bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A12: miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively
Authors: Tang Hua 
Published: May 2016

Abstract
miRNAs typically downregulate the expression of target genes by binding to their 3'UTR, and dysregulation of miRNAs may contribute to tumorigenesis. Here, we found that miR-346 and miR-138 competitively bind to a common region in the 3'UTR of hTERT mRNA and have opposite effects on the expression and function of hTERT in human cervical cancer cells. Furthermore, G-rich RNA sequence binding factor 1 (GRSF1) mediates the miR-346-dependent upregulation of hTERT by binding to the miR-346 middle sequence motif (CCGCAU) which forms a “bulge loop” when miR-346 is bound to the hTERT 3'UTR, facilitating the recruitment of hTERT mRNA to ribosomes to promote translation in an AGO2-independent manner. Conversely, miR-138 suppresses hTERT expression in an AGO2-dependent manner. Interestingly, replacement of the miR-138 middle sequence with that of miR-346 resulted in an upregulation of hTERT expression in a GRSF1-dependent manner. Moreover, miR-346 depends on GRSF1 to upregulate another target gene, activin A receptor, type IIB (ACVR2B), in which miR-346 “CCGCAU” motif is essential. These findings reveal novel mechanisms of miRNA-mediated upregulation of target gene expression and describe the coordinated action of multiple miRNAs to control the fate of a single target mRNA through binding to its 3'UTR.
Citation Format: Hua Tang. miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A12.
Abstract A21: MiR-106a and miR-106b affect growth and metastasis of lung adenocarcinoma
Authors: Enfield Katey SS , Rowbotham David A. , Holly Alice , Anderson Christine , Ng Kevin W. , Minatel Brenda de Carvalho , Dellaire Graham , Pastrello Chiara , Jurisica Igor , MacAulay Calum , Lam Stephen , Lam Wan L. 
Published: May 2016

Abstract
Introduction: MiR-106a and miR-106b are paralogs of the oncogenic miR-17~92, and have been associated with poor outcome and metastasis in several solid tumors. Their role in lung cancer is relatively unexplored. We characterized the expression of miR-106a and miR-106b in a clinical cohort of lung adenocarcinoma (AC) tumors and assessed their ability to regulate growth and metastasis in cell models.
Methods: MicroRNA (miRNA) expression was deduced from small RNA sequencing data derived from clinical lung AC specimens (60 localized, 27 with lymph node invasion) and paired non-malignant tissues. MiR-106a and miR-106b overexpression vectors and controls were stably transfected into immortalized non-malignant Human Bronchial Epithelial Cells (HBECs) and stage I AC cell lines with epithelial expression patterns by lentiviral delivery. Migration and invasion was assessed by Boyden chamber assay, while cell proliferation was assessed by BrdU incorporation assay. Expression of epithelial-to-mesenchymal transition (EMT) markers and other proteins of interest were assessed by Western Blot. Clinical associations in an external cohort were derived using publically available TCGA data.
Results: MiR-106a and miR-106b were significantly overexpressed in lung AC with lymph node invasion. Overexpression of miR-106a and miR-106b significantly increased proliferation of lung AC cell lines, and was associated with decreased levels of predicted target, p21. AC cell lines displayed a marked increase in metastatic phenotypes in vitro, and were associated with increased mesenchymal and decreased epithelial markers, characteristic of EMT. Importantly, tumors with high expression of both miR-106a and miR-106b and mesenchymal marker vimentin had significantly poorer outcome.
Conclusions: MiR-106a and miR-106b are overexpressed in metastatic lung AC. Lung AC cell models indicate these miRNAs are metastatic agonists, affecting the metastatic potential of cells at least in part via induction of EMT. A deeper characterization of this observation may reveal therapeutic intervention points, or, with the development of miRNA therapeutics, miR-106a/b may be promising targets to prevent or treat metastatic disease.
Citation Format: Katey SS Enfield, David A. Rowbotham, Alice Holly, Christine Anderson, Kevin W. Ng, Brenda de Carvalho Minatel, Graham Dellaire, Chiara Pastrello, Igor Jurisica, Calum MacAulay, Stephen Lam, Wan L. Lam. MiR-106a and miR-106b affect growth and metastasis of lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A21.
Abstract A24: HDAC inhibition unmasks a microRNA-mediated mechanism of tumor suppression
Authors: Adams Clare M. , Hiebert Scott W. , Eischen Christine M. 
Published: May 2016

Abstract
Genetic lesions resulting in epigenetic dysregulation have a newly appreciated role in tumor initiation and progression. Alterations in epigenetic enzymes, such as histone deacetylases (HDACs), lead to dynamic changes in the epigenetic landscape that are postulated to alter the expression of critical mediators of tumorigenesis. HDACs not only alter the expression of protein-coding genes, but also affect noncoding RNAs, including microRNA (miRNA). Recent evidence suggests that miRNA are one of the largest classes of regulatory molecules and, given their broad impact on gene expression, it is not surprising they have a significant role in tumorigenesis. Although, small molecule inhibitors of HDACs have demonstrated therapeutic utility, the molecular events underlying the observed selective killing of cancer cells are incompletely resolved. We determined that HDAC inhibition in numerous hematopoietic malignancies relieved the Myc-mediated transcriptional repression of miRNA with known tumor suppressive properties, namely the miR-15 and let-7 families. Specifically, following HDAC inhibition, Myc, which normally represses the miR-15 and let-7 families in cancer cells, transcriptionally activated their expression. In addition, we demonstrated that Myc was required for this HDAC inhibition-induced miRNA upregulation. As a result, transcript levels of the miR-15 and let-7 families increased, which subsequently targeted and decreased the expression of anti-apoptotic Bcl-2 and Bcl-xL, respectively, inducing apoptosis in multiple hematopoietic malignancies. Unexpectedly, we demonstrated that, in normal cells, dysregulated Myc transcriptionally upregulated these miRNA as a means to prevent cellular transformation, revealing a novel mechanism whereby Myc induces apoptosis independent of the p53 tumor suppressor. Our results expose a previously unknown, and surprisingly general, mechanism of Myc-induced apoptosis that capitalizes on miRNA. Importantly, our data provide insight into the molecular underpinnings following HDAC inhibition and contribute new knowledge that should aid in the development of improved cancer therapeutics.
Citation Format: Clare M. Adams, Scott W. Hiebert, Christine M. Eischen. HDAC inhibition unmasks a microRNA-mediated mechanism of tumor suppression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A24.
Abstract A32: The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression
Authors: Han Cecil , Lu Xiongbin , Zhang Xinna 
Published: May 2016

Abstract
MicroRNAs (miRNAs) are small endogenous non-coding RNAs that regulate gene expression by repressing translation and/or promoting degradation of their target mRNAs. Aberrant dysregulation of mature miRNAs is commonly observed in many human cancers and can have a causative function in tumorigenesis. In the nucleus, primary miRNAs (pri-miRNAs) are first processed by the microprocessor containing RNaseIII enzyme Drosha and its cofactor DGCR8. Although the efficiency of Drosha-mediated process is crucial for determining miRNA abundance, the mechanisms for dynamic and specific regulation of miRNA biogenesis in the Drosha microprocessor are poorly understood. A better understanding of miRNA regulation is required to determine how aberrant miRNA activity mechanistically contributes to tumorigenesis and to predict therapeutic target miRNAs. Increasing evidence has shown that regulatory RNA-binding proteins may confer the specificity on the core components (Drosha and DGCR8) in the Microprocessor for recruiting and processing premature pri-miRNAs.
Here, we identified a RNA-binding protein, DEAD-box RNA helicase 1 (DDX1) as a key regulatory component in the Drosha complex, which promotes the processing of a subset of miRNAs including miR-200 family (miR-200a, -200b, -200c, -141, -429). A suppressive role of miR-200s in cancer metastasis has been well known in several cancer types such as ovarian, kidney renal and lung cancer. Inhibiting DDX1 promotes tumor burden in the previous syngeneic ovarian mouse models. Consistent with, low level of DDX1 is associated with poor clinical outcome in patients with serous ovarian cancer and kidney renal clear cell carcinoma. Interestingly, DDX1-dependent miR-200a and miR-200b were also induced after DNA damage and this induction is facilitated by the ATM-mediated phosphorylation of DDX1. These findings suggest that DDX1 may be a key modulator in miRNA maturation in response to cellular signaling pathway and that alteration of level/function of DDX1 may play an important role in tumor progression through dysregulated microRNA pathway.
Citation Format: Cecil Han, Xiongbin Lu, Xinna Zhang. The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A32.
Abstract A40: Epigenomic profiling identifies NCRNAs as novel tumor suppressors in developmental tumors
Authors: Herrero-Martin David , Court Franck , Rello-Varona Santiago , Sainz-Jaspeado Miguel , Buj Raquel , Moran Sebastian , Garcia-Monclus Silvia , Huertas-Martinez Juan , Mora Jaume , Peinado Miquel Angel , Alonso Javier , Alava Enrique de , Monk Dave , Esteller Manel , Tirado Oscar M. 
Published: May 2016

Abstract
Pediatric sarcomas represent a diverse group of rare bone and soft tissue malignancies. Although the molecular mechanisms that propel the development of these cancers are not well understood, identification of tumor-specific translocations in many sarcomas has provided significant insight into their tumorigenesis. Besides of acting as a direct modulator of transcription, fusion proteins appear to exert its oncogenic functions by epigenetic modifications on the transcriptome. Aberrant DNA methylations are thought to be closely related to the development of cancer. Therefore, the identification of specific DNA methylation markers would be helpful for understanding the pathogenetic mechanism as well as for developing new therapeutic strategies. By using the Illumina Infinium HumanMethylation450, we analyze the methylome of Ewing Sarcoma (ES) and Rhabdomyosarcoma (RMS) tumors and cell lines as developmental tumors in comparison to a significant number of normal tissues and cells as a reference. Our results uncover one miRNA with tumor suppressive activities in both tumor entities. Molecular mechanisms associated to these activities are further explored.
Citation Format: David Herrero-Martin, Franck Court, Santiago Rello-Varona, Miguel Sainz-Jaspeado, Raquel Buj, Sebastian Moran, Silvia Garcia-Monclus, Juan Huertas-Martinez, Jaume Mora, Miquel Angel Peinado, Javier Alonso, Enrique de Alava, Dave Monk, Manel Esteller, Oscar M. Tirado. Epigenomic profiling identifies NCRNAs as novel tumor suppressors in developmental tumors. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A40.
Abstract B28: PTENpg1 antisense RNA mediates PTEN suppression in vemurafenib resistance and predicts clinical outcome in melanoma patients
Authors: Vidarsdottir Linda , Azimi Alireza , Serviss Jason , Ingvar Christian , Jönsson Göran , Olsson Håkan , Stolt Marianne Frostvik , Hansson Johan , Brage Suzanne Egyházi , Grandér Dan , Johnsson Per 
Published: May 2016

Abstract
Approximately 50% of cutaneous melanomas carry activating mutations in the serine/threonine protein kinase BRAF. Vemurafenib is a highly potent inhibitor of BRAFV600E and prolongs survival in ~80% of melanoma patients carrying the mutation. Unfortunately, almost all patients develop resistance within 6-8 months of starting treatment. The molecular mechanism explaining this scenario is largely unclear, but loss of PTEN expression, has been suggested.
In this study we reveal a role for the PTEN pseudogene encoded antisense RNA (PTENpg1 asRNA) in epigenetic suppression of PTEN in melanoma cell lines resistant to vemurafenib. Resistant cell lines showed increased PTENpg1 asRNA expression while PTEN expression was suppressed. ChIP analysis showed enrichment of the histone modification enzyme EZH2 and subsequent enrichment of H3K27me3 at the PTEN promoter in the resistant cell line. Total cellular levels of EZH2, DNMT3a and H3k27me3 were, however, unaffected thus indicating specific recruitment of these factors to the PTEN promoter in the resistant cells by a mechanism that is dictated by the increased expression of PTENpg1 asRNA. In addition, we show that PTEN is reactivated by the depletion of EZH2 and DNMT3a and that this reactivation of PTEN re-sensitizes the cells to vemurafenib treatment.
Finally, we show that PTENpg1 asRNA could be a promising prognostic marker of clinical outcome of melanoma patients. PTENpg1 asRNA expression levels were measured in samples from patients that had not received any oncological treatment and were classified with stage III melanomas. We found that high PTENpg1 asRNA expression correlates with short-term survival in melanoma patients.
In conclusions, the PTENpg1 asRNA appears to be an important player in vemurafenib resistance and could be an attractive therapeutic target. In addition, PTENpg1 asRNA is potentially a promising prognostic marker for clinical outcome for melanoma patients.
Citation Format: Linda Vidarsdottir, Alireza Azimi, Jason Serviss, Christian Ingvar, Göran Jönsson, Håkan Olsson, Marianne Frostvik Stolt, Johan Hansson, Suzanne Egyházi Brage, Dan Grandér, Per Johnsson. PTENpg1 antisense RNA mediates PTEN suppression in vemurafenib resistance and predicts clinical outcome in melanoma patients. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B28.
Abstract B35: Differences in extracellular vesicle nucleic acid content show promise as prostate cancer biomarkers
Authors: Jankowski Helen , Goldie Belinda , Brzozowski Joshua , Bond Danielle , Scarlett Christopher , Skelding Kathryn , Weidenhofer Judith 
Published: May 2016

Abstract
Prostate cancer has one of the highest incidence rates of all cancers worldwide. Although 5-year survival rates are high, this is generally attributed to most prostate cancers either exhibiting a slow progression towards metastasis or being indolent. However current treatments for localized disease have devastating effects on quality of life and the biomarkers that are currently available are not accurate enough. This has resulted in many men with indolent disease being unnecessarily treated. Therefore, it is essential to identify new prognostic biomarkers that are accurate, sensitive and able to be tested for in non-invasive ways. Extracellular vesicles (EVs) have gained interest as a promising avenue for cancer biomarkers in recent years. EVs are small spherical shaped vesicles, which are secreted from their tissue of origin and contain high amounts of noncoding RNAs. EVs, from a panel of 20 prostate cell lines from normal, primary cancer or metastatic sites, were investigated by Affymetrix Human Transcriptome arrays (HTA 2.0). This enabled the identification of nucleic acids that contribute to the development of metastasis through comparison with EV and cellular function. EVs were collected from cell culture media devoid of supplements after 48 hours, by ultraconcentration. RNA was extracted with Trizol and evaluated using total RNA Agilent 2100 bioanalyzer chips. RNA was converted to labeled cDNA and hybridized to HTA 2.0 cassettes. Data was normalized using expression console and analyzed using transcriptome analysis console. Bioanalyzer results illustrated a unique RNA profile for each of the 20 cell lines. Preliminary analysis of nucleic acid content showed that the amount of mRNA, miRNA, snRNA, snoRNA, tRNA, and lncRNA packaged into EVs varies between cell lines further highlighting the differences observed with bioanalyzer profiles. Further several transcripts had significantly different abundance levels that discriminated between EVs released from cells of normal prostate, prostate cancer and metastatic origin, showing potential as biomarkers. Further analysis is ongoing to identify what mechanisms contribute to the differential packaging of nucleic acid into EVs in prostate cells and specific nucleic acid changes that could be used as novel biomarkers.
Citation Format: Helen Jankowski, Belinda Goldie, Joshua Brzozowski, Danielle Bond, Christopher Scarlett, Kathryn Skelding, Judith Weidenhofer. Differences in extracellular vesicle nucleic acid content show promise as prostate cancer biomarkers. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B35.
Abstract B40: A two-microRNA signature in urinary exosomes for diagnosis of prostate cancer
Authors: Mouritzen Peter , Fredsøe Jacob Christian , Blondal Thorarinn , Rasmussen Anne Karin , Borre Michael , Haldrup Christa , Andreasen Ditte , Tolstrup Niels , Ørntoft Torben Falck , Sørensen Karina Dalsgaard 
Published: May 2016

Abstract
Antibody based detection of circulating prostate specific antigen (PSA) remains an important test in the diagnosis of prostate cancer. Unfortunately the test identifies a high number of false positives which require further testing to confirm the presence of cancer including several biopsies taken from the prostate itself. Whereas the performance of biopsies on individuals is associated with discomfort and risk of serious side effects, the invasive test also represents an expense to health care systems. Given the high number of false positives, the PSA test is therefore the direct cause of unnecessary suffering of healthy individuals and costs to health systems.
To investigate the possibilities for developing a non-invasive and more specific test, 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.
We have combined our developed technologies and applied this on cell-free urine from two different cohorts of approximately 220 patients each, to identify a number of differentially regulated microRNAs in urine from prostate cancer bearing individuals. Prostate cancer specific signatures have been obtained by different combinations of these differentially regulated microRNAs. The smallest signature is composed of two microRNAs which allows constructing receiver operating characteristic curves with areas under the curve well above 0.8.
Citation Format: Peter Mouritzen, Jacob Christian Fredsøe, Thorarinn Blondal, Anne Karin Rasmussen, Michael Borre, Christa Haldrup, Ditte Andreasen, Niels Tolstrup, Torben Falck Ørntoft, Karina Dalsgaard Sørensen. A two-microRNA signature in urinary exosomes for diagnosis of prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B40.
Abstract IA11: Dependency of prostate cancer on HNRNPL and its associated RNAs
Authors: Fei Teng , Chen Yiwen , Brown Myles , Liu X. Shirley 
Published: May 2016

Abstract
RNA binding proteins (RBPs) play critical roles in RNA metabolism and underlie multiple cellular functions. However, how RBPs act in cancer remains obscure. Using an RBP-focused RNAi screen and a genome-wide CRISPR/Cas9 knockout screen, we identified HNRNPL as an RBP required for prostate cancer growth. To understand the HNRNPL function mechanistically, we profiled the HNRNPL-bound RNA landscape by RIP-seq and linked these RBP-RNA interactions to multiple RNA regulatory processes. HNRNPL directly regulates the alternative splicing of a set of associated RNAs, including those encoding the androgen receptor (AR), the key lineage-specific prostate cancer oncogene. Interestingly, HNRNPL also regulates circular RNA formation. Moreover, we identified LARP, a novel HNRNPL-associated long noncoding RNA (lncRNA), as a cofactor of HNRNPL's gene regulatory function. Collectively, our data reveal HNRNPL and its RNA partners as novel players in prostate cancer growth, suggesting the potential to target RBPs or RBP-RNA interactions therapeutically.
Citation Format: Teng Fei, Yiwen Chen, Myles Brown, X. Shirley Liu. Dependency of prostate cancer on HNRNPL and its associated RNAs. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA11.