component of the chromatin remodeling NuRD complex and a key regulator of metastasis, in the progression of prostate cancer. Chromatin Immunoprecipitation Sequencing (ChIP-Seq) analyses from the mouse prostate tissues showed MTA1 occupancy of several potential oncogenic miRNA target promoters including miR-22. Retrospective investigation of microRNA microarray experiments revealed downregulation of these candidate miRNAs in LNCaP cells silenced for MTA1 expression (shMTA1). Real time PCR evaluation of shMTA1 cell lines, LNCaP, DU145 and PC3M attested the microarray findings. Using miRNA-mRNA target prediction algorithms, miRanda, miRDB and Targetscan, E-cadherin (CDH1) was identified as a potential target with high context score for miR-22. Interestingly, E-cadherin, which has a pivotal role in preventing Epithelial to Mesenchymal Transition (EMT) of tumor cells was also identified as a MTA1 target gene by ChIP-Seq analysis. Further, qRT-PCR and western blot experiments validated that MTA1 levels had an inverse correlation with E-cadherin expression in these cell lines. Transient transfection of miR-22 mimics diminished E-cadherin levels while this expression was restored by miR-22 sponge inhibitors showing that miR-22 can control E-cadherin expression. Ongoing experiments aim to address the direct targeting of E-cadherin 3′UTR by miR-22 using Dual-Glo luciferase reporter assay and the functional consequences of miR-22 promoter regulation by MTA1 utilizing chromatin and RNA immunoprecipitation assays. Our studies reveal a novel and previously unrecognized role for MTA1-mediated miR-22 regulation of E-cadherin.
Citation Format: Swati Dhar, Nasir A. Butt, Avinash Kumar, Xu Zhang, Anait S. Levenson. Metastasis-associated protein 1 drives prostate cancer progression and metastasis through regulation of onco-epimicroRNAs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1895.
Abstract 1902: Downregulation of MYC by miR-3189-3p in glioblastoma
Authors: Jeansonne Duane , Reiss Krzysztof , Peruzzi Francesca 
Published: July 2016

Abstract
Glioblastoma is a devastating malignancy with a median survival of approximately 15 months. This aggressive tumor originates from the glial cells and accounts for nearly 50% of adult brain tumors. Glioblastomas are characterized by rapid proliferation and resistance to standard treatment of surgery, temazolamide and radiation therapy. MicroRNAs are short single-stranded non-coding RNAs that regulate gene expression in both normal and pathological conditions. We have previously found downregulation of miR-3189-3p in glioblastomas and astrocytomas. Using in vitro models, we demonstrated that ectopic expression of this miRNA inhibited glioblastoma cell growth and migration through downregulation of the splicing factor SF3B2 and the guanine nucleotide exchange factor p63RhoGEF, respectively. The miR-3189-3p-mediated inhibition of glioblastoma growth in vivo further confirmed the anti-cancer activity of this microRNA.
Given the strong biological effect of this miRNA on glioblastoma cells, we sought to investigate the implication of other gene targets in miR-3189-3p-mediated effects. The elevated expression of MYC oncogene is found in a variety of cancer types, including glioblastoma. Here, we demonstrated that overexpression of miR-3189-3p results in downregulation of MYC. Since this gene is not a predicted target for miR-3189-3p, we hypothesized that this modulation of MYC expression is mediated through the translational repressor, TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAL1, also called TIAR). We tested the levels of TIAR in cells treated with miR-3189-3p and found no changes in TIAR expression. However, the downregulation of MYC was dependent on TIAR expression, as determined through siRNA-mediated downregulation of TIAR. Further studies are needed to elucidate molecular mechanisms of TIAR-dependent downregulation of MYC by miR-3189-3p. In addition, a putative binding site for miR-3189-3p is located within the open reading frame of MYC; therefore, studies will be performed to determine whether miR-3189-3p downregulates MYC by directly binding outside the 3’-UTR of this transcript.
Citation Format: Duane Jeansonne, Krzysztof Reiss, Francesca Peruzzi. Downregulation of MYC by miR-3189-3p in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1902.
Abstract 1906: Inhibition of miR-186 and repression of aggressive prostate cancer phenotype using a metastatic cell model
Authors: Jones Dominique Z. , Schmidt M. Lee , Hobbing Katharine R. , Clark Geoffrey , Kidd LaCreis R. 
Published: July 2016

Abstract
MicroRNA (miR) dysregulation alters the expression of cancer related genes and contributes to disease states in many cancers. For example, ectopic miR-186 expression leads to enhanced cell proliferation and migration in pancreatic cancer. However, the role of miR-186 in prostate cancer (PCa) remains unclear. Previously, we observed significant upregulation of miR-186-5p in PCa patient serum (stage III/IV) compared to controls. Furthermore, miR-186 was significantly up-regulated in metastatic PCa (PC-3) compared to normal prostate epithelial cells (RWPE1). We hypothesized miR-186 inhibition will reduce aggressive PCa in vitro.
Consequently, miR-186 was transiently and stably inhibited in PC-3 cells. Cell proliferation and colony formation were evaluated for 7 and 21 days via Trypan Blue exclusion and soft agar assays. Aberrant gene expression was evaluated in transfected cells to identify miR-186 targets. Candidate miR-186 targets were selected using published reports on ‘miR-186 and cancer’, availability of robust antibodies, and statistical filtering (false discovery ≥0.05 and ±1.2 fold change).
Mir-186 inhibition in PC-3 cells significantly repressed proliferation and colony formation by 34-64%. Following miR-186 inhibition in PC-3 cells, 2,343 identified mRNA targets were differentially expressed compared to scramble controls (p &lt; 0.05). The target list was reduced to 11 up-regulated candidates. Predicted miR-186 targets are undergoing validation via qRT-PCR, western blots, and luciferase reporter assays. In addition, other studies are in progress to evaluate the impact of miR-186 on cellular proliferation, migration and invasion. Such efforts may lead to the identification of novel biomarkers to improve detection and clinical management strategies for aggressive PCa.
Citation Format: Dominique Z. Jones, M. Lee Schmidt, Katharine R. Hobbing, Geoffrey Clark, LaCreis R. Kidd. Inhibition of miR-186 and repression of aggressive prostate cancer phenotype using a metastatic cell model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1906.
Abstract 1918: The role of miR17-92 in the miRegulatory landscape of Ewing sarcoma
Authors: Schwentner Raphaela , Kauer Maximilian , Herrero-Martin David , Kovar Heinrich 
Published: July 2016

Abstract
MicroRNAs (miRNA) serve to fine-tune gene expression and thus play an important regulatory role in tissue specific gene networks. The identification and validation of miRNA target genes in a given tissue still poses a significant problem since the presence of a seed sequence in the 3′UTR of an mRNA and its expression modulation upon forced ectopic expression of the miRNA do not reliably predict regulation under physiological conditions. The chimeric oncoprotein EWS-FLI1 is the driving pathogenic force in ES. Recently, we reported on the EWS-FLI1 microRNA (miRNA) signature based on knockdown experiments in ES cell lines and on differential expression in primary tumors versus mesenchymal stem cells. Comparison of both datasets revealed the miR17-92 cluster to be the top EWS-FLI1 activated miRNA, which is one of the most potent oncogenic miRNAs. The whole cluster is among the small number of miRNAs down-regulated upon knockdown of EWS-FLI1 in multiple ES cell lines. We now report the use of a combination of AGO2 pull-down experiments by PAR-CLIP - to enrich and sequence RISC-associated RNAs - and of RNAseq upon miRNA depletion by ectopic sponge expression to identify the targetome of miR17-92 in Ewing sarcoma (ES) cells
We found a significant enrichment of PAR-CLIP hits for members of the miR-17-92 cluster in the 3′UTRs of genes up-regulated in response to mir-17-92 but not miR9 and 10b specific sponge expression. Among them, we consistently identified known (i.e. CTGF, MXD1, CYLD1) and a multitude of so far unknown targets of the oncomir-1 cluster in ES in three PAR-CLIP experiments. Interestingly, approximately a quarter of these genes annotate to the TGFB/BMP pathway, the majority mapping downstream of SMAD signaling.
Gene reporter assays using 3’UTRs of select novel candidate genes showed enhancement of luciferase activity upon transfection of a sponge specific to miR-17-92 and 20a, but not to unrelated miR-9 and 10b. Site directed mutagenesis of seed sequences in these 3’UTR confirmed the direct regulation of these genes by miR17-92. Current research focuses on the functional validation of TGFB pathway modulation by miR17-92. This study provides a paradigmatic approach to the comprehensive definition of the targetome for a defined group of miRNAs under physiological conditions.
This study was supported by the 7th framework program of the European Commission (FP7-259348, “ASSET”) and the Austrian Science Fund FWF (24708-B21)
Citation Format: Raphaela Schwentner, Maximilian Kauer, David Herrero-Martin, Heinrich Kovar. The role of miR17-92 in the miRegulatory landscape of Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1918.
Abstract 1925: Regulation of metabotropic glutamate receptor 5 expression by the miR-30 downregulation induced by the SDF-1/CXCR4 system in oral cancer cells
Authors: Kuribayashi Nobuyuki , Uchida Daisuke , Kinouchi Makoto , Koshiji Chikako , Izumi Sayaka , Hakata Kembun , Komiyama Yuske , Tsuchida Shuji , Hasegawa Tomonori , Kawamata Hitoshi 
Published: July 2016

Abstract
We have previously demonstrated that stromal cell-derived factor (SDF)-1/CXCR4 system enhances the metastases of oral cancer cells via induction of metabotropic glutamate receptor (mGluR) 5. However, the mechanism(s) of mGluR5 expression induced by the SDF-1/CXCR4 system are largely unknown. Recently, small non-coding RNAs, microRNAs (miRNAs) are involved in the metastatic process of several types of cancers. In this study, we examined the miRNA association involved in the mGluR5 expression using oral cancer cells, B88, which express functional CXCR4 and exhibit highly metastatic potentials. We examined the metastasis-related miRNAs in SDF-1 stimulated B88 cells by use of a miRNA microarray analysis. Consequently, we isolated miR-30 family which has predictive binding sites in 3’-UTR of mGluR5 mRNA in silico analysis. Among these miRNAs, we confirmed the downregulation of all miR-30 family in SDF-1 stimulated B88 cells by the real-time PCR analysis. Next, we transfected these miR-30 families in SDF-1 stimulated B88 cells. We confirmed the downregulation of mGluR5 by the miR-30a-5p and miR-30c-5p overexpression. These results indicated that SDF-1/CXCR4 system might regulate the metastases of oral cancer by the upregulation of mGluR5 via downregulation of miR-30 family.
Citation Format: Nobuyuki Kuribayashi, Daisuke Uchida, Makoto Kinouchi, Chikako Koshiji, Sayaka Izumi, Kembun Hakata, Yuske Komiyama, Shuji Tsuchida, Tomonori Hasegawa, Hitoshi Kawamata. Regulation of metabotropic glutamate receptor 5 expression by the miR-30 downregulation induced by the SDF-1/CXCR4 system in oral cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1925.
Abstract 1934: MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates prostate cancer stem cell marker CD44
Authors: Bucay Nathan , Sekhon Kiran , Shahryari Varahram , Mitsui Yozo , Deng Guoren , Tabatabai Z. Laura , Majid Shahana , Yamamura Soichiro , Dahiya Rajvir , Tanaka Yuichiro , Saini Sharanjot 
Published: July 2016

Abstract
A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region -miR-383- is frequently downregulated in prostate cancer, plays a critical role in determining tumor initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor initiating cells (TICs)/ stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggests that miR-383 regulates PCa tumor initiating/ stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor initiating capacity of CD44+ PCa cells. Also, ‘anti-metastatic’ effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggests that restoration of miR-383 expression may be an effective therapeutic modality against PCa relapse and metastasis. Importantly, we identified miR-383 as a novel PCa diagnostic biomarker with potential that outperforms that of serum PSA.
Citation Format: Nathan Bucay, Kiran Sekhon, Varahram Shahryari, Yozo Mitsui, Guoren Deng, Z. Laura Tabatabai, Shahana Majid, Soichiro Yamamura, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini. MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates prostate cancer stem cell marker CD44. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1934.
Abstract 1943: A microRNA signature in urinary exosomes for diagnosis of prostate cancer
Authors: Blondal Thorarinn , Rasmussen Anne I. , Thomsen Anni R. , Borre Michael , Fredsøe Jacob , Andreasen Ditte , Falck Ørntoft Torben , Sørensen Karina D. , Mouritzen Peter 
Published: July 2016

Abstract
MicroRNAs constitute a class of small cellular noncoding RNAs (typically 19-23 nt) which function as post-transcriptional regulators of gene expression. The involvement of microRNA in both normal development as well as disease is well established and microRNAs are considered important biomarkers in several diseases including cancer. Surprisingly cell free microRNAs are also found in several biofluids where they have been shown to be very stable, most likely because they are protected from degradation by protein complexes and other particles including exosomes.
Exosomes are nanovesicles secreted into the extracellular environment by a wide range of cell types under normal and pathological conditions. As the profile of exosomal microRNAs may be a fingerprint of the releasing cell type and because they are released in easily accessible body fluids such as blood and urine, their microRNA content holds potential as biomarkers for early detection of malignancy.
We have developed different technologies enabling the detection of prostate cancer microRNA biomarkers in exosomes derived from urine from non-prostate massaged men. The first of these technologies is a highly sensitive LNA™-based qPCR platform for microRNA detection, which enables profiling in biofluids where microRNA levels are extremely low. At this point we have already applied this platform on thousands of biofluid samples including serum/plasma and urine to establish normal reference ranges for circulating microRNAs as well as to identify biomarkers of disease. The second technology is a simple exosome precipitation system which only requires low speed centrifugation to harvest urine exosomes.
Our developed technologies was applied to cell-free urine from three different cohorts including individuals with prostate cancer (PCa) and benign prostate hyperplasia, to identify several differentially regulated microRNAs in urine from PCa bearing individuals. PCa specific signatures were obtained by different combinations of these differentially regulated microRNAs. In conclusion, cell free urine samples holds potential as a liquid biopsy source for exosomal microRNA markers in prostate cancer. Data showing that small miRNA signatures (down to two miRNAs) hold strong diagnostic potential in PCa will be presented.
Citation Format: Thorarinn Blondal, Anne I. Rasmussen, Anni R. Thomsen, Michael Borre, Jacob Fredsøe, Ditte Andreasen, Torben Falck Ørntoft, Karina D. Sørensen, Peter Mouritzen. A microRNA signature in urinary exosomes for diagnosis of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1943.
Abstract 1951: Expression profiling, cellular and clinical implications of mitochondrial miRNAs in colorectal carcinomas
Authors: Ebrahimi Faeza , Gopalan Vinod , Lam Alfred 
Published: July 2016

Abstract
Aim: The aim of this study was to determine the expression profiling and cellular implications of mitochondrial miRNAs (Mitomirs) such asmiR-145, miR-15a, miR-335 and miR-126)in colorectal cancer tissues. Expression changes in matched metastatic tissues were also examined.
Method: Colorectal tissues from163 primary cancers, 96 lymph node, 48 metastatic, 40 adenoma and 42 non-neoplastic tissues were recruited from 389 patients. The expression of Mitomirs in tissues and colon cancer (SW-480, SW-48) and normal (FHC) cell lines were investigated by qRT-PCR. Functional assays including cell proliferation, cell cycle analysis and apoptosis assays were performed with an exogenous miR-126 mimic to detect its in-vitro changes on cancer cell biology. In addition, Western blot was used to detect the targets of miR-126.
Result: Expressions of Mitomirs were down-regulated in colorectal cancer tissues compared to non-tumour colorectal tissues. Higher expression of miR-145 was predominantly noted in colorectal cancers with tumour recurrence (P = 0.058). Expression of miR-335 was significantly reduced distal colorectum compared to proximal colon (P = 0.025). Reduced expression of miR-335 also showed significant correlation with occurrence of lymphovascular permeation (P = 0.019), and late T stage (P = 0.004) of colorectal cancer. Moreover, in microsatellite instability (MSI) positive adenocarcinomas, notable downregulation of miR-15a (P = 0.018) was observed and this reduced expression was significantly correlated with size of tumour (&gt; 40 mm) (P = 0.014). Expression of miR-15a, and miR-145 was reduced in metastatic cell line (SW48). Overexpression of miR-126 in-vitro showed increased apoptosis, reduced cell proliferation and suppression of synthetic phase in cell cycle. Also, overexpression of miR-126 has induced reduced expression of BCL-2 protein and increased expression of P53 protein.
Conclusion: This study suggests that expression of Mitomirs significantly reduces in advanced stages of cancer and even in early stages in comparison to normal tissues. In vitro studies indicated that ectopic expression miR-126 has the capability of inducing apoptosis and reducing viability of cancers cells potentially via modulating its target partners such as BCL-2 and p53.
Citation Format: Faeza Ebrahimi, Vinod Gopalan, Alfred Lam. Expression profiling, cellular and clinical implications of mitochondrial miRNAs in colorectal carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1951.